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  • 2. To Peck Lin, Philomena, and AloysiusTo Janet, Edward, Eleanor, and Rosalind
  • 3. ABC OF ANTITHROMBOTIC THERAPY Edited by GREGORY Y H LIPProfessor of cardiovascular medicine and director, haemostasis, thrombosis and vascular biology unit, university department of medicine, City Hospital, Birmingham and ANDREW D BLANN Senior lecturer in medicine, haemostasis, thrombosis and vascular biology unit, university department of medicine, City Hospital, Birmingham
  • 4. © BMJ Publishing Group 2003 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording and/or otherwise, without the prior written permission of the publishers. First published in 2003 by BMJ Publishing Group Ltd, BMA House, Tavistock Square, London WC1H 9JR British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN 0 7279 17714 Typeset by BMJ Electronic Production and Newgen Imaging Systems Printed and bound in Spain by GraphyCems, NavarraCover image depicts a deep vein thrombosis scan of a leg vein blocked by a thrombus (blood clot, white)in a patient with deep vein thrombosis. With permission from James King-Holmes/Science Photo Library
  • 5. Contents Contributors vi Preface vii1 An overview of antithrombotic therapy 1 Andrew D Blann, Martin J Landray, Gregory Y H Lip2 Bleeding risks of antithrombotic therapy 5 David A Fitzmaurice, Andrew D Blann, Gregory Y H Lip3 Venous thromboembolism: pathophysiology, clinical features, and prevention 9 Alexander G G Turpie, Bernard S P Chin, Gregory Y H Lip4 Venous thromboembolism: treatment strategies 13 Alexander G G Turpie, Bernard S P Chin, Gregory Y H Lip5 Antithrombotic therapy for atrial fibrillation: clinical aspects 16 Gregory Y H Lip, Robert G Hart, Dwayne S G Conway6 Antithrombotic therapy for atrial fibrillation: pathophysiology, acute atrial fibrillation, and cardioversion 20 Gregory Y H Lip, Robert G Hart, Dwayne S G Conway7 Antithrombotic therapy in peripheral vascular disease 24 Andrew J Makin, Stanley H Silverman, Gregory Y H Lip8 Antithrombotic therapy for cerebrovascular disorders 28 Gregory Y H Lip, Sridhar Kamath, Robert G Hart9 Valvar heart disease and prosthetic heart valves 31 Ira Goldsmith, Alexander G G Turpie, Gregory Y H Lip10 Antithrombotic therapy in myocardial infarction and stable angina 35 Gregory Y H Lip, Bernard S P Chin, Neeraj Prasad11 Antithrombotic therapy in acute coronary syndromes 38 Robert D S Watson, Bernard S P Chin, Gregory Y H Lip12 Antithrombotic strategies in acute coronary syndromes and percutaneous coronary interventions 42 Derek L Connolly, Gregory Y H Lip, Bernard S P Chin13 Antithrombotic therapy in chronic heart failure in sinus rhythm 46 Gregory Y H Lip, Bernard S P Chin14 Antithrombotic therapy in special circumstances. I—pregnancy and cancer 51 Bernd Jilma, Sridhar Kamath, Gregory Y H Lip15 Antithrombotic therapy in special circumstances. II—children, thrombophilia, and miscellaneous conditions 55 Bernd Jilma, Sridhar Kamath, Gregory Y H Lip16 Anticoagulation in hospitals and general practice 59 Andrew D Blann, David A Fitzmaurice, Gregory Y H Lip Index 63 v
  • 6. ContributorsAndrew D Blann Sridhar KamathSenior lecturer in medicine, haemostasis, thrombosis and Research fellow, haemostasis, thrombosis and vascular biologyvascular biology unit, university department of medicine, City unit, university department of medicine, City Hospital,Hospital, Birmingham BirminghamBernard S P Chin Martin J LandrayResearch fellow, haemostasis, thrombosis and vascular biology Lecturer in medicine, haemostasis, thrombosis and vascularunit, university department of medicine, City Hospital, biology unit, university department of medicine, City Hospital,Birmingham BirminghamDerek L Connolly Gregory Y H LipConsultant cardiologist, department of cardiology and vascular Professor of cardiovascular medicine and director, haemostasis,medicine, Sandwell and West Birmingham Hospitals NHS thrombosis and vascular biology unit, university department ofTrust, Sandwell Hospital, West Bromwich medicine, City Hospital, BirminghamDwayne S G Conway Andrew J MakinResearch fellow, haemostasis, thrombosis and vascular biology Research fellow, haemostasis, thrombosis and vascular biologyunit, university department of medicine, City Hospital, unit, university department of medicine, City Hospital,Birmingham BirminghamDavid A Fitzmaurice Neeraj PrasadReader in primary care and general practice, Medical School, Consultant cardiologist, City Hospital, BirminghamUniversity of Birmingham, Edgbaston, Birmingham Stanley H SilvermanIra Goldsmith Consultant vascular surgeon, City Hospital, BirminghamResearch fellow in cardiothoracic surgery, haemostasis,thrombosis and vascular biology unit, university department of Alexander G G Turpiemedicine, City Hospital, Birmingham Professor of medicine, McMaster University, Hamilton, Ontario, CanadaRobert G HartProfessor of neurology, department of medicine (neurology), Robert D S WatsonUniversity of Texas Health Sciences Center, San Antonio, USA Consultant cardiologist, City Hospital, BirminghamBernd JilmaAssociate professor in the department of clinical pharmacology,Vienna University Hospital, Vienna, Austriavi
  • 7. PrefaceThe seeds for this book were sown with the establishment of the haemostasis, thrombosis and vascular biology unit at the universitydepartment of medicine, City Hospital, Birmingham—with the coming together of clinicians and scientists interestedin thrombosis and vascular biology, bridging the previous divide in thrombosis between basic science research and the applicationto clinical practice. Indeed, thrombosis is the underlying pathophysiological process in a wide variety of conditions. A greaterunderstanding of the mechanisms leading to thrombosis, and newer developments in the field of antithrombotic therapy make thefield all the more dynamic and exciting. The multidisciplinary team effort and the wide range of research areas studied in our unit forms the core content of the ABC ofAntithrombotic Therapy. In major textbooks on thrombosis the scope is comprehensive, background details on physiology andpathophysiology are abundant, and treatment options are listed to exhaustion—the patient may sometimes almost disappear in thewealth of information. Our approach in this book—typical of the ABC series in the British Medical Journal —tries to synthesise andintegrate the extensive research and clinical data that are needed to manage a particular situation as masterly as it is possible. Wehope we have produced a patient-oriented guide with relevant information from clinical epidemiology, pathophysiology, commonsense clinical judgement, and evidence based treatment options, with reference to recently published antithrombotic therapyguidelines from the American College of Chest Physicians, British Society for Haematology, European Society of Cardiology,American College of Cardiology, and American Heart Association. Our expectant readers are physicians, general practitioners, medical or nursing students, nurses, and healthcare scientists whocare for patients presenting with thrombosis-related problems, and thus, the scope is necessarily wide, ranging from venousthromboembolism to atrial fibrillation and stroke, and to thrombosis in cancer and thrombophilic states. Chapters on clinicalpharmacology and bleeding risk, as well as anticoagulation monitoring are included. Furthermore, this book includes additionalchapters which were not included in the 14 issues of this series when it first appeared in the British Medical Journal. We thank our excellent colleagues for their help, encouragement and contributions, as well as Sally Carter at BMJ Books forencouraging us to complete the series and book, nearly to schedule. Gregory Y H Lip Andrew D Blann Birmingham, April 2003
  • 8. 1 An overview of antithrombotic therapyAndrew D Blann, Martin J Landray, Gregory Y H LipMany of the common problems in clinical practice today relateto thrombosis. The underlying final pathophysiological process Agonists Plasmain myocardial infarction and stroke is thrombus formation Exposed sub Collagen endothelium Adrenaline(thrombogenesis). Common cardiovascular disorders such as ADPatrial fibrillation and heart failure are also associated with Thromboxane Thrombin Fibrinogenthrombogenesis. Thrombosis is also a clinical problem invarious cancers and after surgery, especially orthopaedic. el recepto gpIIb/IIa ogr r block p id ers C loPathophysiology Receptors gpIIb/IIaOver 150 years ago Virchow recognised three prerequisites Secondfor thrombogenesis: abnormal blood flow, vessel wall messengersabnormalities, and blood constituent abnormalities. This Arachadonic acid pathway Di pyconcept has been extended by modern knowledge of the rid am oleendothelial function, flow characteristics, and blood Soluble Shape change inconstituents including haemorheological factors, clotting coagulation pir granule release factors As aggregationfactors, and platelet physiology. As thrombus consists ofplatelets and fibrin (and often bystanding erythrocytes andwhite blood cells), optimum antithrombotic prophylactic Thrombosistherapy can and should be directed towards both. Routes to inhibiting platelet functionAntiplatelet drugsAspirin and agents acting on the cyclo-oxygenase pathway Cellular components Soluble components of the blood of the bloodAspirin irreversibly inhibits cyclo-oxygenase by acetylation of (eg platelets) (eg fibrinogen)amino acids that are next to the active site. In platelets, this is Smoking, inflammationthe rate limiting step in synthesis of thromboxane A2, andinhibition occurs in the megakaryocyte so that all budding Activated platelets Hyperfibrinogenaemiaplatelets are dysfunctional. Because platelets are unable to Thrombusregenerate fresh cyclo-oxygenase in response, the effect ofaspirin remains as long as the lifespan of the platelet (generally Pro-coagulant changes (eg increased VWF, factor V releaseabout 10 days). A severe weakness of aspirin is that its specificity decreased membrane thrombomodulin)for cyclo-oxygenase means it has little effect on other pathwaysof platelet activation. Thus aspirin fails to prevent aggregation Components of the blood vessel wallinduced by thrombin and only partially inhibits that induced byADP and high dose collagen. Antithrombotic doses used in Key components of Virchow’s triad (VWF=von Willebrand factor)clinical trials have varied widely from less than 50 mg to over1200 mg/day, with no evidence of any difference in clinicalefficacy. Absorption is over 80% with extensive presystemic Contraindications to aspirinmetabolism to salicylic acid. Only the parent acetylsalicylic acid Absolute Relativehas any significant effect on platelet function. x Active gastrointestinal x History of ulceration or dyspepsia Adverse effects of aspirin include haemorrhage, ulceration x Children under 12 years oldhypersensitivity and skin rashes, alopecia, and purpura. x Hypersensitivity x Bleeding disorders Sulfinpyrazone also inhibits cyclo-oxygenase (thus x Thrombocytopenia x Warfarin treatmentproducing an aspirin-like state), but is reversible, and alsoinhibits serotonin uptake by platelets. Iloprost is a prostacyclinanalogue that exerts its effects by promoting vasodilatation and Arachadonic acidinhibiting platelet aggregation induced by ADP, therebyopposing the effects of thromboxane A2. Aspirin Cyclo-oxygenase EndoperoxidesDipyridamoleDipyridamole inhibits phosphodiesterase, thus preventing theinactivation of cyclic AMP, intraplatelet levels of which are Prostacyclin Thromboxaneincreased, resulting in reduced activation of cytoplasmic second synthetase synthetasemessengers. However, it may also exert its effect in other ways,such as stimulating prostacyclin release and inhibiting Prostacyclin Thromboxanethromboxane A2 formation. The influence of this drug on thesepathways causes reduced platelet aggregability and adhesion in Platelet metabolism influenced by aspirin 1
  • 9. ABC of Antithrombotic Therapyvitro with increased platelet survival in vivo. Its effect is relativelyshort lasting, and repeated dosing or slow release preparations Warfarinare needed to achieve 24 hour inhibition of platelet function.Clopidogrel and ticlopidine Vitamin K quinol Vitamin K epoxideThese thienopyridine derivatives inhibit platelet aggregationinduced by agonists such as platelet activating factor and Carboxylasecollagen, and also dramatically reduce the binding of ADP to aplatelet surface purinoreceptor. The mechanism of thisinhibitory action seems to be independent of cyclo-oxygenase. N-terminal glutamyl residue γ-carboxy-glutamyl residue of vitamin K dependent proteinsThere is also impairment of the platelet response to thrombin,collagen, fibrinogen, and von Willebrand factor. The peak Biological functionaction on platelet function occurs after several days of oraldosing. Adverse effects include evidence of bone marrow Vitamin K metabolism and the effect of warfarinsuppression, in particular leucopenia, especially with ticlopidine.Other receptor blockersSignal transduction generally occurs when specific receptors onthe surface are occupied by ligands such as ADP, leading tostructural modification of the glycoprotein IIb/IIIa receptor onthe surface of the platelet. This is the commonest receptor on Factors that influence the efficacy of warfarin*the platelet surface and represents the final common pathway Patient factorsfor platelet aggregation, resulting in crosslinking of platelets. x Enhanced anticoagulant effect—Weight loss, increased age ( > 80 years), After intravenous administration of glycoprotein IIb/IIIa acute illness, impaired liver function, heart failure, renal failure, excessreceptor inhibitors such as abciximab, platelet aggregation is alcohol ingestion x Reduced anticoagulant effect—Weight gain, diarrhoea and vomiting,90% inhibited within two hours, but function recovers over the relative youth ( < 40 years), Asian or African-Caribbean backgroundcourse of two days. The major adverse effect is haemorrhage, Examples of drug interactions with warfarinand concurrent use of oral anticoagulants is contraindicated. x Reduced protein binding—Aspirin, phenylbutazone, sulfinpyrazone,Eptifibatide is a cyclic heptapeptide that mimics the part of the chlorpromazinestructure of fibrinogen that interacts with glycoprotein IIb/IIIa. x Inhibition of metabolism of warfarin—Cimetidine, erythromycin,Thus it is a fraction of the size of abciximab and is targeted at sodium valproatethe same structure on the platelet surface. x Enhanced metabolism of warfarin—Barbiturates, phenytoin, Clinical trials with oral glycoprotein IIb/IIIa receptor carbamazepine x Reduced synthesis of factors II, VII, IX, X—Phenytoin, salicylatesinhibitors have been disappointing, with no beneficial effects x Reduced absorption of vitamin K—Broad spectrum antibiotics,seen and even some evidence of harm. laxatives x Enhanced risk of peptic ulceration—Aspirin, NSAIDs, corticosteroids x Thrombolytics—Streptokinase, tissue plasminogen activatorAnticoagulant drugs x Antiplatelet drugs—Aspirin, NSAIDsWarfarin *This list is intended to be illustrative not exhaustiveThis 4-hydroxycoumarin compound, the most widely usedanticoagulant in Britain and the Western world, inhibits thesynthesis of factors dependent on vitamin K (prothrombin;factors VII, IX, and X; protein C; protein S). Factor VII levels fallrapidly (in < 24 hours) but factor II has a longer half life andonly falls to 50% of normal after three days. Warfarin isapproximately 97% bound to albumin, and free warfarin entersliver parenchymal cells and is degraded in microsomes to an Intrinsic pathway Extrinsic pathwayinactive water soluble metabolite that is conjugated and Factors IX, XI, XII Factor VIIexcreted in the bile. Partial reabsorption is followed by renalexcretion of conjugated metabolites. There is a considerable variability in warfarin’s effect on Prothrombinase complexpatients, its effectiveness being influenced by age, racial Factors V, X, calcium phospholipidsbackground, diet, and co-medications such as antibiotics. Thus itdemands frequent laboratory monitoring, the prothrombin Factor XIIItime being compared with a standard to produce the Factor II Factor IIainternational normalised ratio. The degree of anticoagulation Prothrombin Thrombinrequired varies with clinical circumstance, but the target Factor XIIIainternational normalised ratio usually ranges from 2 to 4.Phenindione is an alternative oral vitamin K antagonist, but Fibrinogen Soluble fibrinconcerns regarding the potential for hepatotoxicity,nephrotoxicity, and blood dyscrasias have reduced its rolelargely to individuals with documented hypersensitivity to Insoluble fibrinwarfarin. Adverse effects of warfarin include haemorrhage,hypersensitivity and skin rashes, alopecia, and purpura. Simplified coagulation cascade2
  • 10. An overview of antithrombotic therapyMelagatranThis oral thrombin inhibitor undergoing phase III trials seems Low molecular weight heparin Unfractionated heparinto be well tolerated, with few clinically significant bleeding Enoxaparin sodium (Lovenox) [3.8:1]problems, in patients with venous thromboembolism. Although Nadroparin calcium (Fraxiparin) [3.6:1]considerable pharmacokinetic and animal data exist, solid Dalteparin sodium (Fragmin) [2.7:1]evidence of its effectiveness compared with warfarin and 0.7 % of compositionheparin in patients at high or low risk is still awaited. 0.6Heparin 0.5Heparin is a glycosaminoglycan whose major anticoagulant effectis accounted for by a pentasaccharide with a high affinity for 0.4antithrombin III. This binding results in a conformational change 0.3in antithrombin III so that inactivation of coagulation enzymesthrombin (IIa), factor IXa, and factor Xa is markedly enhanced. Its 0.2short half life means it must be given continuously, and its 0.1extensive first pass metabolism means it must be givenparenterally, preferably by continuous intravenous infusion, and it 0 0 5000 10 000 15 000 20 000is therefore inappropriate for home use. The effect on the Molecular weight (Da)intrinsic clotting cascade must be monitored carefully by Greater antithrombin activitymeasuring the activated partial thromboplastin time (APTT), Greater anti-Xa activity Less anti-Xa activitygenerally aiming for a value 1.5 to 2.5 times that of control. Resistant to PF4 Sensitive to PF4 Unfractionated heparin consists of a heterogeneous mixture Little non-specific binding Non-specific bindingof polysaccharides with an average molecular weight of Greater inhibition of thrombin generation Less inhibition of thrombin generation15 000 Da. Low molecular weight heparins (4000-6000 Da) areweaker inhibitors of thrombin but inhibit factor Xa to a similar The three low molecular weight heparins that have been evaluated in clinical trials of acute coronary syndromes are shown with their respective anti-Xaextent. Different commercial preparations of low molecular and antithrombin activity (PF4=platelet factor 4)weight heparin vary in the ratio of anti-Xa to antithrombinactivity, although the clinical relevance of this is uncertain. Betterabsorption after subcutaneous administration and reducedprotein binding result in greatly improved bioavailability. Theeffective half life after subcutaneous injection is four hours,allowing an injection once daily in most circumstances. Thesemore predictable pharmacokinetics allow the dose to becalculated on the basis of the patient’s weight and reduce the Comparison of low molecular weight and unfractionatedrequirement for frequent monitoring. In those rare cases where heparinsmonitoring is deemed necessary, measurement of plasma levelsof anti-Xa activity is needed. Tests of APTT are unhelpful. Unfractionated Low molecular Major adverse effects of heparin include haemorrhage, heparin weight heparinosteoporosis, alopecia, thrombocytopenia, and hypersensitivity. Action Anti-XIIa, XIa, IXa, VIIa, Mostly anti-Xa antithrombinAt present, the risk of haemorrhage seems to be similar with Route of Subcutaneous Subcutaneouslow molecular weight and unfractionated heparin. However, the administration Intravenousrisk of heparin induced thrombocytopenia seems to be less with Absorption from Slow Improvedthe low molecular weight form. subcutaneous route Protein binding Proteins in plasma and on ReducedHirudin and direct thrombin inhibitors endotheliumHirudin, a 65 amino acid residue anticoagulant peptide with a Bioavailability Subcutaneous—10-30% at > 90%relative molecular mass of 7000 Da purified from the leech low doses, 90% at higherHirudo medicinalis, binds thrombin with high specificity and dosessensitivity. With a true half life of about an hour and a half life Intravenous—100%effect on the APTT of two to three hours, it may be seen as an by definitionalternative to heparin in indications such as unstable angina Effective half life Subcutaneous—1.5 hours 4 hoursand in coronary angioplasty. Intravenous—30 min Many derivatives are available, with hirulog and argatroban Between and within Extensive Minimal individual variationamong the best developed. However, trials of the former have Monitoring APTT Not requiredbeen discouraging: no clear benefit over heparin was shown. (anti-Xa activity)Conversely, argatroban may have a role in the anticoagulation Elimination Liver and kidney Kidneyof patients unable to tolerate heparin as a result of heparininduced thrombocytopenia. Furthermore, in a clinical trial ofpatients with heparin induced thrombocytopenia, use ofargatroban was associated with a reduction in levels of plasmaplatelet activation markers.Thrombolytic agentsThese agents lyse pre-existing thrombus, either by potentiatingthe body’s own fibrinolytic pathways (such as streptokinase) or 3
  • 11. ABC of Antithrombotic Therapyby mimicking natural thrombolytic molecules (such as tissue Fibrinolytic drugsplasminogen activator). The common agents in clinical use arederived from bacterial products (streptokinase) or Examples Source Mechanism of actionmanufactured using recombinant DNA technology Streptokinase Group C haemolytic Complexes with and(recombinant tissue plasminogen activator). Newer drugs aim to streptococci activates plasminogenbe less antigenic and more thrombus specific in an attempt to Urokinase Trypsin-like chemical Direct actingincrease efficacy and specificity of various agents; on present produced by kidney plasminogen activatorevidence, however, the differences between thrombolytic agents Reteplase Recombinant DNA Acivates plasminogen,are only marginal. Because of the lack of site specificity for these (recombinant technology non-immunogenicdrugs, the major adverse effect is that of haemorrhage tissue plasminogen(gastrointestinal, intracranial, etc). The other important adverse activator)effect is that of hypersensitivity reaction, especially withstreptokinase. This usually manifests as flushing, breathlessness,rash, urticaria, and hypotension. Severe anaphylaxis is rare.Hypersensitivity reactions are avoided by using tissue Contraindications to thrombolysisplasminogen activator or recombinant tissue plasminogenactivator, which are not antigenic. Absolute Relative x Recent or current haemorrhage, x Previous peptic ulceration trauma, or surgery x WarfarinStreptokinase x Active peptic ulceration x Liver diseaseDerived from streptococci, this product is an effective x Coagulation defects x Previous use of anistreplasethrombolytic agent for the treatment of acute myocardial x Oesophageal varices or streptokinase within fourinfarction and pulmonary thromboembolism. Acting by x Coma years (use alternative agent)converting plasminogen to plasmin, the main fibrinolytic x Recent or disabling x Hypersensitivity cerebrovascular accident (anistreplase, streptokinase)enzyme, it potentiates fibrinolysis. However, it is not site specific, x Hypertension x Heavy vaginal bleedinglysing thrombus anywhere in the body. Being bacteria derived, it x Aortic dissectionis antigenic, and repeated administration results in neutralisingantibodies and allergic reactions. For example, a singleadministration of 1.5 MU for acute myocardial infarction resultsin neutralising antibodies that have been shown to persist forup to four years and are sufficient to neutralise a repeat Insolubleadministration of a similar dose of the agent in half of cases. fibrin clot Plasminogen PlasminTissue plasminogen activatorIn clinical use this is produced by recombinant DNAtechnology and mimics an endogenous molecule that activates PAI-I Solublethe fibrinolytic system. Thus, recombinant tissue plasminogen D-dimersactivator does not elicit an allergic response and is considered tPAmore clot specific. Nevertheless, it has a short half life and needs uPA Streptokinasecontinuous infusion to achieve its greatest efficacy. Acceleratedadministration of tissue plasminogen activator gives a slightmortality advantage over streptokinase at the cost of a marginal Simplified fibrinolysis (PAI-1=plasminogen activator inhibitor, tPA=tissueincrease in stroke rate. plasminogen activator, uPA=urokinase plasminogen activator)Further readingx Antiplatelet Trialists’ Collaboration. Collaborative overview of thrombin inhibitor, in patients with a DVT. Thromb Haemost 1999;81: randomised trials of antiplatelet therapy, I: Prevention of death, 358-63 myocardial infarction, and stroke by prolonged antiplatelet therapy x International Stroke Trial Collaborative Group. The international in various categories of patients. BMJ 1994;308:81-106 stroke trial (IST): a randomised trial of aspirin, subcutaneousx Blann AD, Lip GYH. Virchow’s triad revisited: the importance of heparin, or both, or neither among 19 435 patients with acute soluble coagulation factors, the endothelium, and platelets. Thromb ischaemic stroke. Lancet 1997;349:1569-81 Res 2001;101:321-7 x Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walengax CAPRIE Steering Committee. A randomised, blinded, trial of JM, et al. Argatroban anticoagulant therapy in patients with clopidogrel versus aspirin in patients at risk of ischaemic events heparin-induced thrombocytopenia. Circulation 2001;103:1838-43 (CAPRIE). Lancet 1996;348:1329-39 x Nurden AT. New thoughts on strategies for modulating plateletx Catella-Lawson F. Direct thrombin inhibitors in cardiovascular function through the inhibition of surface receptors. Haemostasis disease. Coron Artery Dis 1997;8:105-11 1996;20:78-88x Eriksson H, Eriksson UG, Frison L. Pharmacokinetic and x Stirling Y. Warfarin-induced changes in procoagulant and pharmacodynamics of melagatran, a novel synthetic LMW anticoagulant proteins. Blood Coagul Fibrinolysis 1995;6:361-73The figure showing percentage of composition of unfractionated and lowmolecular weight heparin in terms of molecular weight is adapted fromLevine GN, Ali MN, Schafer AI. Arch Intern Med 2001;161: 937-48.4
  • 12. 2 Bleeding risks of antithrombotic therapyDavid A Fitzmaurice, Andrew D Blann, Gregory Y H LipMany of the common cardiovascular disorders (especially in Questions to ask when considering oral anticoagulationelderly people) are linked to thrombosis—such as ischaemic x Is there a definite indication (such as atrial fibrillation)?heart disease, atrial fibrillation, valve disease, hypertension, and x Is there a high risk of bleeding or strong contraindication againstatherosclerotic vascular disease—requiring the use of anticoagulation?antithrombotic therapy. This raises questions regarding the x Will concurrent medication or disease states increase bleeding riskappropriate use of antithrombotic therapy in older people, or interfere with anticoagulation control?especially because strategies such as anticoagulation with x Is drug compliance and attendance at anticoagulant clinic for monitoring likely to be a problem?warfarin need regular monitoring of the international x Will there be regular review of the patient, especially with regard tonormalised ratio (INR), a measure of the induced haemorrhagic risks and benefits of anticoagulation?tendency, and carry a risk of bleeding. The presence ofconcomitant physical and medical problems increases theinteractions and risks associated with warfarin, andanticoagulation in elderly patients often needs an assessment of S Dthe overall risk:benefit ratio. Physical frailty in elderly people may reduce access to patient’s prothrombin time ISI INR=anticoagulant clinics for INR monitoring. The decline in mean normal timecognitive function in some elderly patients also may reduce ISI=international sensitivity ratio. Thecompliance with anticoagulation and the appreciation of mean normal prothrombin time is oftenbleeding risks and drug interactions. However, in recent studies generated from samples from local healthy subjects or a commerciallyof anticoagulation in elderly people, no significant associations available standard. The exact value of theof anticoagulant control were found with age, sex, social ISI depends on the thromboplastin usedcircumstances, mobility, domicillary supervision of medication, in the prothrombin time methodor indications for anticoagulation.WarfarinBleeding is the most serious and common complication ofwarfarin treatment. For any given patient, the potential benefitfrom prevention of thromboembolic disease needs to bebalanced against the potential harm from inducedhaemorrhagic side effects.Minor bleedsMost bleeding problems are clinically minor, although patientsare unlikely to view such bleeds in these terms. The problemsinclude nose bleeds, bruising, and excessive bleeding afterminor injury such as shaving. Patients should be made aware ofthese common problems and be reassured that these events areexpected in patients receiving warfarin treatment. Menorrhagiais surprisingly rare as a major clinical problem, even though itcan be severe.More serious problemsPatients need access to medical care if they have seriousproblems. Such problems are generally due to a high INR.Usually, spontaneous bruising, any bleeding that is difficult toarrest, frank haematuria, any evidence of gastrointestinalbleeding, and haemoptysis, need urgent assessment. Thedefinition of minor or major bleeding lacks clarity: in manycases the patient presents with a concern that may need follow Purpura, petechiae, and haematoma secondary to over-anticoagulationup, and a minor bleed can only be defined as such in retrospect.In most cases, evidence of bleeding suggests some underlyingpathology but may also be due to drug interactions. Forexample, a patient with recurrent haemoptysis may be found tohave hereditary telangectasia. Further investigation of the cause Sudden, unexplained changes to theof bleeding should always be considered, particularly if the efficacy of warfarin may be caused by thebleeding is recurrent. It is also important in these instances to consumption of over the countercheck for concomitant drug use, particularly drugs received multivitamin tablets or foodstuffs that contain high levels of vitamin Kover the counter. Patients should be aware that aspirin and 5
  • 13. ABC of Antithrombotic Therapynon-steroidal anti-inflammatory drugs are particularly Patients at high risk of bleeding with warfarindangerous in combination with warfarin; however, even x Age > 75 yearssupposedly safe drugs such as paracetamol can affect a patient’s x History of uncontrolled hypertension (defined as systolic bloodbleeding tendency. pressure > 180mm Hg or diastolic blood pressure > 100 mm Hg) x Alcohol excess (acute or chronic), liver diseaseIncidence of bleeding problems x Poor drug compliance or clinic attendanceThe incidence of severe bleeding problems that may bring x Bleeding lesions (especially gastrointestinal blood loss, such aspatients to an accident and emergency unit has probably been peptic ulcer disease, or recent cerebral haemorrhage) x Bleeding tendency (including coagulation defects,overestimated. The annual incidence of fatality caused by thrombocytopenia) or concomitant use of non-steroidalwarfarin administration has been estimated to be 1%. However, anti-inflammatory drugs and antibioticsthis is based on old data, and, although difficult to prove, the x Instability of INR control and INR > 3overall improvement in anticoagulation control in the past10-15 years means that a more realistic figure is about 0.2%.Methodological problems have hampered the interpretation ofpreviously reported data, particularly with regard to definitionsof major and minor bleeding episodes, with some investigatorsaccepting hospital admission for transfusion of up to 4 units ofblood as being “minor.” Certainly, the most serious “major”bleed is an intracranial haemorrhage. Reviews of observationaland experimental studies showed annual bleeding rates of0-4.8% for fatal bleeding and 2.4-8.1% for major bleeds. Minorbleeds are reported more often, with about 15% of patientshaving at least one minor event a year.Risk factors for bleedingAge is the main factor that increases risk of bleeding. One studyshowed a 32% increase in all bleeding and a 46% increase inmajor bleeding for every 10 year increase above the age of 40. Early studies suggested an increased risk with increasingtarget INR, but the data were difficult to interpret because resultswere reported in both INR and prothrombin time. The actual riskof bleeding should be taken into account as well as the degree ofanticoagulation (as measured by the INR). One study whichachieved point prevalence of therapeutic INRs of 77% reportedno association between bleeding episodes and target INR. Data from an Italian study in 2745 patients with 2011patient years of follow up reported much lower bleeding rates,with an overall rate of 7.6 per 100 patient years. The reportedrates for fatal, major, and minor bleeds were 0.25, 1.1, and 6.2per 100 patient years respectively. This study confirmed anincreased risk with age and found a significantly increased risk Computed tomography scan showing intracerebral haemorrhageduring the first 90 days of treatment. Peripheral vascular andcerebrovascular disease carried a higher relative risk ofbleeding, and target INR was strongly associated with bleedingwith a relative risk of 7.9 (95% confidence interval 5.4 to11.5,P < 0.0001) when the most recent INR recorded was > 4.5. Datafrom a trial in a UK community showed 39.8 minor, 0.4 major,and no fatal haemorrhagic events per 100 patient years for thetotal study population, with 3.9 serious thromboembolic eventsper 100 patient years, of which 0.79 were fatal. Warfarin is therefore a relatively safe drug, particularly iftherapeutic monitoring is performed well. Analogies are often Risk of bleeding associated with warfarin treatmentmade between therapeutic monitoring of warfarin and x Rate of bleeding episodes associated in the general patientmonitoring of blood glucose for diabetic patients. Given the population is decreasing (possibly due to better management)increase in numbers of patients receiving warfarin, particularly x Risk increases with agefor atrial fibrillation, the scale of the problem is likely to be the x Risk of bleeding is directly related to the achieved intensity of INRsame. There is no reason why warfarin monitoring cannot rather than the target INR (a clear dose-response effect)become as routine as glucose monitoring in diabetes: relevant x Temporal association between measured INR and risk of bleedingsmall machines are available for generating an INR (with x Relative risk of bleeding is increased in patients with cerebrovascular disease and venous thrombosisassociated standards and quality control).OveranticoagulationExcessive anticoagulation without bleeding or with only minorbleeding can be remedied by dose reduction or discontinuation.The risk of bleeding is decreased dramatically by lowering theintended INR from 3-4.5 down to 2-3, although this increases6
  • 14. Bleeding risks of antithrombotic therapythe risk of thrombosis. If bleeding becomes substantial, 2-5 mgof oral or subcutaneous vitamin K may be needed. In patients ASPwith prosthetic valves, vitamin K should perhaps be avoided Myocardial infarction (P=0.002) 36% reduction, PLAbecause of the risk of valve thrombosis unless there is life but only 45 fewer eventsthreatening intracranial bleeding. Alternatives to vitamin Kinclude a concentrate of the prothrombin group of coagulationfactors including II, IX, and X, fresh frozen plasma 15 ml/kg, Stroke (P=0.88)and recombinant factor VIIa.Aspirin 0 1 2 3 4 5 Events per 100 patient yearsAspirin has little effect in terms of bruising but can causeserious gastrointestinal bleeding. The risk of gastrointestinal GI bleeds Cerebral bleedsbleeding is related to dose and should not be problematic at ASP 107 14 (fatal=5)doses of 75 mg/day given as thromboprophylaxis. There iscurrently no consensus as to optimal dose of aspirin for stroke PLA 55 15 (fatal=3)prevention in atrial fibrillation. A meta-analysis of randomisedcontrolled trials using aspirin showed that a mean dose of273 mg/day, increased absolute risk of haemorrhagic stroke to Myocardial infarction, stroke, and bleeding in the hypertension optimal treatment trial (HOT) study (ASP=aspirin, PLA=placebo)12 events per 10 000 people. This relatively small increase mustbe weighed against the reduced risk of myocardial infarction (to137 events per 10 000) and ischaemic stroke (to 39 events per10 000). However, in one trial of patients with well controlledhypertension, use of aspirin 75 mg prevented 1.5 myocardial Aspirin daily No of Events/patients Odds ratio Odds 2P dose (mg) trials* Aspirin Control (95% CI random) reductioninfarctions per 1000 patients a year, which was in addition to (%) (%) Aspirin:control (SD)the benefit achieved by lowering the blood pressure, with no 500-1500 34 1621/11 215 1930/11 236 19% (3) <0.00001effect on stroke. Although there was no increase in the number (14.5%) (17.2%)of fatal bleeding events (seven in patients taking aspirin, 160-325 19 1526/13 240 1963/13 273 25% (3) <0.00001 (11.5%) (14.8%)compared with eight in the placebo group), there was a 1.8% 75-150 12 370/3370 519/3406 32% (6) <0.00001increase in non-fatal, major bleeding events (129 events in (11.0%) (15.2%)patients taking aspirin, compared with 70 in the placebo group) <75 3 316/1827 354/1828 13% (8) NS (17.3%) (19.4%)and minor bleeds (156 and 87, respectively). Total 65 3833/29 652 4766/29 743 23% (2) <0.00001 (12.9%) (16.0%) 0 0.5 1 1.5 2 Heterogeneity between 4 dose categories: Aspirin AspirinRisk of bleeding χ2=3; df=7.7; P=0.06 better worse *Some trials contributed to more than one daily dose category.There have been conflicting results concerning the role of ageas an independent risk factor for haemorrhage induced by Typical odds ratio for each category shown as square (with area proportional to the variance of observed-expected) together with its 99% confidence interval (horizontal line). Typical odds ratioanticoagulants. Advanced age ( > 75 years), intensity of for the total shown as diamond with its 95% confidence interval (horizontal line = width ofanticoagulation (especially INR > 4), history of cerebral vascular diamond). Vertical dotted line passes through point estimate of typical odds ratio for total.disease (recent or remote), and concomitant use of drugs that Effect of different doses of aspirin in secondary prevention of vascular eventsinterfere with haemostasis (aspirin or non-steroidal (There is no significant difference in benefit with different aspirin doses, but atanti-inflammatory drugs) are probably the most important higher doses adverse effects are more likely)variables determining patients’ risk of major life threateningbleeding complications while they are receiving anticoagulationtreatment. Generally elderly people have increased sensitivity to the Variables that may influence the risk of bleeding inanticoagulant effect of warfarin, and require a lower mean daily elderly peopledose to achieve a given anticoagulant intensity. For example, x Increased sensitivity to the effect of anticoagulation, perhaps due topatients aged > 75 years need less than half the daily warfarin increased receptor affinity or lower dietary vitamin K intakedose of patients aged < 35 for an equivalent level of x Concurrent use of drugs that increase bleeding risk x Associated comorbidity and other diseases that decreaseanticoagulation. Whatever the mechanism it is clear that warfarin compliance and increase the risk of bleedingtherapy needs careful justification for being given to elderlypatients, and the dose needs modification and careful monitoring. As there is an exponential increase in bleeding risk with alinear increase in anticoagulant effect, there will be a substantialincrease in bleeding risk with overanticoagulation. For example, Possible reasons for increased sensitivity to anticoagulationthe annual risk of bleeding rises from 1.6% in elderly people in elderly peoplenot treated with anticoagulant drugs (based on the “Sixty-Plus” x Lower body weightstudy), to 5% (relative risk 3) at an INR of 2.5, and to 50% x Differences in pharmacokinetics, with a tendency towards reduced(relative risk 30) at an INR of 4. In another study, total bleeding drug clearance in the elderly either due to decreases in renal orevents were 39% in a group of 31 patients with an INR of 7 hepatic blood flow and function with age per se or diseasecompared with 13% in a group of 100 with a stable INR (odds processesratio 5.4, 95% CI 2.1-13.9). The greatest risk factor for being in x Change in receptor sensitivity x Lower dietary vitamin K intake in the elderly may perhaps be thethis group was (apart from having a high target INR) antibiotic more important causetherapy in the preceding four weeks. 7
  • 15. ABC of Antithrombotic Therapy Multiple drug therapy or polypharmacy is quite common, Further readingwith the consequence of adverse drug interactions, the risk of x Blann AD, Hewitt J, Siddique F, Bareford D. Racial background is awhich rises exponentially with the number of drugs given determinant of average warfarin dose required to maintain the INRsimultaneously and with concurrent diseases. Typical drug between 2.0 and 3.0. Br J Haematol 1999;10:207-9interactions include changes in absorption across intestinal x Erhardtsten E, Nony P, Dechavanne M, Ffrench P, Boissel JP,mucosae and hepatic metabolism. Patients should be cautioned Hedner U. The effect of recombinant factor VIIa (NovoSevenTM) inabout the risk of warfarin-drug interactions when their healthy volunteers receiving acenocoumarol to an Internationalmedication list is altered. The decline in cognitive function in Normalized Ratio above 2.0. Blood Coag Fibrin 1998;9:741-8some elderly patients may mean they do not realise that some x Fitzmaurice DA, Hobbs FDR, Murray ET, Hodder, RL, Allan TF, Rose, PE. Oral anticoagulation management in primary care withdrugs can interact with anticoagulants and so they do not the use of computerised decision support and near-patient testing.mention their use of oral anticoagulants to doctors or A randomised controlled trial. Arch Intern Med 2000;160:2323-48pharmacists. However, elderly patients are likely to attend clinic x Gurwitz JH, Goldberg RJ, Holden A, Knapic N, Ansell J. Age-relatedless often than younger patients, suggesting a greater degree of risks of long term oral anticoagulant therapy. Arch Intern MedINR stability. 1988;148:1733-6 Many diseases associated with stroke and thromboembolism x He J, Whelton PK, Vu B, Klag MJ. Aspirin and risk of haemorrhagic stroke. JAMA 1998;280:1930-5are more common with increasing age. Older patients are often x Haemostasis and Thrombosis Task Force of the British Society forat highest risk, and appropriate anticoagulation therapy reduces Haematology. Guidelines on oral anticoagulation: third edition. Br Jmorbidity and mortality. Careful and continuing evaluation of Haematol 1998;101:374-87patients is necessary to ensure that the risks of bleeding do not x Landefeld CS, Beyth RJ. Anticoagulant related bleeding: clinicaloutweigh the benefits from anticoagulation. epidemiology, prediction, and prevention. Am J Med 1993;95:315-28 x Levine MN, Hirsh J, Landefeld CS, Raskob G. HaemorrhagicThe diagram showing the results of the hypertension optimal treatment complications of anticoagulant treatment. Chest 1992;102:352-63Strial is adapted from Hansson L, et al. Lancet 1998;351:1755-62. The figure x Panneerselvan S, Baglin C, Lefort W, Baglin T. Analysis of riskshowing the effect of different doses of aspirin in secondary prevention of factors for over-anticoagulation in patients receiving long-termvascular events is reproduced from Clinical Evidence (June issue 7), BMJ warfarin. Br J Haematol 1998;103:422-4Publishing Group, 2002. x Palareti G, Leali N, Coccheri S, Poggi M, Manotti C, D’Angelo A, et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet 1996;348:423-8 x van der Meer FJM, Rosendaal FR, Vandenbroucke, Briet E. Bleeding complications in oral anticoagulant therapy. Arch Int Med 1993;153:1557-62 x Hutton BA, Lensing AWA, Kraaijenhagen RA, Prins MH. Safety of treatment with oral anticoagulants in the elderly. Drugs and Aging 1999;14:303-128
  • 16. 3 Venous thromboembolism: pathophysiology,clinical features, and preventionAlexander G G Turpie, Bernard S P Chin, Gregory Y H LipVenous thromboembolism is a common complication amonghospital inpatients and contributes to longer hospital stays,morbidity, and mortality. Some venous thromboembolisms maybe subclinical, whereas others present as sudden pulmonaryembolus or symptomatic deep vein thrombosis. UltrasonicDoppler and venographic techniques have shown deep veinthrombosis of the lower limb to occur in half of all major lowerlimb orthopaedic operations performed without antithromboticprophylaxis. Deep vein thrombosis of the lower limb is also seenin a quarter of patients with acute myocardial infarction, andmore than half of patients with acute ischaemic stroke. Deep vein thrombosis of the lower limb normally starts inthe calf veins. About 10-20% of thromboses extend proximally,and a further 1-5% go on to develop fatal pulmonaryembolism. Appropriate antithrombotic measures can reducethis complication. Until recently, some clinicians were reluctantto provide such prophylaxis routinely. As unfounded fears ofmajor bleeding complications from anticoagulant regimenswane, preventive treatments are used more often with medicaland surgical patients. However, the risk of bleeding can beserious and this has particular bearing in postoperative patients. Venous thromboembolism can also arise spontaneously in Pulmonary angiography showing large pulmonary embolus in leftambulant individuals, particularly if they have associated risk pulmonary arteryfactors such as thrombophilia, previous thrombosis, or cancer.However, in over half of these patients, no specific predisposingfactors can be identified at presentation.Pathophysiology Venous thromboembolism often manifests clinically as deep veinThrombus formation and propagation depend on the presence thrombosis or pulmonary embolism, andof abnormalities of blood flow, blood vessel wall, and blood is possibly one of the preventableclotting components, known collectively as Virchow’s triad. complications that occur in hospitalisedAbnormalities of blood flow or venous stasis normally occur patientsafter prolonged immobility or confinement to bed. Venousobstruction can arise from external compression by enlargedlymph nodes, bulky tumours, or intravascular compression byprevious thromboses. Increased oestrogens at pharmacologicallevels, as seen with oral contraceptive use and with hormone Risk factors and conditions predisposing to venousreplacement therapy in postmenopausal women, have been thromboembolismassociated with a threefold increased risk in the small initial risk x History of venous thromboembolismof venous thromboembolism. Cancers, particularly x Prolonged immobilityadenocarcinomas and metastatic cancers, are also associated x Prolonged confinement to bed or lower limb paralysiswith increased venous thromboembolism. Indeed, on x Surgery, particularly lower limb orthopaedic operations, and majorpresentation, some idiopathic venous thromboembolisms have pelvic or abdominal operationsrevealed occult cancers at follow up. Both oestrogens at x Trauma—For example, hip fractures and acute spinal injurypharmacological levels and cancer can also activate the clotting x Obesity x Major medical illnesses such as acute myocardial infarction,system. ischaemic stroke, congestive cardiac failure, acute respiratory failure x Oestrogen use in pharmacological doses—For example, oral contraception pills, hormone replacement therapyClinical presentation and diagnosis x Cancer, especially metastatic adenocarcinomas x Age > 40 yearsDeep vein thrombosis x Aquired hypercoagulable states—Lupus anticoagulant andDeep vein thrombosis commonly presents with pain, erythema, antiphospholipid antibodies, hyperhomocysteinaemia,tenderness, and swelling of the affected limb. Thus, in lower dysfibrinogenaemia, myeloproliferative disorders such aslimb deep vein thrombosis, the affected leg is usually swollen polycythaemia rubra verawith the circumference of the calf larger than the unaffected x Inherited hypercoaguable states—Activated protein C resistance (factor V Leiden mutation), protein C deficiency, protein Sside. Other causes of leg swelling, erythema, and tenderness deficiency, antithrombin deficiency, prothrombin gene mutationinclude a ruptured Baker’s cyst and infective cellulitis. The 9
  • 17. ABC of Antithrombotic Therapydiagnosis of deep vein thrombosis is therefore more likely when Modified pretest probability for deep vein thrombosisrisk factors are present and less so if there are featuressuggesting alternative diagnoses. For example, ruptured Clinical feature ScoreBaker’s cysts commonly appear in the context of osteoarthritis Tenderness along entire deep vein system 1.0and rheumatoid arthritis. Infective cellulitis is unlikely to Swelling of the entire leg 1.0be bilateral, with clearly demarcated areas of erythema Greater than 3 cm difference in calf circumference 1.0extending proximally. Breaks in the skin, particularly between Pitting oedema 1.0the toes, and coexistent fungal infection are additional clues to Collateral superficial veins 1.0cellulitis. Risk factors present: Objective diagnosis of venous thromboembolism is Active cancer 1.0important for optimal management. Although the clinical Prolonged immobility or paralysis 1.0diagnosis of venous thromboembolism is imprecise, various Recent surgery or major medical illness 1.0probability models based on clinical features have proved to be Alternative diagnosis likely (ruptured Baker’s cyst in − 2.0practical and reliable (interobserver reliability, = 0.85) in rheumatoid arthritis, superficial thrombophlebitis, orpredicting the likelihood of venous thromboembolism. These infective cellulitis)models should be used in conjunction with objective diagnostic Score > 3 = high probablility; 1-2 = moderate probability < 0 = low probabilitytests. Compression ultrasonography remains the non-invasiveinvestigation of choice for the diagnosis of clinically suspecteddeep vein thrombosis. It is highly sensitive in detecting proximaldeep vein thrombosis although less accurate for isolated calfdeep vein thrombosis. In patients with suspected thrombosis D-dimer µg/Land a negative compression ultrasound result, the test should berepeated in seven days because studies have shown that patientswith two or more negative tests over a week who are untreated 20 000have a less than 2% risk of proximal extension or subsequent 10 000deep vein thrombosis. Impedance plethysmography is slightly less specific and 5000sensitive than ultrasonography but may still have a role inpregnant women and suspected recurrent deep veinthrombosis. The gold standard is invasive contrast venography,which is still used when a definitive answer is needed. Newer 1000imaging techniques are being developed, and tools such as 500magnetic resonance venography or computed tomographycould possibly detect pelvic vein thromboses, but further testingis needed to establish their role in the diagnosis of deep veinthrombosis. 100 Blood tests such as fibrin D-dimer add to the diagnosticaccuracy of the non-invasive tests. In one study, the sensitivityand specificity of a D-dimer concentration of > 500 g/l for the 0 Pulmonary No pulmonarypresence of pulmonary embolism were 98% and 39%, embolism embolismrespectively, which give positive and negative predictivevalues of 44% and 98%. The sensitivity of the test even Plasma D-dimer concentrations on day of presentation accordingremained high at three and seven days after presentation to final diagnosis(96% and 93%).Investigations for suspected venous thromboembolism by pretest clinical probabilityPretest probability Fibrin D-dimer Other investigations CommentDeep veinthrombosis: Low Negative No further investigations needed Low or moderate Positive Negative ultrasound compression Consider venography or repeat ultrasound after a week Moderate or high Positive Positive ultrasound compression Treat with anticoagulants High Positive Negative ultrasound compression Consider venography to rule out deep vein thrombosis, especially in high risk patients and those with recurrent pulmonary emboliPulmonaryembolism: Low Negative No No further investigation needed Low or moderate Positive Proceed to ventilation-perfusion If non-diagnostic ventilation-perfusion scan consider serial scan compression ultrasound over two weeks to rule out venous thromboembolism High Positive Proceed to ventilation-perfusion If non-diagnostic ventilation-perfusion scans, proceed to scan (or ultrasound) venography or pulmonary angiography as needed10
  • 18. Venous thromboembolism: pathophysiology, clinical features, and preventionPulmonary embolism Clinical probability for pulmonary embolismPatients presenting with acute pulmonary embolism oftencomplain of sudden onset of breathlessness with haemoptysis Clinical feature Scoreor pleuritic chest pain, or collapse with shock in the absence of Deep vein thrombosis suspected:other causes. Deep vein thrombosis may not be suspected Clinical features of deep vein thrombosis 3.0clinically, but its presence, along with thrombotic risk factors, Recent prolonged immobility or surgery 1.5will make the diagnosis of pulmonary embolism more likely. A Active cancer 1.0similar clinical probability model to that for deep vein History of deep vein thrombosis or pulmonary 1.5thrombosis has been developed for pulmonary embolism. embolism Pulmonary angiography is the gold standard investigation Haemoptysis 1.0for pulmonary embolism, but it is invasive and associated with Resting heart rate > 100 beats/min 1.50.5% mortality. A ventilation-perfusion scan using technetium No alternative explanation for acute breathlessness or 3.0DTPA (ditriaminopentaric acid) is more widely used. However pleuritic chest painthis investigation is non-specific, and is diagnostic in only 30% > 6 = high probability (60%); 2-6 = moderate probability (20%); < 1.5 = lowof cases. Spiral computed tomography scans are more reliable probability (3-4%)but diagnosis is limited to emboli in larger vessels only.Measurement of fibrin D-dimer levels, used for deep veinthrombosis, is helpful, as is compression ultrasound in thedetection of occult deep vein thrombosis. Thromboembolic risk stratification for surgery patientsPrevention strategies x Low risk—Uncomplicated surgery in patients aged < 40 years with minimal immobility postoperatively and no risk factorsAn appropriate strategy for the prevention of venous x Moderate risk—Any surgery in patients aged 40-60 years, majorthromboembolism include pharmacological or physical surgery in patients < 40 years and no other risk factors, minormethods. To optimise treatment, patients should be stratified surgery in patients with one or more risk factorsinto risk categories to allow the most appropriate prophylactic x High risk—Major surgery in patients aged > 60 years, major surgerymeasure to be used. in patients aged 40-60 years with one or more risk factors x Very high risk—Major surgery in patients aged > 40 years with Prophylactic drugs include unfractionated heparin, low previous venous thromboembolism, cancer or knownmolecular weight heparin, oral anticoagulants (such as hypercoagulable state, major orthopaedic surgery, electivecoumarins), thrombin inhibitors (such as hirudin), and specific neurosurgery, multiple trauma, or acute spinal cord injuryfactor Xa inhibitors (such as fondaparinux). The recentlyapproved fondaparinux reduces the risk of venousthromboembolism after orthopaedic surgery by more than halfcompared with low molecular weight heparin and seems likelyto become the treatment of choice after universal availability. Prophylactic physical methods include the use ofcompression elastic stockings, intermittent pneumaticcompression (which provides rythmic external compression at35-40 mm Hg for about 10 seconds every minute), and earlymobilisation to improve venous blood flow in conditionspredisposing to venous stasis.General surgeryPatients at low risk undergoing general surgery do not needspecific prophylaxis other than early mobilisation. In moderaterisk patients, fixed low doses of unfractionated heparin (5000 IUevery 12 hours) or low molecular weight heparin (3400 anti-Xaunits or equivalent) once daily is sufficient. Higher doses of lowmolecular weight heparin (more than 3400 IU anti-Xa daily)should be reserved for high risk general surgery andorthopaedic operations. Compression elastic stockings andintermittent pneumatic compression may protect high risk Ventilation-perfusion scan showing massive pulmonary thromboembolism,patients when used with anticoagulants. They are also effective showing a mismatch between (left) perfusion and (right) ventilation scanswhen used alone in moderate risk patients whereanticoagulants are contraindicated.Orthopaedic surgeryIn very high risk patients, such as those undergoing major Key pointsorthopaedic operations, high dose low molecular weight x Understanding Virchow’s triad aids the treatment of venousheparin or warfarin is appropriate. The current recommended thromboembolismlength of anticoagulant prophylaxis is 7-10 days with low x Numerous situations and risk factors can contribute to venousmolecular weight heparin or warfarin. Extended use may thromboembolismprovide additional benefit. Routine screening with duplex x Diagnosis of venous thromboembolism depends upon a combination of history, risk factors, and investigationsultrasonography is not helpful. Hirudin seems to be superior to x Antithrombotic prophylaxis is safe and effectivelow molecular weight heparin and low dose unfractionated 11
  • 19. ABC of Antithrombotic Therapyheparin as prophylaxis in patients undergoing elective hip Evidence based use of antithrombotic prophylaxisreplacements but is still not universally available. General surgery x Low risk— Early mobilisationNeurosurgery, multiple traumas, and spinal cord injuries x Moderate risk—UH 5000 IU 12 hourly starting two hours beforeIntermittent pneumatic compression is the prophylaxis of surgery, or low molecular weight heparin < 3400 anti-Xa IU daily*,choice for elective neurosurgery. Among the low molecular or compression elastic stockings, or intermittent pneumaticweight heparins, only enoxaparin 30 mg twice daily has been compressionshown to reduce venous thromboembolism without excess x High risk—Low molecular weight heparin > 3400 anti-Xa IU daily†bleeding after elective neurosurgery, multiple traumas, or spinal plus compression elastic stockings, or unfractionated heparin 5000cord injuries and so may be used in these situations. Other low IU eight hourly starting two hours before surgery plus compression elastic stockings, or intermittent pneumatic compression ifmolecular weight heparins have either not been tested or have anticoagulation contraindicatednot conclusively been shown to be of benefit in this setting. x Very high risk—Perioperative warfarin (INR 2-3), low molecular weight heparin > 3400 anti-Xa IU daily† plus compression elasticMedical conditions stockings, or prolonged low molecular weight heparin therapy plusIn general medical patients including heart failure and compression elastic stockingsrespiratory failure, both unfractionated heparin and low Major orthopaedic surgerymolecular weight heparin have been shown to be effective in x Elective hip replacement—Recombinant hirudin 15 mg twice daily,reducing the risk of venous thromboembolism. Low molecular unfractionated heparin 3500 IU eight hourly with postoperative adjustments (APTT 1.2-1.5), or low molecular weight heparinweight heparin has been shown to be more effective than > 3400 anti-Xa IU daily†, or perioperative warfarin (INR 2-3), orheparin in stroke. Low dose heparin has been shown to be fondaparinux 2.5 mg dailyeffective in acute myocardial infarction but this is now largely x Elective knee replacement—Low molecular weight heparin > 3400historic because myocardial infarction patients receive anti-Xa IU daily†, or perioperative warfarin (INR 2-3), ortherapeutic dose anticoagulants. fondaparinux 2.5 mg daily, intermittent pneumatic compression x Surgery for hip fracture—Low molecular weight heparin > 3400 anti-Xa IU daily†, or perioperative warfarin (INR 2-3), orOther considerations fondaparinux 2.5 mg dailyCombined approaches using drugs and physical methods may Elective neurosurgerybe better at preventing thromboembolism than physical x Intermittent pneumatic compression, enoxaparin 30 mg twice dailymethods alone. However, compression elastic stockings and Acute spinal cord injuryintermittent pneumatic compression may be used for moderate x Enoxaparin 30 mg twice dailyor high risk patients when anticoagulation is contraindicated or Traumabest avoided. Inferior vena cava filter placement should be x Enoxaparin 30 mg twice dailyreserved for patients at very high risk of venous Acute myocardial infarctionthromboembolism where anticoagulation as well as physical x Low dose unfractionated heparin 5000 IU twice daily, full dosemethods are contraindicated. Inferior vena cava filter placement unfractionated heparin 40 000 IU infusion over 24 hours, elastictends to cause a long term increase of recurrent deep vein stockings, and early mobilisationthrombosis, even though the immediate risk of postoperative Ischaemic strokepulmonary embolism is reduced. x Low dose unfractionated heparin 5000 IU twice daily Other medical conditions including congestive heart failure x Enoxaparin 40 mg once daily or 30 U twice daily, dalteparin 2500Further reading IU daily, low dose unfractionated heparin 5000 IU twice dailyx Haemostasis and Thrombosis Task Force of the British Society for Cancer patients receiving chemotherapy Haematology. Guidelines on anticoagulation: third edition. Br J x Low dose warfarin (INR < 2), dalteparin 2500 IU daily Haematol 1998;101:374-87x Hyers TM, Agnelli G, Hull RD, Morris TA, Samama M, Tapson V, et *Dalteparin 2500 IU once daily starting two hours before surgery Enoxaparin 20 mg once daily starting two hours before surgery al. Antithrombotic therapy for venous thromboembolic disease. Nadroparin 3100 IU once daily starting two hours before surgery Chest 2001;119:176-93S Tinzaparin 3500 IU once daily starting two hours before surgeryx Kearon C, Hirsh J. Management of anticoagulation before and after †Dalteparin 5000 IU once daily starting 10-12 hours before surgery Danaparoid 750 IU twice daily starting one to two hours before surgery elective surgery. N Engl J Med 1997;336:1506-11 Enoxaparin 40 mg once daily starting 10-12 hours before surgery or 30 mgx Simonneau G, Sors H, Charbonnier B, Page Y, Labaan JP, Azarian twice daily starting after surgery R et al. A comparison of low molecular weight heparin with Tinzaparin 50 IU/kg once daily starting two hours before surgery unfractionated heparin for acute pulmonary embolism. N Engl J Med 1997:337;663-9x Turpie AG, Bauer KA, Eriksson BI, Lassen MR. Fondaparinus vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomised double blind studies. Arch Intern Med 2002;162:1833-40 The box showing evidence based use of antithrombotic prophylaxis isx Walker ID, Greaves M, Preston FE. Guideline: Investigation and adapted from the 6th ACCP guidelines Geerts WH, et al. Chest management of heritable thrombophilia. Br J Haematol 2001;119:132-75S. The figure showing Plasma D-dimer concentrations on 2001:114;512-28 day of presentation according to final diagnosis is adapted from Bounameaux H, et al. Lancet 1991;337:196-200.12
  • 20. 4 Venous thromboembolism: treatment strategiesAlexander G G Turpie, Bernard S P Chin, Gregory Y H LipPulmonary embolism and deep vein thrombosis are treatedusing similar drugs and physical methods. The efficacy ofintravenous infusion of unfractionated heparin was first provedin a randomised trial in 1960. Subsequently, trials concentratedon the dose, duration of infusion, mode of administration, andcombination with warfarin treatment. Later trials have reportedthe efficacy and cost effectiveness of low molecular weightheparin compared with unfractionated heparin.Unfractionated heparinUnfractionated heparin, administered by continuous infusion orsubcutaneous injections adjusted to achieve activated partialthromboplastin time (APTT) greater than 1.5, is effective asinitial treatment of venous thromboembolism. Initialheparinisation should be followed by long term anticoagulationwith oral anticoagulants. APTT is a global coagulation test andnot specific for heparin, and it is also influenced by variousplasma proteins and clotting factors. Measuring plasma heparin Right ileofemoral deep vein thrombosislevels is more accurate but it is impractical and expensive. Asensible approach is to standardise the APTT with plasmaheparin within each laboratory. The most common mistake when starting heparintreatment is failure to achieve adequate anticoagulation. APTTratios of less than 1.5 during the first few days of heparin Antithrombotic treatment is oftentherapy increase the long term risk of venous inadequate in the first few days,thromboembolism recurrence. Hence, the initial bolus dose predisposing to recurrences.should be adequate and APTT monitored every six hours Anticoagulation with warfarin afterduring the first 24 hours of heparin infusion. discharge should continue for at least Oral anticoagulants may be started at the same time and three months, possibly six months. Lowshould be continued for at least three to six months, depending molecular weight heparin is as efficaciouson the individual. The optimal duration of intravenous heparin as unfractionated heparin in prophylaxis and treatmenttreatment is five to seven days because this is the time needed toobtain an adequate and persistent reduction in the vitamin Kdependent clotting factors with oral anticoagulants such aswarfarin. Heparin can then be stopped when concomitant usewith warfarin has achieved an international normalised ratio(INR) of 2-3 for at least 48 hours. In patients with largeileofemoral vein thromboses or major pulmonary embolism, Initial antithrombotic therapy for deep vein thrombosis withheparin infusion can be continued for up to 10 days. unfractionated heparin Heparin use for more than five to six days is associated with 1 Check baseline APTT, prothrombin time, full blood counta rare risk of thrombocytopenia. In a recent trial, only one of 2 Confirm there are no contraindications to heparin therapy308 patients (0.32%) who received unfractionated heparin for 3 Intravenous bolus 5000 IUacute pulmonary embolism developed a thrombocytopenia, 4 Choose between:whereas none of 304 patients receiving low molecular weight Continuous unfractionated heparin infusion—Start infusion at 18 IU/kg/hour (∼30 000/24 hours in a 70 kg man)heparin had this problem. The thrombocytopenia is normally Check APTT every six hours for first 24 hours, then daily thereaftermild, but precipitous falls in platelet count to less than Aim for APTT 1.5-2.5 × normal100 × 109/l can occur. When this happens, antibody mediated Recheck APTT at six hours after each adjustmentinjury to platelets should be suspected. As this condition may be Continue infusion for five to seven daysassociated with arterial or venous thromboembolism, heparin Subcutaneous—Start at 17 500 IU every 12 hours (or 250 IU/kg every 12 hours)should be stopped and warfarin use delayed. Alternative 5 Check platelet count daily for thrombocytopeniaanticoagulation cover should be given by danaparoid, a 6 Warfarin therapy can be started on the first day of heparin therapyheparinoid, or hirudin, a thrombin inhibitor, until the platelet according to local protocolcount rises above 100 000 and it is safe to start warfarin. 7 Continue heparin for at least four to five days after starting warfarinUnfractionated heparin has also been reported to increase 8 Stop heparin when INR greater than 2 for more than 48 hours 9 Continue warfarin therapy for at least three months keeping INRplatelet activation in vivo: low molecular weight heparin had no between 2 and 3 (target 2.5)such effect. 13
  • 21. ABC of Antithrombotic TherapyLow molecular weight heparinLow molecular weight heparin has a more predictable relation Advantages of low molecular weight heparin overbetween dose and response than unfractionated heparin and unfractionated heparindoes not need monitoring or adjustments if the dose is basedon patient body weight. Low molecular weight heparin is also x More reliable relation between dose and response x Does not need monitoringassociated with lower risk of thrombocytopenia. Its use in deep x Does not need dose adjustmentsvein thrombosis and pulmonary embolism is now firmly x Lower incidence of thrombocytopeniaestablished: many trials and meta-analysis have confirmed its x No excess bleedingsuperior efficacy, safer profile, and greater cost effectiveness over x Can be administered by patient at homeunfractionated heparins. However, all low molecular weight x Saves about five to six days’ admission per patientheparins are different, and trials for one product cannot beextrapolated to another. The introduction of low molecularweight heparin has advanced antithrombotic therapy byproviding effective anticoagulation without the need formonitoring or adjustments. It also allows patients withuncomplicated deep vein thrombosis to be treated in thecommunity, saving an average of four to five days’ admission per Duration of anticoagulation therapy for venouspatient. thromboembolism* Three to six monthsCoumarins x First event with reversible† or time limited risk factor (patient may have underlying factor V Leiden or prothrombin 20210 mutation)Warfarin is the most widely used oral anticoagulant for treating More than six monthsvenous thromboembolism. It is well absorbed from the gut, x Idiopathic venous thromboembolism, first eventmetabolised in the liver, and excreted in urine. The lag time for A year to life timewarfarin to take effect may be related to the natural clearance of x First event‡ with cancer (until resolved), anticardiolipin antibody,normal clotting factors from plasma. Of the vitamin K antithrombin deficiencydependent clotting factors, factor II takes the longest to clear. x Recurrent event, idiopathic or with thrombophiliaWarfarin monitoring is performed using an INR rather than *All recommendations are subject to modification by individual characteristicsprothrombin time, which may vary between laboratories. including patient preference, age, comorbidity, and likelihood of recurrenceWarfarin interacts with many other drugs and alcohol. It is also †Reversible or time limited risk factors such as surgery, trauma, immobilisation, and oestrogen useteratogenic and may induce spontaneous abortion. ‡Proper duration of therapy is unclear in first event with homozygous factor V A target INR range of 2-3 is standard for treatment of Leiden, homocystinaemia, deficiency of protein C or S, or multiple thrombophilias; and in recurrent events with reversible risk factorsvenous thromboembolism. Higher levels tend to increaseincidence of bleeding without reducing recurrentthromboembolism and so are unnecessary. The exception tothis is for patients with the antiphospholipid antibodysyndrome, where the risk of recurrent venousthromboembolism is high. Here, an INR of 3-4.5 isrecommended. Warfarin should be started in conjunction with Recent trials with the oral thrombinheparin or low molecular weight heparin when the diagnosis of inhibitor, ximelagatran suggest that, invenous thromboembolism is confirmed, although local certain circumstances, this agent may beprotocols may vary in their starting doses and titration an alternative to warfarin for theschedule. As indicated, heparin should be continued management of venous thromboembolism,concomitantly for five days and until INR is > 2. without the need for anticoagulation monitoring Warfarin therapy should then be maintained for at leastthree months in all patients. However, it has recently beenestablished that longer treatments (such as six months) may benecessary. Patients without a readily identifiable risk factor(idiopathic venous thromboembolism) have higher rates ofrecurrences. These recurrences can be reduced by prolongedanticoagulation. However, there is a corresponding rise in Thrombolytic regimens for pulmonary embolismbleeding complications with prolonged anticoagulation. 1 Check suitability of patient for thrombolysisCurrent recommendations advocate anticoagulation for at least 2 Choose between:six months for the first presentation of idiopathic venous Streptokinase—250 000 IU loading dose then 100 000 IU/hour forthromboembolism. Patients with recurrent venous 24 hoursthromboembolism and hypercoagulable states (acquired or Urokinase—4400 IU/kg loading dose then 2200 IU/kg/hour for 12 hoursinherited) or with cancer (especially while receiving Alteplase—100 mg intravenously over an hourchemotherapy) should take anticoagulation therapy for at least 3 Check APTT two to four hours after starting infusion:a year, and perhaps indefinitely. > 10 seconds prolongation indicates active fibrinolysis 4 Start heparin at 5000-10 000 IU loading followed by 15-25 units/kg/hour when APTT < 2Thrombolytic therapy 5 Adjust according to local protocol to keep APTT 1.5-2.5Unlike heparin and warfarin, which prevent extension andrecurrences of thrombosis, thrombolytic agents (includingstreptokinase, urokinase, and tissue plasminogen activator) lysethe thrombi. It is therefore unsurprising that patients with14
  • 22. Venous thromboembolism: treatment strategiespulmonary embolism treated with streptokinase and urokinase Indications for inferior vena cava filter placementare three times more likely to show clot resolution than patientstaking heparin alone. Even so, thrombolytic therapy of x Patients at high risk of proximal deep vein thrombosis extension where anticoagulation is contraindicatedpulmonary embolism does not dissolve the clot completely as it x Recurrent venous thromboembolism despite adequatedoes with acute coronary thrombosis, and increases the risk of anticoagulationbleeding. Occasionally, thrombolytic therapy is administered via x Chronic recurrent venous thromboembolism with pulmonarya catheter placed in the pulmonary artery. The catheter can be hypertensionused to “disrupt” the thrombus before starting the drug. x Simultaneous surgical pulmonary embolectomy or endarterectomy Until there is more evidence that thrombolytic therapyreduces mortality in pulmonary embolism, this treatmentshould be reserved for patients with massive pulmonaryembolism, cardiorespiratory compromise, and low risk of Mechanical and surgical treatment of pulmonary embolismbleeding. Evidence is emerging that streptokinase can decrease x Inferior vena cava filter placementswelling and pain in deep vein thrombosis. Again, further trials Indications—See box aboveare needed before this can be recommended routinely. x Pulmonary embolectomy Indication—Massive pulmonary embolism compromising cardiac output where thrombolysis has failed or is contraindicatedPhysical methods Experienced cardiac surgical cover essential Where available, catheter transvenous extraction of emboli may beNon-drug treatments include physically preventing an alternative to pulmonary embolectomyembolisation of the thrombi and extraction of thromboemboli x Pulmonary endarterectomy(usually from the pulmonary vasculature). Indication—Chronic recurrent pulmonary embolism with secondary Inferior vena cava filters may be used when anticoagulation is pulmonary hypertensioncontraindicated in patients at high risk of proximal deep veinthrombosis extension or embolisation. The filter is normallyinserted via the internal jugular or femoral vein. It is thenadvanced under fluoroscopic guidance to the inferior vena cava.Filters are now available that are easy to insert, and complicationsare low in skilled hands. For now, this technique should beconsidered in patients with recurrent symptomatic pulmonaryembolism and as primary prophylaxis of thromboembolism inpatients at high risk of bleeding (such as patients with extensivetrauma or visceral cancer), although the evidence is based onuncontrolled case series. The only randomised trial showed areduction in pulmonary embolism but no improvement in shortor long term survival, because of greater risk of recurrent deepvein thrombosis in patients who received a filter. Other mechanical and surgical treatments are usuallyreserved for massive pulmonary embolism where drugtreatments have failed or are contraindicated. None of thesemethods has shown a long term reduction in mortality, butbetter techniques have led to acceptable complication rates andwarrant further evaluation. Vena cavagram showing umbrella delivery device for filter inserted into the inferior vena cava through theTreatment during pregnancy jugular veinUnfractionated heparin and low molecular weight heparin donot cross the placenta and are probably safe for the fetus duringpregnancy. Oral anticoagulants cross the placenta and can Further readingcause fetal bleeding and malformations. Pregnant women withvenous thromboembolism can be treated with therapeutic doses x Decousus H, Leizorovicz A, Parent F, Page Y, Tardy B, Girard P, et al. A clinical trial of vena caval filters in the prevention of pulmonaryof subcutaneous heparin or low molecular weight heparin until embolism in patients with proximal deep vein thrombosis. N Engl Jafter delivery, when warfarin can be used safely. These issues are Med 1998;338:409-15developed in chapter 14. x Geerts WH, Heit JA, Clagett GP, Pineo GF, Colwell CW, Anderson FA Jr, et al. Prevention of venous thromboembolism. ChestThe data on duration of anticoagulation therapy for venous 2000;119:132-75Sthromboembolism is adapted from the 6th ACCP guidelines Hyers TM, x Heit JA, O’Fallon WM, Petterson T, Lohse CM, Silverstein MD,et al. Antithrombotic therapy for venous thromboembolic disease. Chest Mohr DN, et al. Relative impact of risk factors for deep vein2001;119:176-93S thrombosis and pulmonary embolism. Arch Intern Med 2002;162:1245-8 x Levine M, Gent M, Hirsch J, Leclerc J, Anderson D, Weitz J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996;334:677-81 x Walker ID, Greaves M, Preston FE. Guideline: investigation and management of heritable thrombophilia. Br J Haematol 2001;114:512-28 15
  • 23. 5 Antithrombotic therapy for atrial fibrillation:clinical aspectsGregory Y H Lip, Robert G Hart, Dwayne S G ConwayAtrial fibrillation is the commonest sustained disorder ofcardiac rhythm. Although patients often present with symptomscaused by haemodynamic disturbance associated with therhythm itself, the condition carries an increased risk of arterialthromboembolism and ischaemic stroke due to embolisation ofthrombi that form within the left atrium of the heart. Presenceof the arrhythmia confers about a fivefold increase in strokerisk, an absolute risk of about 4.5% a year, although the preciseannual stroke risk ranges from < 1% to > 12%, according tothe presence or absence of certain clinical andechocardiographically identifiable risk factors. From trial data, patients with paroxysmal atrial fibrillationseem to carry the same risk as those with persistent atrialfibrillation. The same criteria can be used to identify high riskpatients, although it is unclear whether the risk is dependent onthe frequency and duration of the paroxysms. Severely damaged left atrial appendageEvidence from clinical trials endocardial surface with thrombotic mass in a patient with atrial fibrillation and mitral valveIt is well established that antithrombotic therapy confers diseasethromboprophylaxis in patients with atrial fibrillation who are atrisk of thromboembolism. A recent meta-analysis ofantithrombotic therapy in atrial fibrillation showed that adjusteddose warfarin reduced stroke by about 60%, with absolute risk Randomised controlled trials have shown the benefit of warfarin and, to areductions of 3% a year for primary prevention and 8% a year for lesser extent, aspirin in reducing thesecondary prevention (numbers needed to treat for one year to incidence of stroke in patients withprevent one stroke of 33 and 13, respectively). In contrast, aspirin atrial fibrillation without greatlyreduced stroke by about 20%, with absolute risk reductions of increasing the risk of haemorrhagic1.5% a year for primary prevention and 2.5% a year for stroke and extracranial haemorrhage.secondary prevention (numbers needed to treat of 66 and 40, However, anticoagulant therapy is stillrespectively). Relative to aspirin, adjusted dose warfarin reduced underprescribed in patients with atrialthe risk by about 40%, and the relative risk reduction was similar fibrillation, particularly in elderlyfor primary and secondary prevention, and for disabling and patients, who stand to benefit mostnon-disabling strokes. However, these data, obtained from wellplanned clinical trials recruiting patients with relatively stableconditions, are unlikely to be fully extrapolable to all patients ingeneral practice, so that some caution is advised. Overall, warfarin (generally at a dose to maintain an Relative risk reduction (95% CI)international normalised ratio (INR) of 2-3) is significantly more AFASAK Ieffective than aspirin in treating atrial fibrillation in patients at SPAFhigh risk of stroke, especially in preventing disablingcardioembolic strokes. The effect of aspirin seems to be on the BAATAFsmaller, non-cardioembolic strokes from which elderly, and often CAFAhypertensive, patients with atrial fibrillation are not spared. Recent clinical trials have suggested that there is no role for SPINAFminidose warfarin (1 mg/day regardless of INR), alone or in EAFTcombination with antiplatelet agents or aspirin, asthromboprophylaxis in atrial fibrillation. However, the role of All trials (n=6) 62% (48% to 72%)other antiplatelet agents (such as indobufen and dipyridamole) in 100 50 0 -50 -100atrial fibrillation is still unclear. One small trial (SIFA) compared Warfarin better Warfarin worsetreatment with indobufen, a reversible cyclo-oxygenase inhibitor,with full dose warfarin for secondary prevention and found no Meta-analysis of trials comparing warfarin with placebo in reducing the riskstatistical difference between the two groups, who were well of thromboembolism in patients with atrial fibrillationmatched for confounding risk factors. Trials of other antiplatelet AFASAK=Copenhagen atrial fibrillation, aspirin, and anticoagulation study; BAATAF=Boston area anticoagulation trial for atrial fibrillation;and antithrombotic drugs (including low molecular weight CAFA=Canadian atrial fibrillation anticoagulation study; EAFT=Europeanheparin) have been performed but have generally been too small atrial fibrillation trial; SPAF=Stroke prevention in atrial fibrillation study;and underpowered to show significant differences. Large SPINAF=Stroke prevention in non-rheumatic atrial fibrillation16
  • 24. Antithrombotic therapy for atrial fibrillation: clinical aspectsmultinational trials comparing a direct thrombin inhibitor Relative risk reduction (95% CI)(ximelagatran) with adjusted dose warfarin in over 7000 patientswith atrial fibrillation at high risk of stroke and thromboembolism AFASAK Isuggest that this agent may be an alternative to warfarin, without SPAF Ithe need for anticoagulation monitoring. The reduction in relative risk with warfarin applies equally EAFTto primary and secondary prevention but, as history of stroke ESPS IIconfers an increased annual stroke risk (12% v 4.5%), the LASAFabsolute risk reduction is greater for secondary prevention. Thenumber of patients with atrial fibrillation needing treatment UK-TIAwith warfarin to prevent one stroke is therefore about three All trials (n=6) 22% (2% to 38%)times greater in primary prevention (37) than in secondaryprevention (12). 100 50 0 -50 -100 Treatment with full dose anticoagulation carries the Aspirin better Aspirin worsepotential risk of major bleeding, including intracranialhaemorrhage. Meta-analysis of the initial five primary Meta-analysis of trials comparing aspirin with placebo in reducing risk of thromboembolism in patients with atrial fibrillationprevention trials plus a further secondary prevention trial AFASAK=Copenhagen atrial fibrillation, aspirin, and anticoagulation study;suggests the risk of haemorrhagic stroke is only marginally EAFT=European atrial fibrillation trial; ESPS II= European stroke preventionincreased from 0.1% to 0.3% a year. Higher rates of major study II; LASAF=Low-dose aspirin, stroke, and atrial fibrillation pilot study;haemorrhage were seen in elderly patients and those with SPAF=Stroke prevention in atrial fibrillation study; UK-TIA=United Kingdom TIA studyhigher intensity anticoagulation. Further recent trials haveconfirmed an increased bleeding risk in patients with INR > 3.Antiplatelet therapy in atrial fibrillationSeveral clinical trials have studied the effects of aspirin in atrial Relative risk reduction (95% CI)fibrillation, with doses ranging from 25 mg twice daily to 1200 mga day. Overall, aspirin reduces the relative risk of stroke by about AFASAK I20% (a figure which just reaches statistical significance) with no AFASAK IIapparent benefit of increasing aspirin dose. Aspirin seems to EAFTcarry greater benefit in reducing smaller non-disabling strokesthan disabling strokes. This may be due to an effect primarily on PATAFcarotid and cerebral artery platelet thrombus formation, rather SPAF IIthan on formation of intra-atrial thrombus. A meta-analysis oftrials directly comparing full dose warfarin with aspirin All trials (n=5) 36% (14% to 52%)confirmed significant reductions in stroke risk about three times 100 50 0 -50 -100greater with warfarin. The SPAF III trial demonstrates that Warfarin better Aspirin betteraddition of fixed low doses of warfarin to aspirin treatment is notsufficient to achieve the benefits of full dose warfarin alone. Meta-analysis of trials comparing warfarin with aspirin in reducing risk of thromboembolism in patients with atrial fibrillation AFASAK=Copenhagen atrial fibrillation, aspirin, and anticoagulation study;Putting the evidence into practice EAFT=European atrial fibrillation trial; PATAF=Prevention of arterialDespite the evidence from the trials, many doctors are reluctant thromboembolism in atrial fibrillation; SPAF=Stroke prevention in atrialto start warfarin treatment for patients with atrial fibrillation. This fibrillation studycould be due to fears (of patient and doctor) of haemorrhagiccomplications in an elderly population, logistical problems ofINR monitoring, and a lack of consensus guidelines on whichpatients to treat and the ideal target INR. Such attitudes mayresult in otherwise avoidable stroke and arterialthromboembolism. A systematic evidence based approach needs Independent predictors of ischaemic stroke in non-valveto be encouraged, targeting appropriate antithrombotic therapy atrial fibrillationat those patients who stand to gain most benefit (those at greatest Consistent predictorsrisk of thromboembolism) and using levels of anticoagulation x Old age x Hypertensionthat have been proved both effective and reasonably safe for both x Previous stroke or transient ischaemic attackprimary and secondary prevention of stroke, if we are to realise in x Left ventricular dysfunction*clinical practice the large reduction in incidence of stroke Inconsistent predictorsachieved in the clinical trials. x Diabetes x Systolic blood pressure > 160 mm Hg† x Women, especially older than 75 yearsWho to treat? x Postmenopausal hormone replacement therapy x Coronary artery diseaseEven though there are impressive figures for relative risk Factors which decrease the risk of strokereduction with warfarin, the figures for absolute risk reduction x Moderate to severe mitral regurgitation(more important in clinical practice) depend greatly on the x Regular alcohol use ( > 14 drinks in two weeks)underlying risk of stroke if untreated. Elderly patients are often *Recent clinical congestive cardiac failure or moderate to severe systolicdenied anticoagulant therapy because of fears of increased dysfunction on echocardiographyhaemorrhage risk. However, the benefits of anticoagulant †In some analyses, systolic blood pressure > 160 mm Hg remained an independent predictor after adjustment for hypertensiontherapy are greater for elderly patients because of the increased 17
  • 25. ABC of Antithrombotic Therapyunderlying thromboembolic risk. Conversely, young patients at Practical guidelines for antithrombotic therapy in non-valvarrelatively low risk of stroke have less to gain from full dose atrial fibrillationanticoagulation as there may be little difference between thenumber of strokes prevented and the number of haemorrhagic Assess risk, and reassess regularlycomplications. Risk stratification is possible using the clinical High risk (annual risk of cerebrovascular accident=8-12%)and echocardiographic parameters and can be used to target x All patients with previous transient ischaemic attack or cerebrovascular accidenttreatment at the most appropriate patients. x All patients aged >75 with diabetes or hypertension Risk stratification for thromboprophylaxis can be x All patients with clinical evidence of valve disease, heart failure,undertaken in many ways. Clinical risk factors would assist with thyroid disease, and impaired left ventricular function onrisk stratification in most cases. Although echocardiography is echocardiography*not mandatory, it would help refine risk stratification in cases of Treatment—Give warfarin (target INR 2-3) if no contraindications anduncertainty. Based on echocardiographic data on 1066 patients, possible in practicethe Atrial Fibrillation Investigators reported that the only Moderate risk (annual risk of cerebrovascular accident=4%)independent predictor of stroke risk was moderate or severe left x All patients < 65 with clinical risk factors: diabetes, hypertension,ventricular dysfunction on two dimensional echocardiography. peripheral vascular disease, ischaemic heart disease x All patients > 65 not in high risk groupLeft atrial size on M mode echocardiography was not an Treatment—Either warfarin (INR 2-3) or aspirin 75-300 mg daily. Inindependent predictor on multivariate analysis. view of insufficient clear cut evidence, treatment may be decided onTransoesophageal echocardiography is rarely needed to individual cases. Referral and echocardiography may helpundertake risk stratification, but “high risk” features include the Low risk (annual risk=1%)presence of dense spontaneous echocardiographic contrast x All patients aged < 65 with no history of embolism, hypertension, diabetes, or other clinical risk factors Treatment—Give aspirin 75-300 mg daily *Echocardiogram not needed for routine risk assessment but refines clinical risk stratification in case of moderate or severe left ventricular dysfunction (see figure below) and valve disease. A large atrium per se is not an independent risk factor on multivariate analysis 20 Stroke rate, % per patient year 15 10 5 0 Normal Mild Moderate-severe LV function LV dysfunction LV dysfunctionTwo dimensional echocardiographyshowing left atrial thrombus in patient with Effect of left ventricular funtion on stroke rate in atrial fibrillationprosthetic valve LV=left ventricleDifferent risk stratification schemes for primary prevention of stroke in non-valvar atrial fibrillation RiskStudy High Intermediate LowAtrial Fibrillation High to intermediate risk: Age < 65 yearsInvestigators (1994) Age > 65 years No high risk features History of hypertension DiabetesAmerican College of Age > 75 years Age 65-75 years Age < 65 yearsChest Physicians History of hypertension Diabetes No risk factorsConsensus (1998) Left ventricular dysfunction† Coronary disease (thyrotoxicosis)* > 1 moderate risk factorStroke Prevention in Atrial Women aged >75 years History of hypertension No high risk featuresFibrillation Systolic blood pressure > 160 mm Hg No high risk features No history of hypertension Left ventricular dysfunction‡Lip (1999) Patients aged > 75 years and with Patients aged < 65 years with clinical Patients aged < 65 years with diabetes or hypertension risk factors: diabetes, hypertension, no risk factors Patients with clinical evidence of heart peripheral arterial disease, failure, thyroid disease, and impaired ischaemic heart disease left ventricular function on Patients aged > 65 not in high risk echocardiography§ group*Patients with thyrotoxicosis were excluded from participation in the test cohort†Moderate to severe left ventricular dysfunction on echocardiography‡Recent congestive heart failure or fractional shortening <25% by M mode echocardiography§Echocardiography not needed for routine risk assessment but refines clinical risk stratification in case of impaired left ventricular function and valve disease18
  • 26. Antithrombotic therapy for atrial fibrillation: clinical aspects(often with low atrial appendage velocities, indicating stasis), the Recommendations for anticoagulation for cardioversion ofpresence of thrombus of the atrial appendage, and complex atrial fibrillationaortic plaque. x For elective cardioversion of atrial fibrillation of > 48 hours duration start warfarin treatment (INR 2-3) three weeks before andWhich INR range? continue for four weeks after cardioversion x In urgent and emergency cardioversion administer intravenousThe evidence suggests that INR levels greater than 3 may result heparin followed by warfarinin an excess rate of haemorrhage, whereas low dose warfarin x Treat atrial flutter similarly x No anticoagulation treatment is required for supraventricularregimens (with INR maintained below 1.5) do not achieve the tachycardia or atrial fibrillation of < 48 hours durationreductions in stroke of higher doses. An INR range of between x Continue anticoagulation in patients with multiple risk factors or2 and 3 has been shown to be highly effective without leading to those at high risk of recurrent thromboembolismexcessive haemorrhage and should therefore be recommended Based on the 6th ACCP Consensus Conference on Antithrombotic Therapyfor all patients with atrial fibrillation treated with warfarin unlessthey have another indication for higher levels of anticoagulation(such as a mechanical heart valve). Although INR monitoring isoften coordinated by hospital based anticoagulant clinics, generalpractitioners are likely to play a more important part with thedevelopment of near patient INR testing. Particular care must be taken and INR levels closely Atrial fibrillation >2 daysmonitored when warfarin is used in elderly patients. It has been durationsuggested that an INR of between 1.6 and 2.5 can providesubstantial, albeit partial, efficacy (estimated to be nearly 90% ofthe highest intensities). Given the uncertainty about the safety Yes Candidate for No anticoagulation?of INRs > 2.5 for atrial fibrillation patients over 75 years, atarget INR of 2 (range 1.6-2.5) may be a reasonable Heparin TTE Start warfarin TOEcompromise between an increased risk of haemorrhage and areduced risk of thrombotic stroke for some patients within this Clotage group, in the absence of additional risk factors, pending No present? Yes TTE and TOEfurther data about the safety of higher intensities. The ongoing MRC sponsored Birmingham atrial fibrillation Clot Reconsidertrial of anticoagulation in the aged (BAFTA) is comparing Cardioversion present? anticoagulation Yes Nowarfarin with aspirin in atrial fibrillation patients over 75 yearsto further define the relative benefits and risks. 2-4 weeks Cardioversion warfarinDC cardioversionNo hard evidence exists in the literature that restoration of Candidate for Yes warfarin? Nosinus rhythm by whatever means reduces stroke risk.Transoesophageal echocardiography performed immediatelybefore cardioversion (to exclude intra-atrial thrombus) may Stop heparin if Heparin for >24 hoursallow DC cardioversion to be performed without prior INR >2 after cardioversionanticoagulation. However, as the thromboembolic risk may Warfarin for minimum 4 weekspersist for a few weeks postprocedure, it is still recommendedthat patients receive warfarin for at least four weeks afterwards. Guidelines for transoesophageal echocardiography guided cardioversionThe figures showing a severely damaged left atrial appendage endocardial TOE=transoesophageal echocardiography; TTE=transthoracicsurface is reproduced from Goldsmith I et al, Am Heart J 2000;140:777-84 echocardiographywith permission from Mosby Inc. The figures showing results of trialscomparing warfarin with placebo, aspirin with placebo, and warfarin withaspirin are adapted from Hart RG et al, Ann Intern Med 1999;131:492-501.The independent predictors of ischaemic stroke are adapted fromHart RG et al, Ann Intern Med 1999;131:688-95. The practical guidelinesfor antithrombotic therapy in non-valvar patients is adapted from Lip Further readingGYH, Lancet 1999;353:4-6. The table containing risk stratification schemesfor primary prevention of stroke is adapted from Pearce LA et al, Am J Med x Hart RG, Pearce LA, Rothbart RM, McAnulty JH, Asinger RW,2000;109:45-51. Guidelines for transoesophageal echocardiography Halperin JL. Stroke with intermittent atrial fibrillation: incidenceguided cardioversion is adapted from the ACUTE Study, N Engl J Med and predictors during aspirin therapy. Stroke Prevention in Atrial2001;344:1411-20. The recommendations for anticoagulation for Fibrillation Investigators. J Am Coll Cardiol 2000;35:183-7cardioversion of atrial fibrillation are based on the 6th ACCP Consensus x Lip GYH. Does atrial fibrillation confer a hypercoagulable state?Conference on Antithrombotic Therapy. Albers GW et al, Chest Lancet 1995;346:1313-42001;119:194-206S. x Lip GYH. Thromboprophylaxis for atrial fibrillation. Lancet 1999; 353:4-6 x Lip GYH, Kamath S, Freestone B. Acute atrial fibrillation. Clinical Evidence June Issue 7. BMJ Publishing Group. 2002 x Straus SE, Majumdar SR, McAlister FA. New edvidence for stroke prevention: scientific review. JAMA 2002;288:1388 x Thomson R, Parkin D, Eccles M, Sudlow M, Robinson A. Decision analysis and guidelines for anticoagulant therapy to prevent stroke in patients with atrial fibrillation. Lancet 2000;355:956-62 19
  • 27. 6 Antithrombotic therapy for atrial fibrillation:pathophysiology, acute atrial fibrillation, andcardioversionGregory Y H Lip, Robert G Hart, Dwayne S G ConwayPathophysiology of thromboembolism Structural Increased stasis Abnormal haemostasis orin atrial fibrillation abnormalities platelet functionThe pathophysiological mechanism for thrombus formation Mitral valveand embolism seems to be abnormalities in blood flow within prolapse Largethe fibrillating (and possibly dilated) left atrium. These left atriumabnormalities predispose to thrombus formation and arterialembolism, especially in the presence of underlying heartdisease. The latter (including valvar heart disease, hypertensiveheart disease, and poor left ventricular function) substantially Large leftincreases the risk for stroke and thromboembolism in patients ventricle,with atrial fibrillation. For example, the thromboembolic risk of low ejection Atherosclerosis fractionatrial fibrillation is 18 times greater if valvar heart disease is Mitral annular (aortic, cerebrovascular)present. In addition, a history of stroke, transient ischaemic calcificationattack, or other thromboembolism substantially increases therisk of stroke in atrial fibrillation (by 2.5 times). Hypertensionand diabetes are also common risk factors for stroke, increasing Virchow’s triad of thrombogenesis needs the presence of structural abnormalities (for example—atherosclerosis, valve disease), abnormal flowthe risk of stroke in atrial fibrillation by nearly twofold. (stasis in left atria, heart failure), and abnormal blood constituents (for example—clotting factors, platelets, etc). All are present in “high risk” patientsAnatomical aspects with atrial fibrillationA left atrial diameter of > 4.0 cm was previously regarded asthe strongest single predictor of increased risk ofthromboembolisation, but atrial dilatation rarely occurs inisolation without associated clinical risk factors such ashypertension. Thus, in the most recent analysis from the AtrialFibrillation Investigators, isolated left atrial dilatation by Mmode echocardiography was not independently predictive of In patients with paroxysmal atrialstroke and thromboembolism on multivariate analysis. fibrillation, thromboembolic eventsNevertheless, patients with lone atrial fibrillation (that is, those seem to cluster in the transition fromwho have no underlying cause for their arrhythmia), have been atrial fibrillation to sinus rhythm,shown to have a low risk of stroke and usually have an atrial size perhaps reflecting embolisation of a < 4.0 cm. Left atrial enlargement has also been associated with preformed clotthe presence of “spontaneous echocontrast” ontransoesophageal echocardiography. With scanning electronmicroscopy, the endocardium of the left atrial appendage showsevidence of damage in mitral valve disease, especially in thepresence of atrial fibrillation.Mechanical aspectsThe loss of atrial systolic function reduces stroke volume, leadingto a corresponding reduction in cardiac output and increasedatrial stasis. The latter results in increased propensity to thrombusformation. The prevalence of thrombus in the left atrialappendage, detected as an incidental finding duringtransoesophageal echocardiography, has been reported to beabout 10-15% in patients admitted with acute atrial fibrillationand up to 30% in patients with atrial fibrillation and recent stroke. Indeed, after cardioversion from atrial fibrillation to sinusrhythm, there is risk of thromboembolism of about 7% ifanticoagulation is not used, with the highest risk one to twoweeks after cardioversion. This may reflect mechanical reasons(embolisation of preformed thrombus), but it is more likely thatthis increased risk is related to atrial dysfunction aftercardioversion (“stunning”) and the delay of the return of atrialsystolic function, which can be up to three weeks or more after Thrombus in the left atrial appendage of patient with mitral valve disease atcardioversion. surgery20
  • 28. Antithrombotic therapy for atrial fibrillation: pathophysiology, acute atrial fibrillation, and cardioversionAtrial fibrillation and hypercoagulabilityIt has been recognised for over 150 years that abnormalities inthe blood vessel wall, blood flow, and blood constituents(Virchow’s triad) may increase the propensity for thrombusformation. Clinical and echocardiographic criteria can helpidentify the first two of Virchow’s postulates forthrombogenesis—namely, abnormalities of blood flow and vessels,such as valvar heart disease and cardiac impairment. Patients withatrial fibrillation also show abnormalities of haemostatic andplatelet markers that are unrelated to aetiology and underlyingstructural heart disease (and alter with antithrombotic therapyand cardioversion), which point towards the presence of ahypercoagulable state in this common arrhythmia. Thus, atrial The development of intra-atrialfibrillation has been described as an arrhythmia which confers a thrombus, and thus the immediate riskprothrombotic or hypercoaguable state. of thromboembolism, is thought to be temporally related to the duration of the arrhythmia, with minimal risk if theAnticoagulation for atrial fibrillation arrhythmia has been present for <48 hoursin special circumstancesAcute atrial fibrillationIn patients presenting with de novo atrial fibrillation, a clearhistory of arrhythmia onset is needed to guide appropriateantithrombotic therapy and timing of cardioversion. Although no randomised trials have specifically addressedthe issue, there is evidence that cardioversion may be safelyperformed without anticoagulation if the arrhythmia has beenpresent for < 48 hours. However, in one series intra-atrialthrombus was detected by transoesophageal echocardiographyin about 15% of patients presenting with acute atrial fibrillation(apparent duration < 48 hours), raising the possibility that thedevelopment of intra-atrial thrombus may be faster than Benefits of anticoagulant treatment in patients withpreviously suspected, or that in many apparent cases of acute non-rheumatic atrial fibrillation in preventing strokeatrial fibrillation the arrhythmia developed asymptomatically NNT (95% CI) > 48 hours before. Thus, in cases of uncertainty, anticoagulation Stroke risk to prevent one strokeis needed. Again, no randomised prospective studies have Low: Aspirin 227 (132 to 2500)addressed the use of intravenous unfractionated heparin or Age < 65 years, no major risk factorssubcutaneous low molecular weight heparin derivatives, but (including previous stroke, systemicboth drugs have been used with good results in the acute and embolism, or transient ischaemic attack;pericardioversion periods. hypertension; and poor left ventricular function as determined by a clinical history of heart failure or left ventricularAtrial fibrillation patients presenting with acute stroke ejection fraction < 50%)The role of antiplatelet drugs after acute stroke in sinus rhythm is Low moderate: Aspirin 152 (88 to 1667)well proved, but there is less certainty about the potential benefits Age 65-75 years, no major risk factors Warfarin 54 (46 to 69)and hazards of anticoagulant treatment in patients with atrial High moderate: Warfarin 32 (28 to 42)fibrillation, particularly the timing of administration. Although Age 65-75 years, no major risk factorsthe benefits of secondary stroke prevention using warfarin in but either diabetes or coronary heartatrial fibrillation patients are dramatic, it must be certain that diseasethere is no ongoing intracerebral haemorrhage (or risk of new High: Warfarin 14 (12 to 17)intracerebral haemorrhage) before starting the drug. Age < 75 years with hypertension, left Previous consensus guidelines from the American College ventricular dysfunction, or both, or age > 75 without other risk factorsof Chest Physicians state that before any antithrombotic drug is Very high: Warfarin 8 (7 to 10)started computed tomography or magnetic resonance imaging Age > 75 years with hypertension, leftscan should be done to confirm the absence of intracranial ventricular dysfunction, or both, or anyhaemorrhage and to assess the size of any cerebral infarction. In age and previous stroke, transientatrial fibrillation patients with no evidence of haemorrhage and ischaemic attack, or systemic embolismsmall infarct size (or no evidence of infarction) warfarin (INR NNT = number needed to treat2.0-3.0) can be given with minimal risk, provided patients arenormotensive. In atrial fibrillation patients with large areas ofcerebral infarction, the start of warfarin treatment should bedelayed for two weeks because of the potential risk ofhaemorrhagic transformation. The presence of intracranialhaemorrhage is an absolute contraindication to the immediateand future use of anticoagulation for stroke prevention in atrialfibrillation. The mortality benefits of aspirin treatment in acutestroke seen in the international stroke trial and Chinese acute 21
  • 29. ABC of Antithrombotic Therapystroke trial were less marked in patients with atrial fibrillation, Rate versus rhythm in atrial fibrillation: ischaemic strokespresumably because of the presence of preformed intra-atrialthrombus rather than new localised platelet thrombus adhering Rateto carotid and cerebral artery atheroma. control Rhythm Relative ratio Study n (%) control (95% CI) pCardioversion of persistent atrial fibrillation AFFIRM 4917 5.7 7.3 1.28 0.12Although there are no randomised studies to show that (0.95 to1.72)successful cardioversion of atrial fibrillation reduces the number RACE 522 5.5 7.9 1.44 0.44of subsequent thromboembolic events, the improvement in (0.75 to 2.78)haemodynamic function and observed reduction in indices of STAF 266 1.0 3.0 3.01 0.52 (0.35 to 25.30)clotting suggest that this may be the case. However, PIAF 252 0.8 0.8 1.02 0.49cardioversion is known to increase the short term risk of (0.73 to 2.16)thromboembolism, and thus, unless the arrhythmia has been Total 5957 5.0 6.5 1.28 0.08present for less than 48 hours, thromboprophylactic measures (0.98 to 1.66)are needed. The mechanism behind pericardioversionthromboembolism is complex and not entirely understood, butit is likely to be associated with the return of atrial systole,temporary “stunning” of the left atrium before return of systolicfunction, and possibly an increase in thrombotic tendencycaused by the procedure itself. The increase in thromboembolic Ischaemic stroke in the AFFIRM studyrisk may therefore persist for two weeks or more after successfulcardioversion. Rhythm control Rate control The American College of Chest Physicians (ACCP) sixth Ischaemic stroke 84 (7.3%)* 79 (5.7%)*recommendations for pericardioversion anticoagulation have INR >2.0 18 (22%) 24 (30%)been summarised in the previous chapter. However, the recent INR < 2.0 17 (20%) 28 (35%)ACUTE study found that by excluding thrombus on Not taking warfarin 48 (58%) 26 (33%)transoesophageal echocardiography before cardioversion, the Atrial fibrillation at time of event 25 (36%) 45 (69%)need for prior anticoagulation could be safely avoided. Patients *Event rates derived from Kaplan Meier analysis, p = 0.680treated in this manner had similar rates of thromboembolism asthose treated with the standard antithrombotic regimen buttheir haemorrhage rates were reduced. Transoesophagealechocardiography guided technique also allowed fastercardioversion of patients and resulted in higher initial successrates, although by eight weeks there was no substantialdifference in death rates, maintenance of sinus rhythm, or infunctional status between the two groups. Transoesophagealechocardiography guided cardioversion is now regarded bymany as the optimum approach to cardioversion and isrecognised as a suitable alternative to standard practice by theACCP. This point is included in the recent American HeartAssociation (AHA)/American College of Cardiology(ACC)/European Society of Cardiology (ESC) guidelinerecommendations. Recent trials comparing a “rate control” strategy with a“rhythm control” strategy for persistent atrial fibrillation showedan excess of thromboembolism in the patients randomised torhythm control (that is—cardioversion), as such eventshappened in patients successfully cardioverted, theanticoagulation stopped and on recurrence of atrial fibrillation,thromboembolism occurred. Thus, anticoagulation should beconsidered long term in patients postcardioversion at high riskof stroke and thromboembolim, or high arrhythmia recurrence Electrical cardioversion of atrial fibrillationrisk after cardioversion.The box showing the benefits of anticoagulant treatment in patients withnon-rheumatic atrial fibrillation in preventing stroke is adapted from StrausSE, et al. JAMA 2002;288:1388. The table showing the rate versus rhythm inatrial fibrillation: ischaemic strokes is adapted from Verheught FWA et al.J Am Coll Cardiol 2003;41:130A. The table showing ischaemic stroke in theAFFIRM study is adapted from the AFFIRM Investigators New Engl J Med2002;347:1825-33. The box showing the recommendations forantithrombotic therapy to prevent ischaemic stroke and systemic embolismin patients with atrial fibrillation undergoing cardioversion is adapted fromthe ACC/AHA/ESC guidelines Eur Heart J 2001;22:1852-9322
  • 30. Antithrombotic therapy for atrial fibrillation: pathophysiology, acute atrial fibrillation, and cardioversionRecommendations for antithrombotic therapy to prevent ischaemic stroke and sytemic embolism in patients with atrialfibrillation undergoing cardioversion*Class 1x Administer anticoagulation therapy regardless of the method (electrical or pharmacological) used to restore sinus rhythmx Anticoagulate patients with atrial fibrillation lasting more that 48 hours or of unknown duration for at least three to four weeks before and after cardioversion (INR 2.0-3.0)x Perform immediate cardioversion in patients with acute (recent onset) atrial fibrillation accompanied by symptoms or signs of haemodynamic instability resulting in angina pectoris, myocardial infarction, shock, or pulmonary oedema, without waiting for prior anticoagulation —If not contraindicated, administer heparin concurrently by an initial intravenous bolus injection followed by a continuous infusion in a dose adjusted to prolong the activated partial thromboplastin time at 1.5-2.0 times the reference control value —Next, provide oral anticoagulation (INR 2.0-3.0) for at least three to four weeks, as for patients who are undergoing elective cardioversion —Limited data from recent studies support subcutaneous administration of low molecular weight heparin in this indicationx Screening for the precence of thrombus in the left atrium or left atrial appendage by transoesophageal echocardiography is an alternative to routine preanticoagulation in candidates for cardioversion of atrial fibrillation —Anticoagulate patients in whom no thrombus is identified with intravenous unfractionated heparin by an initial bolus injection before cardioversion, followed by a continuous infusion in a dose adjusted to prolong the activated partial thromboplastin time at 1.5-2.0 times the reference control value —Next, provide oral anticoagulation (INR 2.0-3.0) for at least three to four weeks, as for patients who are undergoing elective cardioversion —Limited data from recent studies support subcutaneous administration of low molecular weight heparin in this indication —Treat patients in whom thrombus is identified by transoesophageal echocardiography with oral anticoagulation (INR 2.0-3.0) for at least three to four weeks before and after restoration of sinus rhythmClass IIbx Cardioversion without transoesophageal echocardiography guidance during the first 48 hours after the onset of atrial fibrillation —In these cases, anticoagulation before and after cardioversion is optional, depending on assessment of riskx Anticoagulate patients with atrial flutter undergoing cardioversion in the same way as for patients with atrial fibrillationACC/AHA ClassificationClass I —Conditions for which there is evidence or general agreement or both that a given procedure or treatment if useful and effectiveClass II —Conditions for which there is conflicting evidence or a divergence of opinion about the usefulness and efficacy of a procedure ortreatmentClass IIa—Weight of evidence and opinion is in favour of usefulness and efficacyClassIIb—Usefulness and efficacy is less well established by evidence and opinionClass III —Conditions for which there is evidence or general agreement or both that the procedure or treatment is not useful and in some casesmay be harmful*Data from Fuster V et al. J Am Cardiol 2001;38:1231. Further reading x Rate Control Versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. New Engl J Med 2002;347:1834-40 x AFFIRM Investigators. Survival in patients presenting with atrial fibrillation follow up investigation of rhythm management study. New Engl J Med 2002;347:1825-33 x Lip GYH. The prothrombotic state in atrial fibrillation: new insights, more questions, and clear answers needed. Am Heart J 2000;140:348-50 x Fuster V, Ryden LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation. A report of the American College of Cardiology, American Heart Association Task Force on practice guidelines and the European society of Cardiology Committee for Practice Guidelines and Policy Conferences developed in collaboration with the North American Society of Pacing and Electrophysiology. Eur Heart J 2001;22:1852-923 23
  • 31. 7 Antithrombotic therapy in peripheralvascular diseaseAndrew J Makin, Stanley H Silverman, Gregory Y H LipAtherosclerotic peripheral vascular disease is symptomatic asintermittent claudication in 2-3% of men and 1-2 % of womenaged over 60 years. However, the prevalence of asymptomaticperipheral vascular disease, generally shown by a reduced ankleto brachial systolic pressure index, is three to four times greater.Peripheral vascular disease is also a significant cause of hospitaladmission, and is an important predicator of cardiovascularmortality. Pain at rest and critical ischaemia are usually theresult of progression of atherosclerotic disease, leading tomultilevel arterial occlusion. Other causes of arterialinsufficiency—including fibromuscular dysplasia, inflammatoryconditions, and congenital malformations—are much rarer. Ischaemic ulcer on footTherapeutic objectives in peripheral vascular disease includerelieving symptoms and preventing the disease, and anyassociated events, progressing. Antithrombotic therapy in peripheral vascular disease The symptoms of peripheral vascular disease areprogressive. A claudicating patient encouraged to exercise tends Clinical problem Antithrombotic therapy of choiceto report a symptomatic improvement. This effect is generally Intermittent claudication Aspirin (to reduce risk of stroke andnot accepted to be an improvement in the diseased segment of myocardial infarction)blood vessel, but the formation of collateral vessels perfusing Clopidogrelthe ischaemic tissue. Diabetes Aspirin (to reduce risk of stroke and Vasodilating agents, such as naftidrofuryl, have little value in myocardial infarction) Clopidogrelmanaging claudication and peripheral vascular disease as their Embolic arterial occlusion Intravenous heparin and emergencyeffect is small and does not stop progression of the disease. surgical interventionCilostazol has been shown to increase absolute walking distance Acute on chronic arterial Heparin and angioplasty,in some patients by up to 47%. However, it has no clear occlusion intra-arterial thrombolysis or earlyantithrombotic effect and has not been shown to stop disease surgeryprogression. Intraoperative anticoagulation Heparin Unfortunately, not all progression is amenable to during vascular surgeryimprovement and, without the appropriate risk factor Infrainguinal vein bypass and Aspirin (to reduce risk of stroke andmanagement, progression to rest pain and necrosis can be rapid. infrainguinal prosthetic myocardial infarction) bypass Clopidogrel (if unable to take aspirin) Infrainguinal bypass at high Aspirin or consider warfarin thrombotic riskIntermittent claudication Carotid endarterectomy Aspirin or clopidogrelThe role of aspirin as an antiplatelet agent has been shown to Symptomatic carotid stenosis Consider warfarin or aspirin plusbe beneficial beyond doubt. In peripheral vascular disease it and too unwell for surgery dipyridamolereduces the frequency of thrombotic events in the peripheralarteries and reduces overall cardiovascular mortality inclaudicating patients. The dose of aspirin has been the subjectof some debate, but 81-325 mg daily has been shown to be of 160 Event rate/1000 patients/year Event rate per yearvalue. Larger doses have no apparent additional benefit but Placebo 7.7%increase the risk of adverse effects. Aspirin has been shown to Aspirin 5.8% 120reduce the progression of atherosclerosis in a few trials, but this Clopidogrel 5.3%remains unsubstantiated. The role of dipyridamole remains controversial. Several 80 77small studies have shown the benefit of giving it in conjunction 19with aspirin, but it is uncertain if dipyridamole alone is superior 24 58to aspirin. 53 40 In aspirin intolerant patients there is now a clear role forclopidogrel 75 mg once a day. This is as effective as aspirin inpreventing cardiovascular events. If a thrombotic event has 0occurred (whether the patient is taking aspirin or not) there 0 3 6 9 12 15 18 21 24 27 30 33 36may be an advantage in using clopidogrel to prevent further Time from randomisation (months)events, especially in peripheral vascular disease. In non-critical peripheral ischaemia, there is no indication Survival curve from CAPRIE study showing the benefits of aspirin andfor warfarin treatment as the complexities of management and clopidogrel on vascular events, with placebo rates from the Antiplateletbleeding risks seem to far outweigh the benefits, unless the Trialists’ Collaboration24
  • 32. Antithrombotic therapy in peripheral vascular diseasepatient has concomitant problems needing anticoagulationsuch as atrial fibrillation.Critical ischaemiaRest pain and gangrene are markers of critical ischaemia. Thisis nearly always the result of extensive vessel occlusion withabsent pedal pulses. The patient will almost certainly beimmobile because of pain and arterial insufficiency makingwalking impossible. These patients need prophylaxis againstvenous thromboembolism. Patients giving a short history of rest pain of sudden onsetrequire full, immediate anticoagulation with low molecularweight heparin or intravenous unfractionated heparin (thelatter with a target activated partial prothrombin time (APTT)ratio of 1.5-2.5). Warfarin should be avoided initially untilinvestigations and possible interventions are complete. Gangrenous toe indicating critical ischaemia Patients with chronic, progressive pain at rest also need fullanticoagulation. Although the evidence is limited, these patientsare often treated with warfarin to prevent progression,especially if remedial surgery is not possible. The internationalnormalised ratio (INR) should be kept in the range of 2-3. Acute thromboembolic occlusion of the peripheral arteriesrequires immediate anticoagulation with intravenousunfractionated heparin to prevent propagation of the thrombusand to guard against further embolism. Surgical intervention or,less commonly, thrombolytic therapy is indicated. Once theembolus has been cleared, the source needs to be investigatedand this usually requires treatment with warfarin long term.Peripheral artery revascularisationWhen the ischaemia reaches a state where peripheral arteryrevascularisation or reconstruction is necessary, therequirements for antithrombotic therapy change. Neointimal hyperplasia is a considerable problem in thelong term survival of a graft as its consequences (reduced bloodflow caused by reduced lumen) in some respects mimic those ofthe original disease. Hyperplasia of smooth muscle cells canoccur along the entire length of a vein graft, but particularlydoes so at the anastomoses of prosthetic grafts. Aspirin has no apparent effect on graft survival in humans.One trial showed that low molecular weight heparin had a Peripheral angiogram showing chronic occlusions withprofound beneficial effect on graft patency, when compared with multiple collateral vesselsaspirin and dipyridamole over three months, suggesting thatearly treatment with low molecular weight heparin suppressesneointimal hyperplasia. In the United Kingdom most lowmolecular weight heparins have licences only for 14 days’Risk of thrombosis with different vein grafts RecommendedSite of proximal Site of distal antithromboticanastomosis anastomosis Graft material Other factors Thrombotic risk therapyAorta Iliac or femoral Prosthetic Low Antiplatelet*Axilla Femoral Prosthetic Medium AntiplateletFemoral Popliteal (above knee Vein Low Antiplatelet* joint) Prosthetic Low Antiplatelet* Distal (below knee) Vein Good flow ( > 100 ml/min) and Medium Antiplatelet good distal arteries Poor flow ( < 50 ml/min) or poor High Antiplatelet distal arteries Consider warfarin Prosthetic High Antiplatelet Consider warfarin*Antiplatelet therapy not indicated for graft survival but recommended as prophylaxis against cardiovascular events 25
  • 33. ABC of Antithrombotic Therapytreatment, and, until more data are available, the prolonged use oflow molecular weight heparin cannot be recommended. Problems in patients undergoingInfrainguinal bypass infrainguinal bypassAntiplatelet treatment has no beneficial role for graft patency in + The thrombogenic characteristics of prostheticshort (femoral-popliteal) bypass with native vein grafts because graft materials + The poor flow states associated with some grafts,these are high flow and non-thrombogenic. None the less, for example, long bypasses passing over the kneeaspirin has been shown to reduce all cardiovascular end points jointin patients with peripheral vascular disease, and so should be + The medium to long term complication ofcontinued. Anticoagulation with warfarin has not been shown neointimal hyperplasiato be of benefit. Patients with prosthetic femoral-popliteal bypass are adifferent consideration. Taking aspirin with dipyridamolereduces platelet accumulation at the anastomosis. Startingantiplatelet treatment preoperatively leads to improved patencyrates, especially in “high risk” (low flow, prosthetic) grafts oncethe increased complication rate of postoperative woundhaematoma has passed. Again, aspirin (with or withoutdipyridamole) is recommended. Peripheral arterial disease High risk grafts need to be dealt with cautiously. All patients Intermittent claudication 26 201/3123 249/3140 -22.3 86.6 23 (9) (6.4) (7.9)should continue taking aspirin (or clopidogrel). The use of Peripheral grafting 12 67/1249 81/1248 -7.3 29.1 22 (16)warfarin needs to be judged carefully. In cases of poor run off, (5.4) (6.5)marginal quality vein, and previous graft failure, oral Peripheral angioplasty 4 12/472 17/474 -2.0 5.8 29 (35)anticoagulation has been shown to improve primary patency (2.5) (3.6)and limb salvage rates with a target INR of 2-3. If this is being Subtotal 42 280/4844 347/4862 -31.6 121.5 23 (8) (5.8) (7.1)considered then full heparinisation should begin immediately 0 0.5 1.0 1.5 2.0after the operation while oral anticoagulation is started. Antiplatelet Antiplatelet better worseNaturally, older patients are more likely to have bleedingcomplications, including intracranial haemorrhage, and this Meta-analysis from the Antithrombotic Trialists’ Collaboration showing theshould be considered. benefits of antiplatelet treatment in patients with peripheral vascular diseaseAortoiliac and aortofemoral graftsLarge aortoiliac and aortofemoral grafts are at low risk ofthrombosis. Primary patency rates of 80-90% can be expected atfive to ten years. Thus, specific antithrombotic therapy is notindicated. However, once again, the presence of peripheralvascular disease needs antiplatelet therapy to reduce allcardiovascular end points. Among high risk patients, antiplatelet treatment reduces the combined outcome of any serious vascular event by about aPercutaneous transluminal angioplasty quarter, non-fatal myocardial infarctionAlmost all patients undergoing percutaneous transluminal by a third, non-fatal stroke by a quarter,angioplasty have atherosclerotic peripheral vascular disease. As and vascular mortality by a sixth (with nosuch, they should all be treated with aspirin or clopidogrel. apparent adverse effect on other deaths) Studies with radiolabelled platelets have found substantialplatelet accumulation at the sites of angioplasty, and antiplatelettreatment reduces this. In coronary angiography, this treatmenthas been shown to reduce the incidence of new thrombus at thesite of the angioplasty. However, in similar coronary arterystudies, antiplatelet treatment has no effect on restenosiscompared with placebo. It is unclear how these results willextrapolate to peripheral angioplasty, and there are insufficientdata to make recommendations in peripheral vascular disease. Similarly there have not been enough studies to Suggestions from the Antithromboticrecommend the use of dipyridamole, ticlopidine, or clopidogrel Trialists’ Collaborationas an adjunct to aspirin. Although the long term use of x Clopidogrel reduced serious vascular events byantiplatelet drugs is not known to have any long term effect on 10% compared with aspirin, which was similar torestenosis, the drug should be used to prevent cardiovascular the 12% reduction observed with its analoguemortality in patients undergoing percutaneous transluminal ticlopidineangioplasty. x Addition of dipyridamole to aspirin produced no significant further reduction in vascular eventsCarotid stenosis compared with aspirin aloneEvidence for treatment of asymptomatic carotid stenosis ofgreater than 50% is unclear. One trial showed no reduction instroke rate in patients treated with aspirin for two to three years.However, it is increasingly accepted that atherosclerosis affectsall arteries to a greater or lesser extent. With this in mind, and26
  • 34. Antithrombotic therapy in peripheral vascular diseasethe evidence for using aspirin in lower limb atherosclerosis, it is Further readingstill recommended that these patients have antiplatelettreatment to prevent all cardiovascular events. + Jackson MR, Clagett GP. Antithrombotic therapy in peripheral arterial occlusive disease. Chest 2001;119:293-9S Treating patients who have had a transient ischaemic attack + CAPRIE Steering Committee. A randomised, blinded, trial ofor known ischaemic stroke with aspirin has clear benefit as clopidogrel versus aspirin in patients at risk of ischaemic eventsshown by the Antiplatelet Trialists’ Collaboration. The dose is (CAPRIE). Lancet 1996;348:1329-39not clear, but 81-325 mg should be effective without + Antiplatelet Trialists’ Collaboration. Collaborative overview ofunacceptable bleeding risk. Clopidogrel (75 mg daily) is randomised trials of antiplatelet therapy I: prevention of death,recommended for aspirin intolerant patients. Limited evidence myocardial infarction, and stroke by prolonged antiplatelet therapyshows that the combination of aspirin and dipyridamole in various categories of patients. BMJ 1994;308:81-106 + Antiplatelet Trialists’ Collaboration. Collaborative overview of(400 mg daily) may be more beneficial to these patients than randomised trials of antiplatelet therapy II: maintenance ofaspirin alone. vascular graft or arterial patency by antiplatelet therapy. BMJ Inadequate data exist on the use of warfarin in symptomatic 1994;308:159-68carotid stenosis, and so this cannot be recommended because of + Antithrombotic Trialists’ Collaboration. Collaborative meta-analysispossible bleeding complications. of randomised trials of antiplatelet therapy for prevention of death, Carotid endarterectomy is the treatment of choice for all myocardial infarction and stroke in high risk patients. BMJ 2002;324:71-86symptomatic carotid stenosis. Aspirin treatment should becontinued in the perioperative period to prevent plateletdeposition at the site of the endarterectomy and thus reduceintraoperative and postoperative stroke. Platelet deposition isknown to start immediately after the operation, and aspirinstarted in the first few postoperative days seems to providemuch less benefit. In patients with symptomatic disease who are The survival curve from the CAPRIE study is adapted from CAPRIEnot undergoing endarterectomy antiplatelet therapy is essential Steering Committee, Lancet 1996;348:1329-39. The table showing theto reduce the incidence of ischaemic stroke. Again, warfarin graft risk of thrombosis and the table of antithrombotic therapy inshould not be used as not enough evidence exists. In all patients peripheral vascular disease are adapted from Jackson MR, Clagett GP, Chest 2001;119: 293-9S. The meta-analysis showing the benefits ofwith cerebrovascular or carotid disease, antiplatelet therapy is antiplatelet treatment in patients with peripheral vascular disease isrecommended at all stages to decrease the risk of cardiovascular adapted from the Antithrombotic Trialist’s Collaboration, BMJevents. 2002;324:71-86. 27
  • 35. 8 Antithrombotic therapy for cerebrovasculardisordersGregory Y H Lip, Sridhar Kamath, Robert G HartStroke remains one of the leading causes of death and disabilitythroughout the world. It is the third commonest cause of death Symptomatic carotid stenosis >70%in developed countries, exceeded only by coronary artery Major strokedisease and cancer. The incidence of stroke is 1-2 cases in 1000 people a year in Minor strokethe Western world, and is probably slightly higher among Transient ischaemicAfrican-Caribbeans than other ethnic groups. Cerebrovascular attackdisorders are uncommon in people aged < 40 years, but there Transient monocular blindnessis a definite increase with age, with an incidence of 10 cases in Asymptomatic1000 people aged > 75 in a year. Stroke is slightly more carotid disease Strokecommon in men, but women tend to have a poorer prognosis General elderly Vascular death male populationbecause of a higher mean age at onset. The incidence of stroke 0 3 6 9 12 15has been declining in recent decades in many Western countries Annual probability (%)because of better population control of hypertension, smoking,and other risk factors. However, the absolute number of strokes Annual risk of stroke or vascular death among patients in various high riskcontinues to increase because of the ageing population, which is subgroupspredicted to peak in 2015. Thus, the present annual incidenceof 700 000 strokes in the United States is expected to rise to1 100 000 in 2015, without further advances in prevention. About 80-85% of the strokes are ischaemic, with the rest Strokeprimarily haemorrhagic. Even among patients with ischaemicstroke, there is much heterogeneity in aetiological and 15% Primary haemorrhagepathophysiological factors contributing to the disease. • Intraparenchymal 85% • Subarachnoid Atherosclerosis of the major cerebral vessels probablyaccounts for most ischaemic strokes, either as thrombotic Ischaemic strokeocclusion at the site of atherosclerotic plaques or atherogenicembolism. Embolism from a source in the heart (cardioembolicstroke) and lipohyalinosis of the penetrating small cerebral vessels 20% 25% 20% 30% 5%(lacunar stroke) account for a substantial proportion of ischaemic Atherosclerotic Penetrating Cardiogenic Cryptogenic Other, unusual cerebrovascular artery disease embolism stroke causesstrokes. In many patients the aetiology remains unknown. The disease ("Lacunes") • Atrial fibrillation • Prothromboticmajor risk factors for ischaemic stroke include old age, male sex, • Valve disease states • Ventricular • Dissectionsobesity, hypertension, diabetes, and tobacco smoking. thrombi • Arteritis • Many others • Migraine/vasospasm Hypoperfusion Arteriogenic • Drug abuse emboli • Many moreManagement of acute ischaemic strokeThe principles of management of patients with ischaemic stroke Classification of stroke by mechanism, with estimates of the frequency ofinclude slowing the progression of stroke, decreasing the various categories of abnormalitiesrecurrence of stroke, decreasing death and disability, preventingdeep vein thrombosis and pulmonary embolism, andsuppressing fever, managing hypertension and controllingglucose levels. Pathophysiological classification of stroke ThrombosisAntiplatelet treatment x AtherosclerosisAspirin is the only antiplatelet drug evaluated for the treatment x Vasculitisof acute ischaemic stroke and is recommended early in the x Thrombophilic disordersmanagement at a dose of 160-325 mg daily. Two major x Drug abuse such as cocaine, amphetaminesrandomised trials (the international stroke trial (IST) and the EmbolismChinese acute stroke trial (CAST)) have shown that starting x From the heartdaily aspirin promptly ( < 48 hours after the start rather than x From the major cerebrovascular vesselsthe end of the hospital stay) in patients with suspected acute x Unknown sourceischaemic stroke reduces the immediate risk of further stroke or Lipohyalinolysisdeath in hospital, and the overall risk of death and dependency x Small penetrating arteriesat six months later. About 10 deaths or recurrent strokes are Vasospasmavoided in every 1000 patients treated with aspirin in the first x Migraine x Subarachnoid haemorrhagefew weeks after an ischaemic stroke. The benefit of aspirin is seen in a wide range of patients Dissection x Spontaneousirrespective of age, sex, atrial fibrillation, blood pressure, stroke x Traumaticsubtype, and computed tomographic findings. In IST 300 mg of28
  • 36. Antithrombotic therapy for cerebrovascular disordersaspirin was used and in CAST 160 mg. Thus, the two studiesshow that giving aspirin early in acute stroke is safe, althoughside effects should always be considered. Other trials haveshown that continuing treatment with low dose aspirin givesprotection in the longer term. Until further evidence isavailable, however, aspirin should be withheld from patientsreceiving other forms of anticoagulant (except low dose heparin(5000 IU twice daily)) or thrombolytic treatment (and for 24hours after finishing treatment). The results of the IST and CAST studies apply chiefly topatients who had a computed tomography scan to excludeintracranial haemorrhage. A meta-analysis of subgroups fromthe trials showed that aspirin was safe and beneficial. Evenamong patients who did not have a computed tomogram andpatients with haemorrhagic stroke, aspirin treatment did notresult in net hazard. Thus, aspirin can be started in patients withsuspected ischaemic stroke even when computed tomography isnot available immediately. Computed tomogram of the brain showing lacunar infarcts in the anterior limb of theAnticoagulation treatment left internal capsuleHeparin is not routinely recommended for patients with acuteischaemic stroke. There are no randomised trials supportingthe use of standard doses of heparin (for example > 10 000 IUdaily) even in patients with acute stroke and risk factors forrecurrent events. The risk:benefit ratio of heparinadministration is narrow, ill defined, and probably depends onthe pathophysiological subtype of stroke and the factors that Thromboembolism Haemorrhagepredispose to haemorrhage. For patients with atrial fibrillation (stroke + pulmonary embolism) (major bleeding + ICH)and acute ischaemic stroke, there seems to be no net benefit No treatment 5.9%from standard dose heparin (aspirin should be givenimmediately, then warfarin (INR 2.0-3.0) started for secondary Aspirin 300 mg 5.0%prevention as soon as the patient is medically stable). However,a subgroup analysis from IST showed that in acute ischaemic Heparin 5000 U* 5.1%stroke low dose heparin (5000 IU twice daily) reduced death Heparin 5000 U* 4.2% aspirin 300 mgand recurrence, especially if combined with aspirin, and it isindicated if appreciable leg weakness is present for prevention Heparin 12 500 U* 7.2%of venous thromboembolism. Heparin 12 500 U* 7.5% No particular benefit was observed in ischaemic stroke in aspirin 300 mgthe vertebrobasilar region with anticoagulation at six months. 0 1 2 3 4 5 6 7 8Trials with low molecular weight heparins or heparinoids have % of patients experiencing events * Heparin given subcutaneously twice dailyyielded contradictory (but generally negative) results, and theyare not recommended for use at the moment. Thromboembolic and major haemorrhagic events in the International Stroke Trial. ICH=intracranial haemorrhageThrombolytic treatmentThrombolytic treatment for acute ischaemic stroke has been invogue since its immense benefit was seen with myocardialinfarction. The National Institute of Neurological Disorders andStroke (NINDS) rtPA Study Group trial showed thatrecombinant tissue plasminogen activator administered withinthree hours of onset of acute cerebral infarct at a dose of Cardiac disorders predisposing to stroke0.9 mg/kg (maximum 90 mg) given over an hour under strict Major risktreatment protocols increased the likelihood of minimal or no x Atrial fibrillationdisability at three months by at least 30%. This benefit was seen x Prosthetic mechanical heart valvein all stroke patients. Recombinant tissue plasminogen activator x Mitral stenosisis licensed for treating acute cerebral infarct in several countries. x Severe left ventricular dysfunction with mobileHowever, the risk:benefit ratio is narrow because of substantial left ventricular thrombus x Recent myocardial infarctionrisk of intracerebral haemorrhage, and the need to start x Infective endocarditistreatment (after computed tomographic assessment) within Minor risk*three hours of stroke onset severely restricts the number of x Mitral annular calcificationpatients who can be treated. x Mitral valve prolapse Streptokinase is not approved for use in acute cerebral x Patent foramen ovaleinfarct because of the results of three large trials, which were x Calcific aortic stenosisterminated early due to excessive bleeding. These trials used x Atrial septal aneurysmstreptokinase at a dose of 1.5 million units given more than *Occasionally can cause cardioembolic stroke, but the riskthree hours after stroke onset. Intra-arterial thrombolytic of initial stroke is low and often unrelated when identified during the evaluation of patients with cerebral ischaemiatreatment for patients with large artery occlusions (such as of 29
  • 37. ABC of Antithrombotic Therapythe internal carotid artery, middle cerebral artery, or Risk factors for haemorrhagic transformation of ischaemicbasilarartery) remains investigational. In the United Kingdom, strokethrombolytic treatment is not licensed for treatment of stroke,pending results from ongoing clinical trials (for example, IST-3). x Hypertension x Concomitant use of two or more antiplatelet or antithrombotic therapiesStroke prevention x Major early infarct signs on pretreatment computed tomography, including brain oedema and mass effectIn broad terms, antiplatelet agents are more effective in x Severe neurological deficitcerebrovascular atherogenic strokes, and anticoagulants aremore effective in primary and secondary prophylaxis againstcardioembolic stroke. Details of the second European stroke prevention study (ESPS-II)Antiplatelet agents x Randomised, placebo controlled, double blind trial of aspirinAmong patients with vascular disorders (such as coronary (50 mg), dipyridamole (400 mg), or both versus placeboartery disease, previous stroke or transient ischaemic attack, and x Two year follow up of > 6600 patients (secondary prevention ofperipheral vascular disease) antiplatelet agents substantially stroke)reduce the incidence of non-fatal stroke, non-fatal myocardialinfarction, vascular mortality, and composite end point of Placebo compared Aspirin Dipyridamole Aspirin +stroke, myocardial infarction, and vascular death. with: alone alone dipyridamole A variety of antiplatelet drugs with varying mechanisms of Reduction of 18% (P = 0.013) 16% (P = 0.015) 37% (P < 0.001)action are used to minimise stroke in patients at high risk. stroke riskThese include aspirin (irreversible inhibitor of cyclo-oxygenase), Reduction of 13% (P = 0.016) 15% (P = 0.015) 24% (P < 0.001)clopidogrel (which inhibits adenosine diphosphate induced risk of strokeplatelet aggregation) and dipyridamole (precise mechanism of or deathaction not yet clear). Aspirin remains the most commonly used x Clear additive benefit in stroke reduction (36%) when aspirin andantiplatelet drug, partly because of its cost effectiveness. dipyridamole were used in combination Aspirin is effective for stroke prevention in doses rangingfrom 30 mg/day to 1300 mg/day. Its beneficial effect is seen inall age groups and sexes. The European stroke prevention studyII (ESPS II) showed that a combination of aspirin and Further readingdipyridamole (sustained release 200 mg tablets twice daily) x Adams HP. Emergency use of anticoagulation for treatment ofsignificantly reduced the risk of stroke and all vascular events patients with ischemic stroke. Stroke 2002;33:856-61compared with aspirin alone. An important ongoing trial x Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis(ESPRIT) is seeking to replicate these results. of randomised trials of antiplatelet therapy for prevention of death, Clopidogrel is a newer thienopyridine derivative without the myocardial infarction, and stroke in high-risk patients. BMJadverse effect profile of ticlopidine. The CAPRIE (clopidogrel 2002;324:71-86 x Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P.versus asprin in patients at risk of ischaemic events) study Antithrombotic and thrombolytic therapy for ischemic stroke. Chestshowed that clopidogrel is slightly more effective than aspirin in 2001;119:300–20Sreducing the combined outcome of stroke, myocardial x Atkinson RP, DeLemos C. Acute ischemic stroke management.infarction, and vascular death among patients with Thromb Res 2000;98:V97-111atherosclerotic vascular disease. Although clopidogrel seems to x CAPRIE Steering Committee. A randomised, blinded trial ofbe as safe as aspirin, it is considerably more expensive, and it clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-39remains to be seen whether its use in routine practice is cost x CAST Collaborative Group. CAST: randomised placebo-controlledeffective. Its use is justified in patients who are intolerant to trial of early aspirin use in 20 000 patients with acute ischaemicaspirin or who develop a stroke while taking aspirin. stroke. Lancet 1997;349:1641-9 x International Stroke Trials Collaborative Group. IST: a randomisedAnticoagulation treatment trial of aspirin, subcutaneous heparin, both, or neither amongAnticoagulation in the form of warfarin has a role in a variety 19 435 patients with acute ischaemic stroke. Lancet 1997;349: 1569-81of cardiac disorders in primary and secondary prevention of x Mohr JP, Thompson JLP, Lazar RM, Levin B, Sacco RL, Furie KL,stroke. Cardiac disorders that predispose to stroke and et al for the Warfarin-Aspirin Recurrent Stroke Study Group. Aunequivocally seem to benefit from anticoagulation therapy comparison of warfarin and aspirin for the prevention of recurrentinclude atrial fibrillation (with additional risk factors putting ischemic stroke. N Engl J Med 2002;345:1444-51patients at moderate to high risk), mitral stenosis (with orwithout atrial fibrillation), and mechanical valve prosthesis. Incontrast, recent randomised trials (SPIRIT, WARSS) did not The flow diagram showing a classification of stroke by mechanism withshow advantages of warfarin over aspirin for secondary estimates of the frequency of various categories of abnormalities isprevention of non-cardioembolic brain ischaemia. At present, adapted from Albers GW et al, Chest 2001;119:300-20. Annual risk of stroke or vascular death among patients in various high risk subgroups iswarfarin should not be used routinely for patients with adapted from Wilterdink and Easton, Arch Neurol 1992;49:857-63. Thecommon causes of non-cardioembolic stroke, pending results figure showing thromboembolic and major haemorrhagic events in thefrom ongoing randomised trials. IST is adapted from IST Collaborative Group. Lancet 1997;349:1569-81.30
  • 38. 9 Valvar heart disease and prosthetic heart valvesIra Goldsmith, Alexander G G Turpie, Gregory Y H LipThromboembolism and anticoagulant related bleeding aremajor life threatening complications in patients with valvarheart disease and those with prosthetic heart valves. In thesepatients effective and safe antithrombotic therapy is indicated toreduce the risks of thromboembolism while keeping bleedingcomplications to a minimum.AssessmentRisk factors that increase the incidence of systemic embolismmust be considered when defining the need for startingantithrombotic therapy in patients with cardiac valvar disease andprosthetic heart valves. These factors include age, smoking,hypertension, diabetes, hyperlipidaemia, type and severity of valve Valve thrombosis of a bileaflet prosthetic mitrallesion, presence of atrial fibrillation, heart failure or low cardiac valveoutput, size of the left atrium (over 50 mm on echocardiography),previous thromboembolism, and abnormalities of thecoagulation system including hepatic failure. Secondly, the type, number, and location of prosthesesimplanted must be considered. For example, mechanicalprostheses are more thrombogenic than bioprostheses or Considerations for antithrombotic therapy in patients withhomografts, and hence patients with mechanical valves require valve diseaselifelong anticoagulant therapy. However, the intensity of x Assessment of risk for thromboembolic events, which may betreatment varies according to the type of mechanical prosthesis patient related or valve prosthesis relatedimplanted. First generation mechanical valves, namely the x Indications for starting treatment x Choice of antithrombotic agentStarr-Edwards caged ball valve and Bjork-Shiley standard x Duration of treatment and optimal therapeutic rangevalves, have a high thromboembolic risk; single tilting disc x Antithrombotic therapy in special circumstances (surgicalvalves have an intermediate thromboembolic risk; and the procedures, pregnancy, and resistance to oral anticoagulants)newer (second and third generation) bileaflet valves have low x Management of treatment failures and complicationsthromboembolic risks. In patients with a bioprosthesis in sinus rhythm,antithrombotic therapy with an antiplatelet drug may suffice,whereas patients with homografts in sinus rhythm may not needany antithrombotic therapy. Thromboembolic events arecommoner with prosthetic mitral valves than aortic valves and in Types of prosthetic valves and thrombogenicitypatients with double replacement valves compared with thosewith single replaced valves. Moreover, the risk of thromboembolic Type of valve Model Thrombogenicityevents is greatest in the first three months after implantation. Mechanical Caged ball Starr-Edwards ++++Choice of antithrombotic agent Single tilting disc Bjork-Shiley, Medtronic Hall +++Warfarin is the most used oral anticoagulant, and its dose is Bileaflet St Jude Medical, ++guided by achieving a target international normalised ratio Sorin Bicarbon, Carbomedics(INR) range. The use of heparin is confined to short periodswhen anticoagulant cover is needed and oral anticoagulants are Bioprostheticstopped. The dose of heparin is adjusted to achieve at least Heterografts Carpentier-Edwards, + to + + Tissue Med (Aspire), Hancock IItwice normal level of activated partial thromboplastin time(APTT) regardless of cardiac rhythm and type or position of Homografts +prosthesis. Fixed weight-adjusted low molecular weight heparinmay be used as an alternative to unfractionated heparin.Antiplatelet drugs, such as low dose aspirin or dipyridamole, areused in patients with bioprosthesis in sinus rhythm and inaddition to anticoagulants in the high risk patients withmechanical valves. Risk factors for patients with Patients with mechanical valves and those with bioprostheses bioprostheses include previousand associated risk factors require lifelong anticoagulant cover. In thromboembolic events, atrialpatients with a bioprosthetic valve in sinus rhythm anticoagulant fibrillation, enlarged left atrial cavity,cover with warfarin for the first three postoperative months may and severe cardiac failuresuffice, followed by low dose aspirin treatment for life.Alternatively, some surgeons give only low dose aspirin after 31
  • 39. ABC of Antithrombotic Therapysurgery in patients with bioprostheses in sinus rhythm (providingaspirin is not contraindicated). Patients with homografts usually Mechanicaldo not require any antithrombotic therapy. Old generation New generationIndications for antithrombotictherapy Caged ball Single tilting disc Second generation Third generation bileaflet bileafletNative valve diseaseOral anticoagulant treatment is indicated in all patients who Starr-Edwards Medtronic Hall St Jude Medical Sorin Bicarbonhave established or paroxysmal atrial fibrillation with native andvalve disease regardless of the nature or severity of the valve Bjork-Shileydisease. In patients with mitral stenosis in sinus rhythm,treatment is guided by the severity of stenosis, the patient’s age,size of the left atrium, and the presence of spontaneous Biologicalechocontrast or echocardiographic evidence of left atrialappendage thrombus. In these patients a target INR of 2.5(range 2-3) is recommended. Similarly, in patients with mitral Human Animalregurgitation treatment is indicated in the presence ofcongestive cardiac failure, marked cardiomegaly with lowcardiac output, and an enlarged left atrium. In the absence of Homograft Autograft Pericardial Porcinecardiac failure, previous thromboemboli, or heart failure,antithrombotic therapy is not indicated in patients with isolated Stented or stentless Stented or stentlessaortic or tricuspid valve disease. Mitral valve prolapse per se does not require anticoagulant Types of heart valve prosthesescover, although sometimes aspirin is recommended because ofthe association with cerebrovascular events.Percutaneous balloon valvuloplastyIn patients with mitral stenosis, the presence or absence of leftatrial thrombus is first confirmed by transoesophagealechocardiography. In the presence of thrombus, valvuloplasty isdeferred and anticoagulant treatment started for two months Comparison of mechanical and biological valve prosthesesbefore the procedure, with a target INR range of 2-3. In the Mechanical Biologicalabsence of atrial thrombus but in the presence of risk factors— Durable—valves lasting 20-30 years Limited life span—10% ofnamely, previous thromboembolism, enlarged left atrium, homografts and 30% ofspontaneous echocontrast, or atrial fibrillation—oral heterografts fail withinanticoagulant treatment should be started a month before the 10-15 yearsprocedure. Thrombogenic—patients require Low thrombogenic During the procedure, intravenous heparin (2000-5000 IU lifelong anticoagulant therapy potential—lifelongbolus) should be given to all patients immediately after anticoagulation is not requiredtrans-septal catheterisation. After the procedure, subcutaneous Preferred in younger patients with Preferred in older patients withheparin should be given for 24 hours and oral anticoagulant > 10-15 years life expectancy < 10-15 years life expectancytreatment restarted 24 hours after the procedure in patients Preferred in patients who require Preferred in those who cannot lifelong anticoagulant therapy (or will not) take lifelongwith risk factors, especially in the presence of atrial fibrillation anticoagulant therapyor spontaneous echocontrast. Patients in sinus rhythm who are undergoing aorticvalvuloplasty do not need long term anticoagulant treatment.However, treatment with heparin during the procedure isrequired.Mitral valve repairAfter mitral valve repair, oral anticoagulation (target INR 2.5) isneeded for the first six weeks to three months, and thereaftertreatment is guided by the presence or absence of risk factorssuch as atrial fibrillation, heart failure, and enlarged left atrium.Heart valve replacementAntithrombotic therapy in patients with replaced heart valves isguided by the type of prosthesis implanted (mechanical orbiological), position of the implant, associated risk factors (suchas atrial fibrillation), previous thromboembolism, bleeding risk,and the patient’s age. Patients with porcine or pericardial bioprostheses in sinusrhythm may be started on lifelong antiplatelet treatment with Examples of biological and mechanical valve protheses: (left) stentless porcinelow dose aspirin as soon as they can swallow the drugs. valve, (middle) stented porcine valve, (right) Sorin Bicarbon valve32
  • 40. Valvar heart disease and prosthetic heart valvesHowever, many centres start oral anticoagulant treatment the Intensity of anticoagulation guidelines for Europeday after implantation, maintaining an INR range of 2-3 for thefirst three months. Lifelong anticoagulant treatment is European Society of British Society ofrecommended for patients with associated risk factors. These Cardiology 1995 INR Haematology 1998factors are previous thromboembolism, left atrial thrombus, range INR targetmarked cardiomegaly, heart failure, dilated left atrium, or Mechanical valves*spontaneous echocontrast. Aortic: Patients with mechanical heart valves require lifelong First generation 3.0-4.5 3.5anticoagulant treatment, and patients with first generation Second generation 2.5-3.0 3.5†valves (with the highest thromboembolic risk) need a higher Third generation 2.5-3.0 3.5†target INR than patients with single tilting disc prostheses Mitral 3.0-3.5 3.5(intermediate thromboembolic risk) or the newer bileaflet Bioprosthetic valvesprosthesis (lower thromboembolic risk). In sinus rhythm: Most centres start (or restart) oral anticoagulant treatment Aortic 2.5-3.0 for three No anticoagulation‡the day after implantation, with or without heparinisation. As monthsthe thromboembolic risk is highest in the early postoperative Mitral 3.0-3.5 for three 2.5 for three months.period, it is advisable to give heparin and to continue it until the months. No No anticoagulationoral anticoagulant treatment achieves the target INR. The dose anticoagulation after after three monthsof heparin should be adjusted to achieve twice the normal level three monthsof APTT regardless of cardiac rhythm and type or position of In atrial fibrillation:the valve. Rheumatic valvar 3.0-4.5 2.5 The European and North American guidelines have minor heart diseasedifferences. The duration of antithrombotic therapy also varies Patients with 3.0-4.5 + 100 mg — recurrent emboli aspirinaccording to a number of factors. Lifelong anticoagulant under adequatetreatment is indicated for patients with mechanical valves and anticoagulationthose with bioprosthetic valves or native valve disease with Non-valvar atrial 2.0-3.0 2.5additional risk factors. fibrillation with risk factors *First generation valves include Starr-Edwards and Bjork-Shiley; secondAntithrombotic therapy in special generation valves include St Jude Medical and Medtronic Hall; and third generation valves include the Sorin Bicarbon bileaflet valve †For second and third generation mechanical aortic valves a target INR of 2.5 iscircumstances used ‡Low dose aspirin is used by most centres in the United KingdomModification of anticoagulant treatment may be required inpatients who have prosthetic valves and are undergoingnon-cardiac surgical procedures, who are are pregnant, or whohave resistance to oral anticoagulants.Surgical proceduresFor minor procedures, such as certain dental surgery orcryotherapy, where blood loss is expected to be minimal andeasily manageable, anticoagulant treatment may be continued.After dental extraction bleeding can be stopped with oraltranexamic acid (4.8%) mouth wash. However, before a planned Intensity of anticoagulation guidelines for North Americaminor surgical procedure, the INR should be adjusted tobetween 1.5 and 2.0. This can be achieved by stopping or AHA and ACC ACCP 2001 INRadjusting oral anticoagulant treatment one to three days before 1998 INR range (target range)the procedure depending on the drug used. In most cases, Mechanical valvesresumption of oral anticoagulant treatment is possible on the First, second, and thirdsame day as the procedure, and interim heparin treatment is generation valves:not needed. Patients undergoing endoscopic procedures and in Aortic 2.0-3.0 2.5 (2.0-3.0)whom an endoscopic biopsy is anticipated should be managed Mitral 2.5-3.5 3.0 (2.5-3.5)in the same way as patients needing major non-cardiac surgical Bioprosthetic valvesprocedures. In sinus rhythm: For major non-cardiac surgical procedures, in which there is Aortic Aspirin 2.5 (2.0-3.0) fora substantial risk of bleeding, anticoagulation should be 80-100 mg/day three monthsdiscontinued for several days (generally four to five days) before Mitral Aspirin 2.5 (2.0-3.0) forsurgery and the INR should be normalised at 1.0. The risk of 80-100 mg/day. three monthsthromboembolism increases, and so interim heparin treatment No anticoagulationshould be given in a dose that prolongs the APTT to twice the after three monthscontrol value. However, heparin should be stopped in time to In atrial fibrillation:bring the APTT down to near normal at the time of operation Aortic 2.0-3.0 2.5 (2.0-3.0)and resumed as soon as possible postoperatively. An alternative Mitral 2.5-3.5 2.5 (2.0-3.0)approach would be to use therapeutic fixed weight-adjusted AHA = American Heart Association; ACC = American College of Cardiology;doses of low molecular weight heparin. ACCP = American College of Chest Physicians 33
  • 41. ABC of Antithrombotic TherapyPregnancy Management of temporary interruption of oralIn pregnant women with prosthetic valves, the incidence of anticoagulantsthromboembolic complications is increased. Hence, adequateantithrombotic therapy is particularly important. Warfarin use x Discontinue oral anticoagulation five days before the procedure x Measure INR three days before procedurein the first trimester of pregnancy is associated with a If INR < 2 start low molecular weight heparin in therapeutic dosessubstantical risk of embryopathy and fetal death, and so If INR > 2.5 consider giving Vitamin K1 1-2 mg orally and start lowwarfarin should be stopped when a patient is trying to become molecular weight heparin in therapeutic doses. Repeat INRpregnant or when pregnancy is detected. Instead, twice daily measurement the day before proceduresubcutaneous unfractionated heparin should be given to x Continue low molecular weight heparin until evening beforeprolong the APTT to twice the control value, and this treatment procedure (last injection not less than 12 hours preprocedure)may be continued until delivery. Alternatively, unfractionated x Restart warfarin night of or day after procedure x Restart low molecular weight heparin 12-24 hours after procedureheparin may be given until the thirteenth week of pregnancy, and when haemostasis is establishedthen a switch made to warfarin treatment until the middle ofthe third trimester. Then warfarin can be stopped andunfractionated heparin resumed until delivery. Because lowdose aspirin is safe for mother and child, it may be used in Indications for lifelong oral anticoagulation in valve diseaseconjunction with anticoagulant treatment in women at high risk x Mechanical prosthesesof thromboembolism. However, low molecular weight heparin x Chronic or paroxysmal atrial fibrillation in the presence of native(which does not cross the placental barrier) may be an valve disease, bioprosthesis, valve repair, or valvuloplastyalternative to unfractionated heparin in this setting, although x Native valve disease and previous thromboembolismthere are limited data on its efficacy or safety in pregnancy. x Mitral valve stenosis, irrespective of rhythm, in association with highOther pregnancy related issues are discussed in chapter 14. transmitral valve gradient, left atrial thrombus, spontaneous echocontrast, large left atrium ( > 50 mm), low cardiac output, or congestive heart failure Further reading x Bonow RO, Carobello D, de Leon AC, Edmunds LH Jr, Fedderly BJ, Freed MD, et al. ACC/AHA guidelines for the management of patients with valvular heart disease. J Am Coll Cardiol 1998; 32:1486-8 x Gohlke-Barwölf C. Anticoagulation in valvular heart disease: new aspects and management during non-cardiac surgery. Heart 2000;84:567-72 x Haemostasis and Thrombosis Task Force of the British Society for Haematology. Guidelines for prevention of thromboembolic events in valvular heart disease. Eur Heart J 1995;16:1320-3034
  • 42. 10 Antithrombotic therapy in myocardial infarctionand stable anginaGregory Y H Lip, Bernard S P Chin, Neeraj PrasadAcute Q wave myocardial infarction I aVR V1 V4The use of thrombolytic treatment in acute myocardialinfarction is now established beyond doubt. However, primaryangioplasty is now proved to be an effective alternative and isused increasingly in preference to thrombolysis in many centres II aVL V2 V5worldwide.Thrombolytic treatmentCurrent key issues relate to the clinical situations in which III aVF V3 V6thrombolysis may be beneficial or contraindicated. For example,all patients with a history suggesting cardiac ischaemia andaccompanying electrocardiographic changes indicating acutemyocardial infarction should be considered for thrombolysis.However, patients with only ST segment depression on an V3R V4R V5R V6Relectrocardiogram or with a normal electrocardiogram do notbenefit from thrombolysis, and treatment should therefore bewithheld. Exceptions to this are when there is evidence of new Electrocardiogram indicating acute inferior myocardial infarctiondevelopment of left bundle branch block or a true posteriormyocardial infarction (shown by ST segment depression withdominant R waves present in leads V1 and V2). These situationsrequire thrombolytic treatment. Indications and contraindications for thrombolysis in acute Thrombolytic treatment should be given within six hours of myocardial infarctionthe onset of symptoms and electrocardiographic changes for Indicationspatients to derive full benefit. Patients with persisiting pain and x Clinical history and presentation strongly suggestive of myocardialST segment elevation may still benefit from thrombolysis up to infarction within 6 hours plus one or more of: 1 mm ST elevation in two or more contiguous limb leads12 hours from the onset of symptoms. Beyond that, few patients 2 mm ST elevation in two or more contiguous chest leadswill benefit, and there is no clear evidence of whether this New left bundle branch blockbenefit outweighs the risk of haemorrhage. 2 mm ST depression in V1-4 suggestive of true posterior Thrombolytic treatment should be offered to all eligible myocardial infarctionpatients presenting with an acute myocardial infarction x Patients presenting with above within 7-12 hours of onset withregardless of age, sex, or site of infarct. In general, patients over persisting chest pains and ST segment elevation x Patients aged < 75 years presenting within 6 hours of anterior wall75 years and those with anterior myocardial infarction or myocardial infarction should be considered for recombinant tissueprevious heart attack have a higher mortality. Therefore, the plasminogen activatorabsolute reduction in mortality in these patients will be greater. ContraindicationsMany of the accepted contraindications (absolute and relative) Absolutecome from observational studies only. Some conditions, such as x Aortic dissectiondiabetic proliferative retinopathy and menstruation, are no x Previous cerebral haemorrhagelonger considered to be absolute contraindications. x Known history of cerebral aneurysm or arteriovenous Reperfusion of the artery affected by infarction occasionally malformationfails with thrombolytic treatment. If this happens patients will x Known intracranial neoplasm x Recent (within past 6 months) thromboembolic strokehave ongoing chest pain or acute electrocardiographic changes. x Active internal bleeding (excluding menstruation)In these instances the optimal management is still uncertain, x Patients previously treated with streptokinase or anisolatedalthough readministration of an alternative thrombolytic agent plasminogen streptokinase activator complex (APSAC or(“rescue thrombolysis”) or emergency percutaneous anistreplase) should receive recombinant tissue plasminogentransluminal coronary angioplasty (“rescue” or “salvage” activator, reteplase, or tenecteplasepercutaneous transluminal coronary angioplasty) has been Relativeadvocated. Rescue thrombolysis more than doubles the x Severe uncontrolled hypertension (blood pressure > 180/110 mmbleeding complications. Also, the limited data available showed Hg) on presentation or chronic severe hypertension x Current use of anticoagulants or known bleeding diathesisbenefit only in cases where plasma fibrinogen concentration x Recent (within past 2-4 weeks) trauma including head injury orwas > 1.0 g/l and where recombinant tissue plasminogen traumatic or prolonged ( > 10 minutes) cardiopulmonaryactivator was given if initial streptokinase did not achieve 25% resuscitationreduction of maximal ST elevation on the pretreatment x Recent (within 3 weeks) major surgery, organ biopsy, or puncture ofelectrocardiogram. non-compressible vessel All thrombolytic agents are plasminogen activators. x Recent (within past 6 months) gastrointestinal or genitourinary or other internal bleedingStreptokinase is the cheapest widely available agent. However, it x Pregnancyis highly antigenic, and neutralising antibodies preclude use of x Active peptic ulcer diseasethis agent more than once in a patient. Thus, it should not be 35
  • 43. ABC of Antithrombotic Therapyreadministered after 48 hours from the initial infusion.Tenecteplase, reteplase, and recombinant tissue plasminogen Lives saved/1000 peopleactivator (alteplase) have been shown to be as good as 50 Loss of benefit per hour of delay:streptokinase in reducing mortality after acute myocardial 1.6 – 0.6 lives per 1000 peopleinfarction. They are suitable alternatives if a patient has alreadyreceived streptokinase. In the GUSTO trial, recombinant tissue 40 3000plasminogen activator produced greater mortality reduction 14 000than streptokinase, especially in patients aged under 75 yearswho presented within six hours of onset of anterior myocardial 30 12 000infarction. Patients presenting within six hours of inferiormyocardial infarction accompanied by right ventricular infarct, 9000 20haemodynamic compromise, or anterior wall extension mayalso benefit. Tenecteplase has the advantage of being easilyadministered as a single bolus injection. 10 7000Antiplatelet treatmentThe concurrent use of aspirin with a thrombolytic drug reduces 0mortality far more than either drug alone. In the ISIS-2 trial, 0 6 12 18 24streptokinase reduced mortality by 25%, aspirin by 23%, and Hours from onset of symptoms to randomisationthe combination of aspirin with streptokinase by 42%. Inaddition, there was no increase in incidence of stroke or major Lives saved per thousand people in relation to time of administration ofbleeding by giving aspirin and streptokinase in combination. thrombolytic treatment from onset of symptoms of chest pain. Numbers along the curve are the number of people treated at different timesAnticoagulant treatmentThe use of “full dose” heparin, either intravenously or bysubcutaneous injections, is not warranted routinely afterstreptokinase (or anistreplase) infusion, with no difference inmortality during hospitalisation and an increased risk ofcerebral haemorrhage and other major bleeding. Patients who Antithrombotic therapy in acute Q wave myocardialmay benefit from heparin treatment after streptokinase (or infarction and after myocardial infarctionanistreplase) are those at high risk of developing All patients should receivethromboembolism. These patients include those with large x Aspirin 300 mg orally as soon as possible and 75-300 mg dailyinfarctions, atrial fibrillation, or congestive cardiac failure. thereafter On the other hand, recombinant tissue plasminogen x Consideration for thrombolysis x blockers, nitrates, and other standard antianginal drugs asactivator, tenecteplase, and reteplase have short half lives and appropriatethus have only small systemic fibrinolytic effects. The highreocclusion rates seen in patients given recombinant tissue Choice of thrombolytic agentsplasminogen activator may be stopped by concomitant use of x Streptokinase 1.5 MU intravenously over an hourfull dose heparin (for at least 24 hours). Several trials of x Recombinant tissue plasminogen activator 15 mg intravenous bolusangiographic patency have also reported a favourable followed by 0.75 mg/kg (maximum 50 mg) infusion over 30 minutes, then at 0.5 mg/kg (maximum 35 mg) over 60 minutessynergistic effect of heparin after recombinant tissue x Reteplase 10 MU intravenous bolus, repeated once after 30 minutesplasminogen activator. x Tenecteplase 30-50 mg (according to body weight) intravenously For patients with persistent risk factors for systemic over 10 secondsembolisation, consideration should be given to starting oralwarfarin or continuing heparin treatment as subcutaneous Adjuvant heparin treatment x In all patients receiving recombinant tissue plasminogen activator—injections beyond 48 hours. All other patients should receive 75 U/kg intravenous bolus with recombinant tissue plasminogenprophylactic heparin (unfractionated or low molecular weight activator infusion, followed by 1000-1200 U/hour to maintainheparin) until they are sufficiently mobile to minimise venous APTT ratio 1.5-2.0 for 48 hoursthromboembolism. Finally, trials comparing the use of hirudin x In all patients receiving reteplase or tenecteplase—75 U/kgand heparin after recombinant tissue plasminogen activator intravenous bolus with first reteplase bolus, followed by 1000-1200showed hirudin to be no better than heparin at reducing U/hour to maintain APTT ratio 1.5-2.0 for 48 hourscardiovascular death or reinfarction at 30 days. Prevention of systemic and venous thromboembolism x In all patients with acute myocardial infarction—low dose low molecular weight heparin until ambulatoryPostmyocardial infarction and stable x In patients receiving streptokinase at high risk of systemic orcoronary artery disease venous thromboembolism—measure APTT from four hours after thrombolysis. Start intravenous heparin at 1000-1200 U/hour once APTT ratio has fallen to less than 2.0. Continue for 48 hours,Antiplatelet treatment maintaining APTT at ratio 1.5-2.0. Alternatively, use low molecularData from the Antiplatelet Trialists’ Collaboration, which weight heparinanalysed more than 100 trials and 100 000 patients, including x In all patients at high risk of systemic or venous20 000 with acute myocardial infarction, confirmed that thromboembolism—heparin infusion may be continued beyond 48antiplatelet treatment reduced cardiovascular events in acute hours or converted to 15 000 U subcutaneously twice dailymyocardial infarction by 25%, representing a two year treatment (alternatively, use low molecular weight heparin) or to warfarinbenefit in 36 out of 1000 patients treated. (INR 2-3) for up to three months x In patients with atrial fibrillation—warfarin treatment after heparin Aspirin is the most widely used antiplatelet drug and is infusion should continue indefinitelyeffective at doses from 75 to 300 mg daily in patients who have36
  • 44. Antithrombotic therapy in myocardial infarction and stable anginahad myocardial infarction and those with stable coronary artery Risk factors for systemic embolisation when anticoagulationdisease. Although there is no substantial difference in efficacy should be consideredbetween lower and higher doses of aspirin within the statedrange, higher doses are associated with greater side effects. x Large anterior wall myocardial infarction x Myocardial infarction complicated by severe left ventricular Dipyridamole and ticlopidine have both been compared dysfunctionwith aspirin. Dipyridamole showed no benefit over aspirin in x Congestive heart failurethe PARIS trials. Ticlopidine may be slightly better than aspirin x Echocardiographic evidence of mural thrombus or left ventriculartreatment but is associated with undesirable side effects such as aneurysmneutropenia and thrombocytopenia. In the CAPRIE study, x Previous emboliwhich compared clopidogrel with aspirin over two years in x Atrial fibrillationpatients with vascular disease (ischaemic stroke, myocardialinfarction, peripheral vascular disease), clopidogrel was slightlybetter in reducing the number of vascular events (5.32% v5.83%, P = 0.04). Importantly, clopidogrel was as well toleratedas aspirin. Therefore, it would be reasonable to give patientsclopidogrel after acute myocardial infarction if aspirin werecontraindicated or not tolerated. The glycoprotein IIb/IIIa antagonists have been tried inconjunction with thrombolysis in acute myocardial infarction,but the various regimens used in recent trials did not confer anyadditional benefit over conventional treatment. However, therewas some evidence of more rapid and complete reperfusion,and these agents warrant further evaluation and refinement.Anticoagulant treatmentLong term anticoagulation with heparin followed by warfarin isnot needed routinely except in patients at higher risk of venousor systemic thromboembolism. Intracardiac thrombi usually occur within 48 hours afteracute myocardial infarction and tend to embolise within the firstfew weeks. Low dose dalteparin has been shown to reduce theincidence of intramural thrombus (21.9% v 14.2%, P = 0.03) in Echocardiogram showing thrombus at left ventricular apex in patient with dilated cardiomyopathypatients given thrombolytic treatments, although this is at a risk (A=thrombus, B=left ventricle, C=left atrium)of small increase in minor bleeding complications. Thus, inpatients at high risk of mural thrombus formation, dalteparinshould be started as soon as possible after the diagnosis ofacute myocardial infarction. Warfarin should be continued for two to three months,except in the case of atrial fibrillation, when it may be Further readingmaintained indefinitely. While a patient is taking warfarin, x Cairns JA, Theroux P, Lewis D, Ezekowitz M, Meade TW.aspirin use may increase the risk of bleeding, but, pending Antithrombotic agents in coronary artery disease. Chestfurther evidence, many clinicians still continue to use low dose 2001;119:228–52S x Collins R, MacMahon S, Flather M, Baigent C, Remvig L,aspirin for its antiplatelet effect. Although thrombus is Mortensen S, et al. Clinical effects of anticoagulant therapy incommonly associated with left ventricular aneurysm (up to suspected acute myocardial infarction: systematic overview of60%), systemic emboli are uncommon (4-5%), and long term randomised trials. BMJ 1996;313:652-9anticoagulation does not seem to further reduce the risk of x ISIS-2 Collaborative Group. Randomised trial of intravenoussystemic embolisation; thus, anticoagulant treatment is not streptokinase, oral aspirin, both, or neither among 17,187 cases ofcurrently indicated in these patients in the long term. suspected acute myocardial infarction: ISIS-2. Lancet 1988;II:349-60 x Oldroyd KG. Identifying failure to achieve complete (TIMI 3) Venous thromboembolism is often associated with acute reperfusion following thrombolytic treatment: how to do it, when tomyocardial infarction, although its incidence has fallen since the do it, and why it’s worth doing. Heart 2000;84:113-5introduction of thrombolytic treatment. Although no trials have x Mounsey JP, Skinner JS, Hawkins T, MacDermott AF, Furniss SS,compared the efficacy of low molecular weight heparin with Adams PC, et al. Rescue thrombolysis: alteplase as adjuvantunfractionated heparin in preventing venous treatment after streptokinase in acute myocardial infarction. Brthromboembolism after acute myocardial infarction per se, it is Heart J 1995;74:348-53 x The GUSTO Investigators. An international randomized triallikely that these agents are equally effective, and are increasingly comparing 4 thrombolytic strategies for acute myocardialused in clinical practice. infarction. N Eng J Med 1993;329:673-82 x National Institute for Clinical Excellence. Technology appraisalThe box showing antithrombotic therapy in acute Q wave myocardial guideline no 52. Guidance on the use of drugs for early thrombolysis in theinfarction and after myocardial infarction is adapted from the 6th ACCP treatment of acute myocaardial infarction. London: NICE, 2002consensus conference on antithrombotic therapy. The figure showing lives x Ohman EM, Harrington RA, Cannon CP, Agnelli G, Cairns JA,saved in relation to time of administration of thrombolytic treatment from Kennedy JW. Intravenous thrombolysis in acute myocardialonset of symptoms of chest pain is adapted from Collins R, et al, N Engl J infarction. Chest 2001;119:253-77SMed 1997;336:847-60. 37
  • 45. 11 Antithrombotic therapy in acute coronarysyndromesRobert D S Watson, Bernard S P Chin, Gregory Y H LipThe use of antithrombotic therapy in acute coronary syndromeshas reduced the incidence of death and Q wave myocardial De novo thrombosi sf platelets and soluble c rom circuinfarction dramatically in recent years. Antithrombotic drugs in oagul ati o n l a t i n g Coronary facroutine use include antiplatelet drugs (aspirin, clopidogrel, and artery Debris and h aemo tors from rupturglycoprotein IIb/IIIa receptor antagonists) and anticoagulants ed p rrhag la q ue e(unfractionated and low molecular weight heparin, warfarin, and Cholesterol and platelet richdirect thrombin inhibitors). atheromatous plaques (not necessarily stenosed)PathogenesisThrombosis is the basic pathophysiological process underlyingthe acute coronary syndromes. Thus, antithrombotic therapy isthe cornerstone of management, and the appropriate choice of Vasospasm inantithrombotic drugs to reduce platelet aggregation or interfere artery or arterioles Occlusion reduces lumen by thrombuswith the clotting process can be critical. Rupture of the fibrous cap of an atheromatous plaqueexposes the lipid core, which is highly thrombogenic andcontains an abundance of procoagulant tissue factor. Plaque Downstream ischaemia or infarctionrupture (exposing surface binding glycoproteins) allowsplatelets to adhere to the plaque, become activated, and releasethromboxane A2, which causes further platelet aggregation and Thrombosis in relation to acute coronary syndromesvasoconstriction. As the platelets aggregate around theruptured plaque, membrane glycoprotein IIb/IIIa receptorsundergo a configuration change to bind fibrinogen and form acomplex platelet linkage. Further incorporation of fibrin andred blood cells within this platelet-rich thrombus results in apartial or total occlusion of the coronary artery. Alternatively,thrombus may break off from a ruptured plaque and occlude adownstream vessel. Occlusion may also follow from trapping ofcirculating thrombi formed elsewhere in the circulation.Antithrombotic drugsAntiplatelet drugsAspirinAspirin has been in use for more than 150 years and is cheapand effective. It has been shown to reduce the risk of fatal and Thrombus within right coronary artery (arrow) in a patient with unstable anginanon-fatal myocardial infarction by at least 50% in patients withunstable angina. Aspirin blocks cyclo-oxygenase and formationof thromboxane A2, thus reducing platelet aggregation inducedvia this pathway. Aspirin is the cornerstone of treatment in acute coronary 35 % of patients Neithersyndromes and chronic coronary artery disease. The beneficial Aspirineffects of aspirin seem to be sustained for at least two years and 30 Heparinregardless of the dose used. However, 75-150 mg daily may Aspirin and heparin 25have a lower incidence of gastrointestinal side effects than thehigher doses used in some randomised studies. 20ADP receptor antagonists 15Ticlopidine and clopidogrel are ADP inhibitors. Evidence existsthat ticlopidine reduces mortality, recurrent infarction, stroke, 10and angina at least to six months after myocardial infarction or 5unstable angina. Ticlodipine has fewer gastrointestinal effectsthan aspirin but may cause reversible neutropenia and 0 Refractory Myocardial Death Any eventthrombocytopenia ( < 1% of patients), which dictates angina infarctiontherapeutic monitoring with regular blood counts. Clopidogrel is a derivative of ticlopidine that seems to be six Reduction of adverse events in patients treated with aspirin, heparin, or bothtimes more effective than its predecessor in preventing platelet compared with neither drug38
  • 46. Antithrombotic therapy in acute coronary syndromesaggregation. Clopidogrel has shown better tolerability with lessbleeding than aspirin and fewer haematological side effects thanticlopidine. In the CURE trial—a randomised, double blind,parallel group study of 12 562 patients with acute coronarysyndrome or non-Q wave myocardial infarction—patientsreceived aspirin 75-325 mg and then were randomly assigned toadditional clopidogrel (300 mg load followed by 75 mg daily) orplacebo for three months to a year. Additional clopidogrelresulted in a 20% relative risk reduction in the primary end point(cardiovascular death, myocardial infarction, or stroke)(P < 0.0001), mainly caused by a 23% relative reduction inmyocardial infarction. However, there was a 34% excess of majorbleeding (3.6% v 2.7% in placebo; P = 0.003). These observations raise the question of whethercombination antiplatelet treatment (such as aspirin withclopidogrel) is preferable to other treatments (such as heparinwith glycoprotein IIb/IIIa receptor inhibitors) in the acutephase of acute coronary syndromes and suggest that prolonged Effects of clopidogrel plus aspirin in patients with acute coronary syndromesantiplatelet treatment is better for high risk patients. without ST segment elevation. From the clopidogrel in unstable angina to prevent recurrent events (CURE) trial investigatorsGlycoprotein IIb/IIIa receptor inhibitorsAbciximab is a (large molecule) monoclonal antibody and thefirst glycoprotein IIb/IIIa receptor antagonist to be developed.Eptifibatide is a peptide receptor antagonist, whereas tirofiban isa non-peptide receptor antagonist. Both eptifibatide andtirofiban are small molecules, apparently non-immunogenic,and therefore suitable for repeat infusions. They have a shorter Drug (%) Placebo (%)half life (90-120 minutes) than abciximab (12 hours). Because PRISM Tirofiban 5.8 7.1they are mainly renally cleared, their doses should be adjustedin patients with renal impairment. PRISM-PLUS Tirofiban 8.7 11.9 In trials with patients with acute coronary syndromes the rate PARAGON-A Lamifiban 11.6 11.7of death, reinfarction, and refractory angina was reduced when PURSUIT Eptifibatide 14.2 15.7glycoprotein IIb/IIIa inhibitors were added to aspirin and PARAGON-B Lamifiban 10.6 11.5heparin. In the largest study, PURSUIT, a bolus injection of GUSTO IV 24h Abciximab 8.2 8eptifibatide followed by a 72 hour infusion resulted in a 9.6% GUSTO IV 48h Abciximab 9.1 8relative risk reduction in death and myocardial infarction whengiven to patients with acute coronary syndromes already Total (27 051 patients) 11.3 12.5 0.91 (0.85 to 0.99)receiving aspirin and heparin. In the PRISM and PRISM-PLUS 0 1 2studies, tirofiban, when given in addition to aspirin and heparin, Glycoprotein Placeboachieved a 43% relative risk reduction in mortality and IIb/IIIa better betterreinfarction at seven days. This benefit was sustained at 30 days.Patients taking tirofiban and aspirin without heparin had an Glycoprotein IIb/IIIa inhibitors v conventional treatment in six trials. Resultsexcess mortality rate, and this treatment arm was stopped early. show odds ratio (95% confidence interval) for death and myocardial infarction at 30 day follow up The CAPTURE trial studied patients with acute coronarysyndromes scheduled for percutaneous coronary angioplasty.The use of abciximab for about 24 hours before the proceduresubstantially reduced the risk of mortality, myocardialinfarction, or need to proceed to other revascularisation. The benefits are greatest in patients with elevated levels oftroponin T or I, indicating that assessment of subtle indices ofcardiac damage predicts patients at higher risk and those most Patients Patients not undergoing undergoinglikely to benefit from treatment. Economic evaluations of the PCI: intervention No PCI: interventioncosts of using intravenous glycoprotein IIb/IIIa inhibitors Within 5 days Within 5 dayssuggest that, for patients with elevated troponin levels, 11 are Within 30 days Within 30 daysneeded to be treated to prevent one death or acute myocardialinfarction at 30 days. The equivalent cost effectiveness is about PCI or CABG: No PCI or CABG:£5000 an outcome. Within 5 days Within 5 days Using glycoprotein IIb/IIIa inhibitors for acute coronary Within 30 days Within 30 dayssyndrome in addition to conventional antithrombotic therapy isapproved by the British National Institute for Clinical 0 0.8 1.0 1.1 0 0.9 1 1.1Excellence (NICE). However, interpretation of trial evidence iscomplicated by patient heterogeneity. Although adjunctive Glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes:treatment before revascularisation procedures in acute patients undergoing percutaneous coronary intervention and patients not undergoing percutaneous coronary intervention. Results show odds ratiocoronary syndromes shows clear benefit, there is some (95% confidence interval) for death or myocardial infarctionuncertainty of benefit if these drugs are used only as “medical” (CABG=coronary artery bypass graft surgery, PCI=percutaneous coronarymanagement without revascularisation. intervention) 39
  • 47. ABC of Antithrombotic TherapyAnticoagulant treatmentLow molecular weight heparinLow molecular weight heparins possess more anti-Xa activitythan unfractionated heparins. They have a more predictable Antithrombotic therapy is theanticoagulant effect and cause less thrombocytopenia. Titrated cornerstone of management in acuteappropriately against body weight, low molecular weight heparin coronary syndromesprovides effective anticoagulation and does not need regularmonitoring of the activated partial thromboplastin time.However, platelet count monitoring to detect thrombocytopeniais recommended if treatment is extended beyond a few days.Studies suggest similar safety profiles to unfractionated heparinwhen used with glycoprotein IIb/IIIa inhibitors. The therapeutic benefits of low molecular weight heparins arenow clear. Recent randomised trials comparing the efficacy ofvarious low molecular weight heparins showed enoxaparin andnadroparin to be more effective in reducing mortality in unstableangina than either aspirin or unfractionated heparin alone. In the Trial LMWH Timing of Event rate (%) endpoint LMWH UHESSENCE study, enoxaparin reduced the incidence of death, Short term results:myocardial infarction, and reccurent angina at 14 days from FRIC Dalteparin Day 1-6 3.9 3.619.6% to 16.6% when compared with unfractionated heparin. ESSENCE Enoxaparin Day 14 4.6 6.1This benefit was maintained at 30 days and a year. TIMI 11-B Enoxaparin Day 14 5.7 6.9 Dalteparin in addition to aspirin was more effective than FRAXIS Nadroparin Day 14 4.9 4.5 Total 0.86 (0.72 to 1.02)aspirin alone in the FRISC study. It reduced cardiac events and P=0.07death (1.8% v 4.8%) when used in acute coronary syndromes Long term results:but was no better than adjusted dose unfractionated heparin. FRIC Dalteparin Day 6-45 4.3 4.7 Low molecular weight heparin is, therefore, at least as good ESSENCE Enoxaparin Day 43 6.2 8.2as unfractionated heparin in managing unstable angina (with TIMI 11-B Enoxaparin Day 43 7.9 8.9 FRAXIS Nadroparin Day 90 8.9 7.9trials showing enoxaparin and nadroparin to be even better). It Total 0.89 (0.77 to 1.03)has practical advantages because it has more consistent P=0.12antithrombin effects and is easier to administer, and frequent 0 1 2 LMWH better UH betterassessment of antithrombotic effect (activated partialthromboplastin time monitoring) is not neccesary. In view of Comparison of low molecular weight heparins with unfractionated heparinsthese findings, low molecular weight heparins (enoxaparin and in patients with acute coronary syndromes. Results show odds ratio (95% confidence interval) for death and myocardial infarction at long and shortnadroparin) should be used routinely to treat unstable angina term follow up (LMWH=low molecular weight heparin, UH=unfractionatedconcurrently with aspirin in place of unfractionated heparin. heparin)Unfractionated heparinAn uncontrolled study showed that heparin treatment inunstable angina reduced the risk of progression to myocardialinfarction by 80%. Other studies show a definite reduction inthe incidence of refractory angina and myocardial infarctionwith the use of unfractionated heparin compared with placebo(risk reduction 0.29). Treatment with heparin and aspirin seemsto be more effective than either heparin or aspirin alone. In ameta-analysis on the effect of adding heparin to aspirin inpatients with unstable angina, combination treatment resulted 10 Patients with adverse event (%)in 33% reduction in deaths or myocardial infarction. Heparin Hirudin RR=0.90 P=0.06 8Direct thrombin inhibitorsNewer and powerful anticoagulants, such as the direct thrombininhibitor hirudin, are being investigated. Several trials compared 6 RR=0.83 P=0.004the effects of hirudin with unfractionated heparin and showed aslight reduction in primary end points, and a pooled analysis of 4 RR=0.72 P<0.001these trials showed a 22% relative risk reduction in myocardialinfarction or deaths at 72 hours. Bleeding, however, may be a 2problem. Hirudin is now approved for patients with heparininduced thrombocytopenia but is not yet licensed for treatmentof acute coronary syndromes. The direct thrombin inhibitors 0 72 hours 7 days 35 daysmelagatran and ximelagatran are currently under investigationfor use in patients with acute coronary syndromes. TimeWarfarin Comparison of hirudin therapy with unfractionated heparin in patients withSeveral trials have investigated using warfarin for unstable angina. acute coronary syndromes (RR=relative risk)In many studies, warfarin was given to patients two days afterunfractionated heparin infusion and continued for ten weeks tosix months with an international normalised ratio (INR) adjusted40
  • 48. Antithrombotic therapy in acute coronary syndromesto between 2.0 and 3.0. Earlier studies showed low fixed doses of Antithrombotic therapy in acute coronary syndromes: awarfarin gave no benefit. However, limited evidence suggests that summaryin patients with acute coronary syndromes, combinationtreatment with aspirin and warfarin adjusted to INR 2.0-3.0 may Aspirin x Acute treatment with aspirin is used in all patients with suspectedreduce event rates and hospitalisations. acute coronary syndromes in the absence of contraindications and Pending further trials and in view of potential bleeding risks for long term treatment thereafterand need for INR monitoring, warfarin is best reserved for Clopidogrelpatients with other indications for warfarin use such as coexistent x In acute coronary syndrome patients clopidogrel is used for acuteatrial fibrillation, known left ventricular aneurysm with mural treatment and for longer term treatment for at least 9-12 months.thrombus formation, or previous recurrent thromboembolic Beyond this, treatment will depend on the risk status of the patientstroke. Warfarin should not be used as the sole antithrombotic and individual clinical judgmentdrug in acute cases because of its delayed onset of action. x Clopidogrel is used for immediate and long term treatment in patients who do not tolerate aspirin and in patients receiving a stent x Clopidogrel is given to acute coronary syndrome patientsThrombolytic treatment scheduled for angiography unless there is a likelihood that the patient will proceed to urgent surgery (within 5 days)Thrombolytic treatment is not recommended for unstable Low molecular weight heparinangina and non-Q wave infarction. It has not been shown to x In aspirin treated patients, low molecular weight heparin is betterreduce cardiovascular events and death and may worsen clinical than placebo. There are also data in favour of low molecular weightoutcomes by increasing bleeding complications, as well as heparin (enoxaparin) over unfractionated heparin when administered as an acute regimenincreasing bleeding within a ruptured atherosclerotic plaque.This worsens obstruction to coronary flow and exposes Glycoprotein IIb/IIIa receptor inhibitors x Treatment with a glycoprotein IIb/IIIa receptor blocker isclot-bound thrombin to flowing blood, creating an even more recommended in all patients with acute coronary syndromesprothrombotic environment. In addition, the thrombus in undergoing percutaneous coronary interventions. The infusionunstable angina is often platelet-rich, unlike the fibrin-rich should be continued for 12 hours (abciximab) or 24 hoursthrombus seen in infarction, and thus may be less responsive to (eptifibatide, tirofiban) after the procedurethrombolytic treatment. x Medical treatment with a glycoprotein IIb/IIIa receptor blocker during the first days after admission, followed by percutaneousThe figure showing reduction of adverse events in patients treated with coronary intervention or bypass surgery, yields a significantaspirin, heparin sodium, or both compared with neither drug is adapted reduction in death and non-fatal myocardial infarction at 72 hours,from Theroux P et al, N Engl J Med 1988:319;1105-11. The effects of from 4.3 to 2.9%clopidogrel plus aspirin in patients with acute coronary syndromes isadapted from the CURE trial investigators, N Engl J Med 2001;345: x Diabetic patients with acute coronary syndrome derive particular494-502. The figures showing glycoprotein IIb/IIIa inhibitors v benefit from glycoprotein IIb/IIIa receptor inhibitorsconventional treatment, comparing the effects glycoprotein IIb/IIIa Fibrinolytic treatmentinhibitors in acute coronary syndrome patients who are undergoing x In contrast to acute coronary syndromes with ST segment elevation,percutaneous coronary intervention with those who are not, and thrombolytic therapy is not recommended for patients with acutecomparing low molecular weight heparin with unfractionated heparin in coronary syndromes without persistent ST segment elevationpatients with acute coronary syndrome are all adapted from Bertrand M,et al, Eur Heart J 2002;23:1809-40. The figure comparing hirudintreatment with unfractionated heparin in patients with acute coronarysyndromes is adapted from Glenn N et al, Arch Intern Med2001;161:937-48Further readingx Anand SS, Yusuf S, Pogue J, Weitz JI, Flather M. Long term oral x Fragmin and fast revascularisation during instability in coronary anticoagulant therapy in patients with unstable angina or suspected artery disease (FRISC-II) Investigators. Long term low molecular non-Q wave myocardial infarction. The OASIS (warfarin) substudy. mass heparin in unstable coronary artery disease: FRISC-II Circulation 1998;98:1064-70 prospective multicentre randomised study. Lancet 1999;354:701-7x British Cardiac Society Guidelines and Medical Practice Committee, x PRISM-PLUS Investigators. Inhibiton of the platelet glycoprotein and Royal College of Physicians Clinical Effectiveness and IIb/IIIa receptor with tirofiban in unstable angina and non Q-wave Evaluation Unit. Guideline for the management of patients with myocardial infarction. N Engl J Med 1998;338:1488-97 acute coronary syndrome without persistent ECG ST segment x The PURSUIT Trial Investigators. Inhibiton of platelet glycoprotein elevation. Heart 2001;85:133-42 IIb/IIIa with eptifibatide in patients with acute coronary syndromes.x The CAPTURE Investigators. Randomised placebo controlled trial N Engl J Med 1998;339:436-43 of abciximab before and during intervention in refractory unstable x National Institute for Clinical Excellence (NICE). Guidance on the angina: The CAPTURE study. Lancet 1997;349:1429-35 use of glycoprotein IIb/IIIa inhibitors in the treatment of acutex Cohen M, Demers C, Gurfinkel EP, Turpie AG, Fromell GJ, coronary syndromes. NICE Technology Appraisal Guidance No 12. Goodman S, et al. A comparison of low molecular weight heparin London: NICE, 2000 with unfractionated heparin for unstable coronary artery disease x Task force on the management of acute coronary syndromes of the (ESSENCE). N Engl J Med 1997;337:447-52 European Society of Cardiology. Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2002;23:1809-40 41
  • 49. 12 Antithrombotic strategies in acute coronarysyndromes and percutaneous coronary interventionsDerek L Connolly, Gregory Y H Lip, Bernard S P ChinAcute coronary syndromes High and low risk patients with suspected acute coronary syndromesAll patients suspected of having acute coronary syndromeshould be managed as medical emergencies and monitored in High risk x Recurrent or persistent chest pains with associatedthe critical care unit. Baseline tests must include 12 lead electrocardiographic changes (ST segment depression or transientelectrocardiography, chest x ray examination, and venous blood ST elevation) despite anti-ischaemic treatmentsamples for analyses of haemoglobin and markers of x Elevated troponin concentrationsmyocardial damage, preferably cardiac troponin T or I. x Age > 65 years x Comorbidity, especially diabetesInitial management x Development of pulmonary oedema or haemodynamic instability within observation periodAssessment x Development of major arrhythmias (repetitive ventricularPatients with persistent ST segment elevation on 12 lead tachycardia or ventricular fibrillation)electrocardiography need immediate reperfusion treatment x Early postinfarction unstable angina(thrombolysis or intervention). Patients with ST segment Low riskdepression, inverted T waves, or pseudonormalisation of T waves x No recurrence of chest pains within observation periodon the electrocardiogram, but with a clinical history suggesting x Troponin or other markers of myocardial damage not elevatedcardiac ischaemia should receive initial treatment for angina. x No ST segment depression or elevation on electrocardiogram This would include aspirin 300 mg followed by a low dose (T wave inversion is classified as intermediate risk)of 75-150 mg daily. In cases of aspirin intolerance, clopidogrelshould be used. Blockers and nitrates should also be given.Rate limiting calcium antagonists can be used if blockers arecontraindicated or are already being used. Ideally, patientsshould be given low molecular weight heparin (such as Management strategies for patients with suspected acuteenoxaparin) according to their weight. If low molecular weight coronary syndromes, with risk stratification by troponin andheparin is unavailable, unfractionated heparin may be used. A stress tests*bolus of 5000 U is given, followed by an infusion adjusted to get Low riskan activated partial thromboplastin time (APTT) ratio of 1.8 to Results of tests2.5. In light of data from the CURE and PCI-CURE study, x Cardiac troponin result is negative or low (troponin T < 0.01 g/lclopidogrel (given for at least one month and up to nine or troponin I equivalent) on two occasionsmonths) should be considered in addition to aspirin when an x Stress test indicates a low risk categoryearly non-interventional approach is planned. The optimal dose Action x If free from cardiac symptoms, no more cardiac interventions neededof aspirin to limit bleeding is probably 75 mg, particularly with x Subsequent outpatient review appropriate for further investigationsclopidogrel. A glycoprotein IIb/IIIa receptor inhibitor should and adjustment of drug treatmentbe added to aspirin and heparin for patients in whom Intermediate riskcatheterisation and percutaneous coronary intervention are Results of testsplanned. In these patients clopidogrel could be considered if x Impaired left ventricular function, or haemodynamic abnormalitiesthey are not at high risk for bleeding. or arrhythmia during the acute phase but x Normal cardiac troponin result (troponin T < 0.01 g/l, or troponinObservation I equivalent), with a stress test indicating intermediate risk or x Moderately elevated cardiac troponin (troponin T 0.01-0.1 g/l, orPatients should be observed over the next eight to 12 hours. troponin I equivalent) with stress test indicating low risk categoryPatients at high risk of progressing to acute myocardial Actioninfarction or death should receive a glycoprotein IIb/IIIa x Many cardiologists perform coronary angiography on thesereceptor inhibitor (eptifibatide or tirofiban) in addition to patients, but clear evidence of benefit is lackingheparin and aspirin or clopidogrel (alone or with asprin). High riskAbciximab would be used in high risk patients undergoing Results of testspercutaneous coronary intervention. There is no role for x Maximal cardiac troponin result is high (troponin T > 0.1 g/l, orthrombolytic therapy in patients without acute ST segment troponin I equivalent) orelevation, except in the situations of a true posterior myocardial x Stress test indicates high risk categoryinfarction, or a presumed new left bundle branch block. Action x Coronary angiography should be arranged, unless contraindicated, and performed urgently, before discharge from hospitalSubsequent management x Patients with suitable lesions for percutaneous coronary interventionWhen patients have been free from symptoms and ischaemic should be given clopidogrel, which should also be given to patientselectrocardiographic changes for > 48 hours, and any with coronary lesions not suitable for any revascularisationintravenous treatments and heparin have been stopped for *If patient is unable to perform an exercise electrocardiogram, an alternative > 24 hours, risk assessment with stress testing should be non-exercise (pharmacological) stress test, such as a stress echocardiograph orperformed unless contraindicated. Stress testing for risk isotope myocardial stress perfusion study, should be arranged unless contraindicated. In all cases, aggressive risk factor management and regularassessment is unnecessary if a patient is already in a high risk aspirin treatment (or clopidogrel, or both, depending on clinical situation) is necessarycategory for which coronary angiography is indicated.42
  • 50. Antithrombotic strategies in acute coronary syndromes and percutaneous coronary interventionsAntithrombotic treatmentLow molecular weight heparin should be given for at least twodays, and for up to eight days or longer in cases of recurrentischaemia or where myocardial revascularisation is delayed orcontraindicated. Patients requiring a bypass operation may havetheir glycoprotein IIb/IIIa receptor antagonist infusion stoppedbefore or at the time of cardiac surgery, although clopidogrelshould be withheld for five to seven days.Risk stratification and antithrombotic strategiesRecent trials have shown that patients with elevated troponinbenefit from treatment with low molecular weight heparin,glycoprotein IIb/IIIa blockers, or an invasive strategy, whereas Time course of different cardiac biochemical markerspatients without troponin elevation showed no such benefit. In these high risk patients, angiography with a view torevascularisation should be performed on the same admission.Infusion of glycoprotein IIb/IIIa receptor inhibitors should bestarted while waiting and preparing for angiography andcontinued for 12 hours (abciximab) or 24 hours (tirofiban) afterangioplasty is performed. Low risk patients can be mobilised and discharged if (atleast 12 hours after the onset of symptoms of a suspected acutecoronary syndrome) the symptoms have not recurred, cardiactroponin concentrations are normal, electrocardiograms remainnormal (or unchanged compared with a recording from beforethe current presentation), and cardiac enzyme activities are notraised. Risk assessment with stress testing should be performedbefore a patient is discharged unless contraindicated.Pros and cons of invasive strategyThere are arguments for and against an invasive approach toacute coronary syndromes. In the FRISC-II trial an invasivestrategy had, after a year, saved 1.7 lives in 100 patients andprevented 2.0 non-fatal myocardial infarctions and 20readmissions. It provided earlier and better symptom relief atthe cost of 15 more patients with coronary artery bypassgrafting and 21 more with percutaneous transluminal coronaryangioplasty, and these results were independent of treatment Death or myocardial infarction in patients with elevated troponinwith dalteparin or placebo. In the BHF RITA3 trial of patients concentration or negative troponin result in contemporary trials. Thewith unstable angina, myocardial infarction, or non-ST segment FRISC-II trial also used low molecular weight heparin, and the bars for theelevation, an invasive strategy reduced refractory or severe TACTICS trial show the strategies used (I=invasive strategy, C=conservative strategy)angina, with no increase of death or myocardial infarction,compared with a conservative strategy. Against these benefits isthe need to have adequate provision of facilities and trained Clinical suspicion of acute coronary syndrome physical examination, electrocardiographic monitoring, blood samplesstaff to undertake such procedures. Persistent ST No persistent ST UndeterminedPercutaneous coronary intervention segment elevation segment elevation diagnosisArterial thrombi occur soon after percutaneous coronary Thrombolysis Aspirin, LMWH, Aspirininterventions for coronary artery disease, usually at the site of Percutaneous coronary clopidogrel,*the dilated segment. Arterial thrombi are rich in platelets, red intervention β blockers, nitratesblood cells, fibrin, and leucocytes and may contribute to vesselreocclusion with the consequent need for revascularisation. The High risk Low riskrisk of reocclusion depends on the extent of segment dilatationand vessel injury, as well as local shear forces. Antiplatelet and Second troponin measurementantithrombin drugs generally reduce the risk of occlusion orthe need for further intervention but are not perfect. Wherefacilities are available, percutaneous coronary angioplasty is an Glycoprotein IIb/IIIa Positive Twice negativealternative to thrombolytic treatment as a means of reperfusion Coronary angiographyin acute myocardial infarction. Stress test PCI, CABG, or medical management Coronary angiography Depending upon clinical andAntiplatelet treatment angiographic featuresPatients with coronary artery disease undergoing angioplasty European Society of Cardiology recommended strategy for acute coronaryshould continue taking antiplatelet drugs as usual. For patients syndromes (CABG=coronary artery bypass graft, LMWH=low molecularnot receiving regular antiplatelet treatment, aspirin 100-325 mg weight heparin, PCI=percutaneous coronary intervention. *Omit clopidogrelshould be given orally at least two hours before angioplasty. if patient likely to go to CABG within 5 days) 43
  • 51. ABC of Antithrombotic Therapy Aspirin substantially reduces the rate of intracoronary 10 % of patientsthrombus formation at the treatment site and restenoses. Theaddition of dipyridamole to aspirin adds little extra benefit and Primary angioplasty 8is not recommended. Ticlopidine alone has not been shown to Thrombolysis P=0.02be more effective than aspirin alone in patients undergoing 6 P=0.003percutaneous interventions. Although clopidogrel is marginallybetter than aspirin in patients with atherosclerotic vascular 4disease (CAPRIE study), direct comparisons between aspirin P=0.007and clopidogrel in coronary intervention have not revealed 2 P<0.001marked differences. Thus, ticlopidine and clopidogrel are useful 0alternatives for patients scheduled for percutaneous coronary Death Recurrent MI Total stroke IC bleedingangioplasty who are unable to take aspirin. Odds ratio 0.66 0.53 0.35 0.07 After intervention, antiplatelet combination treatment (aspirin (95% CI) (0.46 to 0.94) (0.34 to 0.80) (0.14 to 0.77) (0.0 to 0.43)plus ticlopidine) is superior to aspirin alone at reducing Meta-analysis of 10 randomised trials that compared thrombolytic treatmentischaemic complications and cardiac events, particularly after with primary angioplasty in acute myocardial infarction (MI=myocardialintracoronary stent placements. The stent anticoagulation infarction, IC=intracranial)restenosis investigators (SARI) trial, compared aspirin-ticlopidinecombination treatment with aspirin-warfarin combinationtreatment and aspirin alone and showed that patients takingaspirin-ticlopidine had the best 30 day mortality (0.5% v 2.7% v 4.0 Cumulative incidence of primary end point (%)3.6% respectively, P = 0.001). Total bleeding complicationsoccurred in 5.5% of those taking aspirin-ticlopidine, quite highwhen compared with 1.8% in those taking aspirin only 3.0(P < 0.001), and the incidence of neutropenia was not significantlydifferent. The CLASSICS trial showed clopidogrel-aspirin Aspirincombination treatment to be as effective as ticlopidine-aspirin 2.0 Aspirin and warfarincombination treatment after angioplasty and stent placement. Aspirin and ticlopidine 1.0Glycoprotein IIb/IIIa receptor antagonistsDespite adequate treatment with antiplatelet drugs, plateletactivation still continues along other pathways not blocked by 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30these agents. This is where the glycoprotein IIb/IIIa receptorantagonists, which block the final common pathways of platelet Days after stentingaggregation, have contributed most to the management ofangioplasty and stenting. Cumulative incidence of primary end points (mortality, target lesion revascularisation or thrombosis, non-fatal myocardial infarction) in patients Abciximab, eptifibatide, and tirofiban have all been shown to treated with aspirin alone (557 patients), aspirin and warfarin (550 patients),reduce reocclusion and cardiovascular events, including deaths or aspirin and ticlopidine (546 patients) after coronary artery stentingand myocardial infarctions, at 30 days when used in patientsundergoing elective and urgent angioplasty and stenting. Thesebenefits are additional to those achieved with antiplatelet drugs, Some factors prediposing to in stent thrombosis afterand the effects were most prominent with abciximab. The EPIC, placementEPILOG, and CAPTURE trials all showed that abciximab x Underdilation of the stent x Poor inflowinfusion reduced major complication rates during balloon x Proximal and distal dissections x Outflow obstructionangioplasty, a benefit that was sustained at 30 days’ follow up. x Vessel diameter < 3 mmThe EPISTENT trial showed that abciximab reduces majorcomplications during stent placement and was superior to acombination of abciximab and balloon angioplasty. In the onlydirect comparison of glycoprotein IIb/IIIa antagonists, the All 1570 patients 475 patients undergoing angioplasty 0.030 Probability of death or myocardial infarctionTARGET trial randomised 5308 patients to tirofiban or RR=0.34 (95% CI 0.14 to 0.79) RR=0.56 (95% CI 0.29 to 1.09)abciximab before percutaneous transluminal coronary 0.025angioplasty or stent, or both: by six months the primary endpoint was similar in both treatment arms (14.9% with tirofiban v 0.02014.3% with abciximab, P > 0.05), as was mortality (1.9% v 1.7%, 0.015P > 0.05). Patients with unstable angina, acute myocardialinfarction, and other risk factors (such as diabetes) for 0.010postprocedure in stent thrombosis or restenosis stand to benefit Heparin onlymost from glycoprotein IIb/IIIa receptor antagonists. 0.005 Tirofiban plus heparin In light of this, glycoprotien IIb/IIIa drugs should be 0considered in all patients at risk of developing in stent stenosis 0 6 12 18 24 30 36 42 48 2 4 7 14 21 28 Hours Daysor with acute coronary syndrome scheduled for percutaneouscoronary interventions. If percutaneous coronary intervention Drug infusion PTCAis planned in unstable angina, glycoprotein IIb/IIIa receptorantagonist infusions should be started before intervention and PRISM-PLUS results showing cumulative incidence of death or myocardialcontinued for 12 hours (abciximab) or 24 hours (tirofiban, infarction (PTCA=percutaneous transluminal coronary angioplasty,eptifibatide) after the procedure. RR=relative risk)44
  • 52. Antithrombotic strategies in acute coronary syndromes and percutaneous coronary interventions Several economic evaluations have found that routine use of Antithrombotic therapy in coronary angioplasty and stentglycoprotein IIb/IIIa drugs after percutaneous coronary placement proceduresinterventions is extremely cost effective for patients at high riskof myocardial infarction or death. In such patients, the number Before procedure x Aspirin 80-325 mg once daily at least 2 hours before procedure.needed to treat to save one life or prevent one acute myocardial Ticlopidine 250 mg twice daily or clopidogrel 75 mg once dailyinfarction at 30 days may be as low as 30, or about £5000 per started 24 hours before procedure if aspirin contraindicatedoutcome. x Glycoprotein IIb/IIIa receptor antagonists should be considered in high risk patients with acute coronary syndromesAnticoagulant treatment During and after procedureMost patients with acute coronary syndromes undergoing x Heparin* bolus to achieve activated clotting time (ACT) ∼300angioplasty would have been pretreated with heparin. Several seconds. Give 70-150 U/kg or 7000 U for women and 8000 U forsmall studies have shown that patients with unstable angina men. If ACT not achieved give extra bolus of 2500-5000 U. Reducewho receive heparin before intervention have a higher rate of heparin bolus to achieve ACT ∼200 seconds if glycoprotein IIb/IIIa receptor agonist is to be usedsuccess and lower postprocedure reocclusion rates. x In high risk patients, abciximab as bolus and infusion should be Increasing numbers of patients with unstable angina are now given at least 10 minutes before angioplasty and stent placementbeing treated with low molecular weight heparin. However, such and continued for 12 hours after proceduredrugs tend to have a longer half life than unfractionated heparin After procedureand their effects are not completely reversed by protamine x Start clopidogrel 300 mg orally, followed by 75 mg daily for 4 weekssulphate if necessary. Low molecular weight heparins can be x Remove femoral sheath as soon as ACT falls below 150-180safely substituted for unfractionated heparin as a procedural secondsanticoagulant during percutaneous coronary intervention. x Heparin infusion is not routinely necessary after uncomplicated angioplasty During percutaneous coronary interventions, heparin Heparin infusion after a procedure is indicated ifshould be given to avoid postprocedure complications. The x Femoral sheath to be retained—Heparin infusiondose of unfractionated heparin given should be sufficient to 1000-1200 U/hour until 4 hours before sheath is to be removed.increase the activated clotting time (ACT) to 250-300 seconds Check ACT and remove sheath when ACT < 150 secondsas measured with the HemoTec device (or 300-350 seconds x Patients at high risk for in stent thrombosiswith the Hemochron device). Unfractionated heparin dose may x Patients with other indications for anticoagulation, such as atrialneed to be adjusted for weight or sex. If glycoprotein IIb/IIIa fibrillation or mechanical heart valvesreceptor agonists are being used, then unfractionated heparin *Details given for unfractionated heparin, but low molecular weight heparin canboluses should be reduced to achieve a target ACT of about be used as an alternative in percutaneous coronary interventions200 seconds. Although the traditional means of assessingheparin anticoagulation has been with the APTT, the ACT is an Further readingassay of whole blood clotting time that can be performedrapidly at the bedside and catheterisation laboratory. x The Task Force on the management of acute coronary syndromes of the European Society of Cardiology. Management of acute Routine use of unfractionated heparin (either as infusion or coronary syndromes in patients presenting without persistent STsubcutaneously) after angioplasty is probably not indicated for segment elevation. Eur Heart J 2002;23:1809-40uncomplicated procedures. Studies have shown excess bleeding x Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD,complications with heparin treatment without a reduction in Hochman JS, et al. ACC/AHA 2002 guideline update for thethe number of cardiac ischaemic events. Patients who do not management of patients with unstable angina and non-ST segmentreceive heparin treatment after coronary interventions can have elevation myocardial infarction. J Am Coll Cardiol 2002;40:1366-74their femoral sheaths removed earlier, resulting in shorter x Fox KA, Poole-Wilson PA, Henderson RA, Clayton TC, Chamberlin DA, Shaw TR, et al for the Randomized Intervention Trial ofhospital stays, fewer bleeding complications, at the risk of a Unstable Angina (RITA) Investigators. Interventional versussimilar incidence of cardiac end points including reocclusion. conservative treatment for patients with unstable angina or With the advent of glycoprotein IIb/IIIa receptor non-ST-elevation myocardial infarction: the British Heartantagonists, heparin infusions postprocedure should not be Foundation RITA3 randomised trial. Lancet 2002;360:743-51necessary routinely. Femoral sheaths should be removed once x Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK, et althe ACT has fallen to less than 150-180 seconds. Adjunctive for the Stent Anticoagulation Restenosis Study Investigators. A clinical trial comparing three antithrombotic-drug regimens aftertreatment with low molecular weight heparin or unfractionated coronary-artery stenting. N Engl J Med 1998;339:1665-71heparin may still be warranted after angioplasty and stent x Roffi M, Moliterno DJ, Meier B, Powers ER, Grines CL, DiBattisteimplantation in patients at high risk of in stent thrombosis. PM, et al. Impact of different platelet glycoprotein IIb/IIIa receptor Full anticoagulation with heparin followed by warfarin in inhibitors among diabetic patients undergoing percutaneouspatients undergoing angioplasty with stenting is no better at coronary intervention: do tirofiban and Reopro give similar efficacyreducing the number of adverse effects than combination outcomes trial (TARGET) 1 year follow up? Circulationtreatment with aspirin and ticlopidine, but at increased risk of 2002;105:2730-6bleeding with warfarin. Use of hirudin, the direct thrombininhibitor, was associated with a reduction of early cardiac events The meta-analysis of trials comparing thrombolytic treatment withand restenosis at 96 hours but was no different from the primary angioplasty is adapted from Weaver WD, et al, JAMAheparin treatment arm at seven months. 1997;278:2093. The figure showing incidence of primary end point in patients treated with aspirin alone, aspirin and warfarin, or aspirin and ticlopidine after coronary artery stenting is adapted from Leon MB, et al, N Engl J Med 1998;339:1665-71. The figure showing the results from the PRISM-PLUS study is adapted from PRISM-PLUS Study Investigators. N Engl J Med 1998;338:1488-97. The figure showing the time course of cardiac biochemical markers is adapted from Wu AH, et al, Clin Chem 1999;45:1104-21. The figures of death or myocardial infarcton in patients with elevated troponins or negative troponin result, and the strategy for acute coronary syndromes are adapted from Bertrand ME, et al, Eur Heart J 2002;23:1809-40. 45
  • 53. 13 Antithrombotic therapy in chronic heart failure insinus rhythmGregory Y H Lip, Bernard S P ChinChronic heart failure is one of the few remaining areas incardiovascular medicine where the use of antithrombotic 60 Two year age adjusted incidence of stroke per 1000 patients Risk factor Absenttherapy remains controversial. This is largely because of Presentconflicting outcomes from existing studies, a lack of 50appropriately conducted randomised clinical trials, anddifficulty in defining the syndrome of heart failure and its 40thromboembolic complications. 30Stroke and systemic embolism in 20heart failureLeft ventricular dysfunction increases the risk of thrombosis 10and systemic embolism, and these thromboembolic events addto the high morbidity associated with this condition. In addition, 0 Hypertension Coronary Congestive Atrialischaemic and thromboembolic events—particularly stroke, heart disease heart failure fibrillationmyocardial ischaemia, and myocardial infarction—contribute to Risk ratio 3.4 2.4 4.3 4.8the high hospital admission rates in these patients. The incidence of thromboembolism and the factors Two year age adjusted incidence of stroke for every thousand patients in the Framingham studyassociated with a high thromboembolic risk have beenaddressed in many studies, but the reported incidence of theseevents seems to vary between studies, depending on studymethodology and populations. Retrospective analyses of recentheart failure trials have estimated this risk to be between 1.3%and 4.6% depending on the severity of heart failure. Forexample, mild to moderate chronic heart failure seems to beassociated with an annual stroke risk of about 1.5% (V-HeFT The risk of recurrent strokes in heartand SOLVD studies), compared with an annual stroke risk in failure patients is higher than with initial events. In heart failure patients, secondthe general population of less than 0.5%. The annual risk of and recurrent stroke rates may be as highstroke increases to almost 5% in severe chronic heart failure. as 9% every yearEvidence from the Framingham study shows that chronic heartfailure is a major risk factor for stroke, second only to atrialfibrillation. Long term oral anticoagulation is beneficial in certaingroups of patients with chronic heart failure, but the role ofanticoagulation for patients with chronic heart failure ingeneral is less clear. For example, oral anticoagulation isextremely effective in reducing stroke risk and other embolicevents in patients with atrial fibrillation and chronic heartfailure. Indeed, there is a wide variation in the use of oralanticoagulants in patients with chronic heart failure. Although oral anticoagulation reduces thromboembolicevents in various cardiovascular diseases, the potential risks ofbleeding must also be considered. Importantly, the control ofRates of stroke, pulmonary embolism, myocardial infarction, and total mortality in recent heart failure trials Mean (SD) annual risk of events (%) Mean Prevalence of ejection Follow up atrial Pulmonary MyocardialStudy (NYHA) NYHA fraction Mean age (years) fibrillation (%) Stroke embolism infarction DeathSOLVD I-III 0.25 60 3.3 6 3.8 (1.3) 5.3 (1.6) 9.6 (2.9) 23.7 (7.2)V-HeFT-I II-III 0.30 58 2.3 15 4.1 (1.8) 5.6 (2.5) — 43.0 (18.7)V-HeFT-II II-III 0.29 61 2.6 15 4.7 (1.8) 5.7 (2.2) 5.2 (2.0) 34.7 (13.3)CONSENSUS III-IV — 71 0.5 50 2.3 (4.6) — — 46.6 (44)PROMISE III-IV 0.21 64 0.5 — 2.0 (3.5) — — 27.1 (54)SAVE — 0.30 59 3.5 — 4.6 (1.5) — 13.6 (3.9) 18.9 (5.4)46
  • 54. Antithrombotic therapy in chronic heart failure in sinus rhythmanticoagulation is reported to be more difficult, and bleeding Stroke risk and heart failurecomplications commoner, in chronic heart failure because ofhepatic congestion and potential drug interactions that may Annual riskoccur. Stroke in general population aged 50-75 years 0.5% Studies have reported stroke incidences in heart failure of Stroke in mild chronic heart failure—NYHA II-III 1.3-1.8%up to 11%. However, many of these trials were small, Stroke in severe chronic heart failure—NYHA III-IV 3.5-4.6%non-randomised and biased towards more severe disease. Recurrent stroke rates in chronic heart failure 9%Importantly, atrial fibrillation was common among participants, Stroke in atrial fibrillation 4.5%many of whom did not receive warfarin during the period of Stroke in atrial fibrillation and chronic heart failure 8-12%follow up. Nevertheless, given that the risk of stroke in thegeneral population aged 50-75 years is less than 0.5% a year, anestimated stroke incidence of 2% in patients with chronic heartfailure represents a fourfold increased risk. With increasing age,the absolute risk of stroke rises, while its risk relative to thegeneral population falls. The commonest vascular occlusive event in heart failure isnot stroke but myocardial infarction. Sudden cardiac death iscommon in heart failure and has been attributed to fatalarrhythmia. However, pathological studies of sudden cardiacdeaths have detected fresh coronary thrombi in many cases,indicating that acute coronary occlusion may have been theprimary event in the death. Many heart failure patients withmyocardial infarction also die before reaching hospital. Hence,myocardial infarction and acute coronary occlusion may bemore common in heart failure than estimated. Sedentary patients with chronic heart failure patients arealso at increased risk of developing venous thromboembolism,particularly in the legs. Pulmonary embolism can originatefrom deep vein thrombosis of the legs or, rarely, from a Apical thrombus in patient with poor left ventricularthrombus in the right ventricle. functionLeft ventricular thrombus formationChronic heart failure patients in sinus rhythm are at high risk ofventricular thrombus formation because they fulfil Virchow’striad for thrombogenesis. These patients have:x “Abnormal blood flow “ with stasis, with low cardiac output,dilated cardiac chambers, and poor contractility of the heart;x “Abnormal vessel walls”, with endothelial damage or Factors predisposing to prothrombotic statedysfunction or both; in heart failurex “Abnormal blood constituents”, with abnormalities of Endothelial dysfunctionhaemostasis, platelets, and coagulation. x Impaired nitric oxide release Autopsy and surgical studies have detected ventricular x Reduced anticoagulant statusmural thrombi in 25-50% of heart failure patients. Such mural Altered flow characteristicthrombi have been associated with increased mortality. In x Left ventricular dilatationchronic heart failure with left ventricular dysfunction, abnormal x Abnormal left ventricular wall motionwall motion leads to alterations in regional blood flow and x Left ventricular aneurysminflow velocity, whereas impaired ventricular contractility results x Reduced pump actionin further intracavitary blood stasis. Evidence exists for local Altered coagulationplatelet activation and cytokine recruitment, such as tumour x Increased platelet activation and aggregationnecrosis factor, which can trigger the clotting cascade. This is x Increased clotting x Reduced fibrinolytic activityparticularly so after acute myocardial infarction, when highlevels of catecholamines are circulating freely. Markers of Neurohormonal and inflammatory activation x Increased catecholaminesendothelial injury and dysfunction are also elevated in heart x Increased inflammatory cytokinesfailure, although in many cases these may be caused byunderlying atherosclerosis. Endothelial damage promotesmonocyte and platelet adhesion to the endothelium,predisposing to thrombosis in situ. The interplay of altered localflow characteristics, heightened clotting factors, and endothelialcell dysfunction gives rise to left ventricular thrombusformation. Certain conditions are more likely to predispose to leftventricular thrombus formation. Patients with a dyskinetic leftventricular segment or left ventricular aneurysm and those whohave had acute and extensive myocardial infarction involvingthe anterior wall are at highest risk. Left ventricular dilatationand severity of left ventricular dysfunction (measured by 47
  • 55. ABC of Antithrombotic Therapyejection fraction) also correlate well with risk of thrombusformation. However, mitral regurgitation may have someprotective effect.Risk factors for systemic embolisation Factors predisposing to left ventricularGiven the high prevalence of left ventricular thrombus thrombus formation and embolisationformation in patients with left ventricular aneurysm and heart Left ventricular thrombus formationfailure, it is perhaps surprising that the rate of stroke in patients x After acute extensive myocardial infarctionwith documented left ventricular thrombi is low. This could be x Acute anterior myocardial infarctionbecause of the difficulty in determining the presence of x Left ventricular aneurysmthrombus clinically. The best method is by cross sectional x Left ventricular dilatationechocardiography, but this can only detect thrombi greater than Systemic embolisation of left ventricular thrombi0.5 cm in diameter. Microthrombi that forms early in x New or acute thrombus (within two weeks of formation)myocardial infarction and which pose a serious threat of x Protruding segmentembolism would not therefore be detected. Conversely, an x Normal adjacent wall functionorganised chronic thrombus, which is more easily detectable onechocardiography is less likely to embolise. A newly formed left ventricular thrombus is likely toembolise as are thrombi that are mobile, protruding, orpedunculated with a narrow stalk. Left ventricular thrombipresent for more than three months would have undergonefibrous organisation and endothelialisation and so are morestable. The only parameters shown by studies to achieve statisticalsignificance as a predictor of thromboembolic events is peakoxygen uptake during symptom limited maximal exercisetesting and the severity of heart failure (measured by left Identifying risk factors that predispose to systemic embolisation of left ventricularventricular ejection fraction). The left ventricular ejection thrombi is important because it allowsfraction is a powerful predictor of stroke in patients who have patients at highest risk only to be treated.had a myocardial infarction. Patients with left ventricular Currently, the identification of risk factorsejection fraction less than 28% at particularly high risk. has been inferred from observationalFurthermore, for every absolute decrease of 5% in left data of heart failure trials and smallerventricular ejection fraction, the risk of stroke increases by 18%. non-randomised studies Patients with idiopathic dilated cardiomyopathy tend to havea higher rate of systemic thromboembolism than patients withischaemic cardiomyocapthy. Only women with periparturmcardiomyopathy have higher risks of thromboembolism thanpatients with idiopathic dilated cardiomyopathy. Atrialfibrillation, age, and previous thromboembolic events areindependent risk factors for stroke but confer further risks topatients with heart failure. Atrial fibrillation is associated with astroke risk of about 5% every year. Major risk factors for cardioembolic strokeAntithrombotic treatment in chronic heart failureWarfarin x Atrial fibrillationThe need for oral anticoagulation in chronic heart failure has x Mitral stenosisbeen inferred from mainly observational and retrospective x Prosthetic mechanical valves x Presence of left ventricular mural thrombusstudies of mortality from heart failure. In the PROMISE study, x Previous thromboembolism (stroke, pulmonarylower incidences of stroke were reported with anticoagulation embolism, deep vein thrombosis)(1.9% v 2.5%). In a follow up study of patients with idiopathic x Poor left ventricular ejection fraction ( < 28%)dilated cardiomyopathy, 18% of patients not taking warfarin x Acute left ventricular wall aneurysmhad a stroke, whereas none occurred among the patients x Recent myocardial infarctionreceiving warfarin over 11 years of follow up. Several studies of x Idiopathic dilated cardiomyopathy x Infective endocarditispatients who had myocardial infarction showed that long term x Atrial myxomawarfarin treatment to reduce rates of death, recurrent x Reduced peak oxygen uptake at maximalmyocardial infarction, and stroke was effective. exercise Other studies have also shown that warfarin reducesmortality from sudden coronary death and recurrentmyocardial infarction. Both the CONSENSUS and SOLVDstudies showed that patients receiving warfarin had a lowermortality than those patients receiving antiplatelet treatment orthose without antithrombotic therapy. In a retrospective surveyof the SOLVD participants, anticoagulant monotherapyreduced the risk of sudden cardiac death by 32%. Amongparticipants with non-ischaemic heart failure, this risk fell by48
  • 56. Antithrombotic therapy in chronic heart failure in sinus rhythmStudies comparing the effect of antithrombotic therapy in heart failure Treatment (anticoagulation v Stroke incidence every Thromboembolic incidenceStudy antiplatelet agents v placebo) 100 patient years every 100 patient years MortalitySOLVD Aspirin v placebo No effect No effect Lower with aspirin but benefit of enalapril bluntedSOLVD Warfarin v placebo No effect No effect Lower with warfarinV-HeFT-I Aspirin v warfarin v placebo 0.5 v 1.9 v 2.0 0.5 v 2.9 v 2.7CONSENSUS Warfarin v placebo ND ND Lower with warfarinPROMISE Warfarin v placebo 1.9 v 2.9 NDFuster et al Anticoagulants v placebo ND None v 3.5 No effectKatz et al Aspirin v warfarin v placebo 1.1 v 7.5 v 0.8 ND Lower with aspirin. No effect with warfarinND = no data providedFull references in Lip GYH, Gibbs CR Quart J Med Cochrane Reviews (see Further reading)nearly 70%. The benefit of warfarin use is not uniform, as forexample, the V-HeFT-1 Trial did not show any substantialbenefit with warfarin use. Data from the SOLVD and V-HeFTstudies were observational, without randomisation or controlwith respect to oral anticoagulation. In addition, interpretationof these data is potentially confounded—patients who wereconsidered to be at highest risk of thromboembolism may have Indications for warfarin treatment inbeen treated with warfarin, and this would substantially reduce chronic heart failuretheir long term risk of thromboembolic events. Strongly recommended Balanced against its potential benefits, warfarin increases the x Atrial fibrillationrisk of intracranial haemorrhage by 0.3%. This complication x Previous ischaemic strokesincreases with higher therapeutic targets (for example, INR x New left ventricular mural thrombus formation3.0-4.5). In heart failure patients with sinus rhythm, assuming a x Unstable, mobile left ventricular thrombus2% risk of ischaemic stroke, warfarin use must reduce the risk Individual consideration to be givenby at least 20% to outweigh the threat of intracranial x Idopathic dilated cardiomyopathieshaemorrhages. Recurrent stroke rates in heart failure patients x Poor left ventricular ejection fraction ( < 28%) x Acute left ventricular aneurysmare also high (about 9% a year), and a reduction of only 10%would outweigh the risk of bleeding complications with Not recommended x Sinus rhythm in absence of other risk factorswarfarin. Secondary prevention of ischaemic strokes by warfarin x Chronic left ventricular aneurysmin patients with heart failure should be considered. x Presence of chronic organised left ventricular Similarly, not all patients with documented left ventricular mural thrombusthrombi carry a high risk of embolisation. “High risk” patientssuch as those who have had an extensive acute anteriormyocardial infarction or who show a new mural thrombus oncross sectional echocardiography should be considered foranticoagulation. Long term therapy (more than three months)is generally not recommended because of low embolisationrates from chronic left ventricular thrombi (unless the mass ismobile and pedunculated or other high risk factors exist). Despite the limited evidence, some authorities recommendanticoagulation for patients with idiopathic dilatedcardiomyopathy, whereas others using the postmyocardialinfarction studies and data from SOLVD and CONSENSUS,advocate the use of warfarin in patients with ischaemiccardiomyopathy. A recent Cochrane systematic review does not Aspirin has been shown to reduce therecommend warfarin routinely for all heart failure patients in incidence of myocardial infarction andsinus rhythm because of conflicting conclusions from death in men and women over 50 years,retrospective analyses and case series. More evidence is needed patients with unstable angina andfrom randomised trials, such as the WATCH study (see later). myocardial infarction, and in patients with atherosclerotic cerebrovascularAspirin disease, whereas aspirin improves theUse of aspirin in heart failure is controversial, but it is patency rates of saphenous-veincommonly used in patients with chronic heart failure who are aortocoronary bypass graftsin sinus rhythm, because of its general efficacy as anantithrombotic agent in vascular disease. In addition, aspirin ingeneral reduces the incidence of stroke and death in patientswith recurrent episodes of cerebral ischaemia. Furthermore,aspirin has been shown to be moderately effective in reducingvenous thrombosis and thromboembolism in patientsundergoing hip surgery. 49
  • 57. ABC of Antithrombotic Therapy Most trials of angiotensin converting enzyme (ACE)inhibitors, bar the SAVE study, have shown possible attenuationof their protective effects in heart failure after myocardialinfarction when combined with aspirin. Several reasons havebeen put forward, not least because aspirin and ACE inhibitorsexert effects on the same prostaglandin pathways. Concomitantaspirin can also limit sodium excretion and impair renalfunction in patients with chronic heart failure. The justificationfor using aspirin in chronic heart failure is strongest where anischaemic aetiology is suspected. Indeed, aspirin reduces rates Further readingof death, recurrent myocardial infarction, and stroke when usedin or shortly after acute myocardial infarction. x Al-Khadra AS, Salem DN, Rand WM, Udelson JE, Smith JJ, Konstam MA. Warfarin anticoagulation and survival: a cohort Although observational trials have shown a beneficial analysis from the Studies of Left Ventricular Dysfunction. J Am Collreduction of stroke with aspirin in patients with chronic heart Cardiol 1998; 31:749-53failure, in general this reduction is less than that seen with x Cleland JG. Anticoagulant and antiplatelet therapy in heart failure.warfarin. Two studies have shown aspirin to be more beneficial Curr Opin Cardiol 1997 12:276-87than warfarin in preventing strokes in heart failure. Both studies x Dries DL, Rosenberg YD, Waclawiw MA, Domanski MJ. Ejectionhowever were not randomised and it is possible that fraction and risk of thromboembolic events in patients with systolicparticipants in the warfarin arm were more seriously ill or at dysfunction and sinus rhythm: evidence for gender differences in the studies of left ventricular dysfunction trials. J Am Coll Cardiolhigher risk of systemic embolism (for example, associated atrial 1997; 29:1074-80fibrillation). Aspirin had no effect on mortality or risk of x Dunkman WB, Johnson GR, Carson PE, Bhat G, Farrell L, Cohn JN,systemic embolism in patients with documented left ventriuclar for the V-HeFT VA Cooperative Studies Group. Incidence ofthrombi. thromboembolic events in congestive heart failure. Circulation A recent Cochrane systematic review concluded that there 1993;87:VI194-101was conflicting evidence to support the use of antiplatelet drugs x Lip GYH, Gibbs CR. Does heart failure confer a hypercoagulable state? Virchow’s triad revisited. J Am Coll Cardiol 1999;5:1424-6to reduce the incidence of thromboembolism in patients with x Lip GYH, Gibbs CR. Anticoagulation for heart failure in sinuschronic heart failure who are in sinus rhythm. There was also rhythm: a systematic Cochrane review. Quart J Med 2002;95:451-9no direct evidence to indicate superior effects from oral x Lip GYH, Gibbs CR. Antiplatelet agents versus control oranticoagulation, when compared with aspirin, in patients with anticoagulation for heart failure in sinus rhythm: a Cochranechronic heart failure. Pending further evidence, aspirin cannot systematic review. Quart J Med 2002;95:461-8be recommended routinely for all patients with chronic heart x Lip GYH. Intracardiac thrombus formation in cardiac impairment:failure (in sinus rhythm or atrial fibrillation) with or without left the role of anticoagulant therapy. Postgrad Med J 1996;72:731-8 x Loh E, St. John Sutton M, Wun CC, et al. Ventricular dysfunctionventricular thrombi for the prevention of stroke and and the risk of stroke after myocardial infarction. New Engl J Medthromboembolism. Current guidelines should be tailored to 1997;336:251-257individual risks and benefits. x Uretsky BF, Thygesen K, Armstrong PW, Cleland JG, Horowitz JD, Other antiplatelet drugs have not been represented in Massie BM, et al. Acute coronary findings at autopsy in heart failureprevious trials. Clopidogrel, which inhibits platelet function by patients with sudden death: results from the assessment ofinhibiting adenosine-induced platelet aggregation does not treatment with lisinopril and survival (ATLAS) trial. Circulation 2000;102:611-6inhibit cyclo-oxygenase. Thus, it should not attenuate thebeneficial actions of ACE inhibitors in the manner of aspirin.The large, ongoing randomised controlled WATCH study usingclopidogrel, aspirin, and warfarin seeks to identify the optimalantithrombotic agent with the best risk:benefit ratio in theprevention of stroke and thromboembolism in heart failure.Acute heart failurePatients with acute and decompensated heart failure not onlyhave high levels of circulating catecholamines that may furtheractivate the clotting cascade, but also tend to be less ambulatory We thank Professor JG Cleland (University of Hull, United Kingdom),and can be confined to bed or chair. The risk of venous for helpful comments during the preparation of this reviewthromboembolism is therefore increased and in fact, The figure showing the two year adjusted incidence of stroke in thethromboembolic complications add to the burden of prolonged Framingham study is adapted from Wolfe CD et al. Stroke 1991;22:983hospitalisation and mortality in these patients. Givingsubcutaneous injections of unfractionated or low molecularweight heparin as prophylaxis can reduce the risk of venousthromboembolism, but trial evidence in chronic heart failure islacking. No recent clinical trials show that warfarin or aspirinare effective in the primary prevention of venousthromboembolism or systemic complications in patients withacute heart failure who are in sinus rhythm.50
  • 58. 14 Antithrombotic therapy in special circumstances.I—pregnancy and cancerBernd Jilma, Sridhar Kamath, Gregory Y H LipAntithrombotic therapy duringpregnancy Disorders during pregnancy for which antithrombotic therapy is commonly consideredPregnancy predisposes to venous thromboembolism for several x Prophylaxis and treatment of venous thromboembolismreasons. These include a change in the balance between x Prophylaxis in patients with valvar disease (for example, mitralprocoagulant and anticoagulant factors in the blood. Any stenosis)conditions that predispose a woman to thromboembolism x Prophylaxis in patients with mechanical prosthetic valveswhen she is not pregnant will also predispose her to x Antiphospholipid syndrome x Prophylaxis against pregnancy induced hypertension andthromboembolism when she is pregnant. intrauterine growth retardation Generally, antithrombotic therapy started in a non-pregnantpatient for a particular disorder needs to be continued duringthe pregnancy and in the puerperium. The use and type ofantithrombotic therapy depends on the risk:benefit ratio, taking Potential risks of antithrombotic therapy during pregnancyinto consideration the potential harm to the mother and thefetus. Maternal disadvantages and risks The potential risks of antithrombotic therapy during Unfractionated heparin x Haemorrhage (uteroplacental, especially during labour)pregnancy can be divided into maternal and fetal risks, and x Heparin induced thrombocytopeniainclude teratogenicity and bleeding. Unfractionated heparin x Osteoporosisand low molecular weight heparins do not cross the placenta x Regular monitoringand are probably safe for the fetus, although bleeding at the Low molecular weight heparinuteroplacental junction is possible. Nevertheless, data are sparse x Bleeding risk, especially during labourfor low molecular weight heparin, with no reliable comparativetrials or convincing dose assessment. Warfarin x Bleeding In contrast to heparin, coumarin derivatives cross the x Regular monitoringplacenta and can cause both bleeding in the fetus andteratogenicity. Coumarin derivatives can cause an embryopathy Risk to the fetus or child(which consists of nasal hypoplasia or stippled epiphyses or Heparinboth) after in utero exposure during the first trimester of x Seems to be safepregnancy. In addition, central nervous system abnormalities Low molecular weight heparincan occur after exposure to such drugs during any trimester. x Seems to be safeThe main risk of embryopathy occurs if coumarin derivatives Warfarinare taken between six weeks and 12 weeks of gestation. At the x Embryopathy, especially if mother is exposed between 6 and 12time of delivery, the anticoagulant effect in the fetus can lead to weeksbleeding in the neonate. x Central nervous system malformations during any time of the Heparin and low molecular weight heparins are not gestationsecreted into breast milk and can probably be given safely to Low dose aspirinnursing mothers. High dose aspirin should be avoided, as it x Potential risk of birth defects and bleeding risk in the first trimestercould (theoretically) impair platelet function and produce x Safe in second and third trimesterhypoprothrombinaemia in the infant, if neonatal vitamin Kstores are low, as well as cause Reye’s syndrome. Warfarin doesnot induce an anticoagulant effect in an infant who is breast fedand therefore could be used safely in the postpartum period; Suspected deep vein thrombosisthus, patients who are receiving long term heparin treatmentcould be switched over to warfarin post partum if and whenconsidered appropriate. With regard to other agents, Compression ultrasonographyphenindione should be avoided, and acenocoumarol requiresprophylactic vitamin K for the infant. Positive Negative*Venous thrombosis and pulmonary embolism Treat Serial compression ultrasonography on days 3 and 7Antithrombotic prophylaxis for the prevention of venousthromboembolic disorders in pregnancy is indicated when apatient has experienced a previous thromboembolic episode or Positive Negativeis considered to be at particularly high risk because of a * Consider contrast leg venography,predisposing condition. computed tomography scan, or Treat Follow patient Unfractionated heparin 5000 IU twice daily is generally magnetic resonance imaging if clinically isolated iliac vein thrombosis is suspectedadequate in non-pregnant women. Heparin requirements canbe highly variable in pregnancy. A once daily dose of low Diagnosis of suspected deep vein thrombosis in pregnancy 51
  • 59. ABC of Antithrombotic Therapymolecular weight heparin is a useful alternative tounfractionated heparin and has been shown to be safe andeffective in pregnancy. Patients who develop thromboembolism during pregnancycould be treated initially with at least five days of intravenous Poor outcome Favourable outcome 100 Percentageheparin treatment, followed by a twice daily subcutaneous doseof unfractionated heparin. The dose is adjusted by maintaining 80the activated partial thromboplastin time (APTT) within thetherapeutic levels. Heparin could temporarily be stopped 60immediately before delivery and then resumed in thepostpartum period to minimise the risk of haemorrhage during 40labour. The duration of antithrombotic therapy in thepostpartum period should be maintained for a minimum of 20three months, possibly up to six months. 0 ≤5 >5 ≤5 >5 First pregnancy Subsequent pregnancyPatients with prosthetic heart valves (n=52) (n=19)The precise safety of warfarin during pregnancy continues to be Warfarin daily dose (mg)debated, but it is probably appropriate to withhold warfarin Distribution of warfarin dose and poor outcome according to order ofbetween six and 12 weeks of gestation and for the latter half of pregnancy. The risk of pregnancy complication in patients treated withthe third trimester, because of the risk of causing embryopathy warfarin is higher when the mean daily dose exceeds 5 mg (P<0.001)and postpartum haemorrhage respectively. Based on this, therecommended options for use of antithrombotic therapy inpatients with a mechanical heart valve during pregnancyinclude:x Adjusted dose of unfractionated heparin twice daily tomaintain the APTT within therapeutic range, or low molecularweight heparin throughout the pregnancyx Warfarin throughout the pregnancy, except for the first Antiphospholipid syndrome in pregnancy: a randomisedtrimester (either for the entire trimester or between six and controlled trial of aspirin v aspirin plus heparin12 weeks) and for the latter half of the third trimester (whenwarfarin should be replaced by unfractionated or low molecular Low dose aspirin Low dose aspirin plusweight heparin). (n=47) heparin (n=51) The risks and benefits of this approach should be explained Live birth rate (%) 72 78to patients, who should be allowed to make an informed choice. Mean (SD) birth weight (g): 3221 (781) 3127 (657)There are real concerns over the incidence of abortions and Range 890-5300 718-4319fetal malformations in patients treated with warfarin in the first Gestation attrimester. Concerns over long term heparin treatment in delivery (%):pregnant women include heparin induced thrombocytopenia < 30 weeks 1 1and osteoporosis. 30-36 weeks 3 1 Prepregnancy counselling is vital for patients who are > 36 weeks 30 38receiving long term warfarin treatment, and a cardiologist and Embryo loss (%) 9 3obstetrician should explain the risks to patients. Patients who Fetal loss (%) 4 8are established on long term warfarin treatment and plan tobecome pregnant could then take twice daily heparin beforegetting pregnant. Alternatively, and assuming that the risk ofwarfarin to the fetus in the first six weeks of gestation is notworrisome, they could continue taking warfarin and havefrequent checks to see if they are pregnant. If they are, theyshould immediately switch over to heparin. Again, close liaisonbetween obstetrician, midwife, general practitioner, cardiologist,and neonatologist is vital. Antithrombotic therapy in antiphospholipid syndrome Scenario ManagementAntiphospholipid syndrome History of pregnancy loss Aspirin plus heparin (APTT inAntiphospholipid syndrome predisposes a pregnant woman to therapeutic range)thromboembolism and pregnancy losses. Abortion in a History of thromboembolism but no Heparin alone (APTT inprevious pregnancy predisposes to further abortions or pregnancy loss therapeutic range)stillbirths in subsequent pregnancies. A combination of aspirin No history of adverse events Heparin alone 5000 IU twice daily; close observationand heparin to prolong the APTT to within the therapeuticrange (APTT ratio 2.0-3.0) thoughout the pregnancy wouldsubstantially decrease pregnancy losses and othercomplications. However, one recent trial suggested that lowdose aspirin (75 mg) may suffice (see box), but small numbersmerit some caution pending further data.52
  • 60. Antithrombotic therapy in special circumstances. I—pregnancy and cancerPre-eclampsia and intrauterine growth retardation Study Aspirin Placebo Peto odds ratio Weight Peto odds ratioOn the basis of small, retrospective studies, low dose aspirin (95% CI fixed) (%) (95% CI fixed)( < 150 mg daily) was thought to be useful as prophylaxis in McParland, 1990 1/48 10/52 18.5 0.18 (0.05 to 0.61)patients with a history of pre-eclampsia and intrauterine growth Morris, 1996 4/52 7/50 18.6 0.52 (0.15 to 1.82)retardation in preventing similar adverse events during the Bower, 1996 9/31 12/29 26.0 0.59 (0.20 to 1.68)current pregnancy. However, a large (nearly 10 000 women) Zimmerman, 1997 4/13 2/13 9.0 2.30 (0.38 to 13.77)randomised controlled trial (CLASP) of aspirin 60 mg Harrington, 2000 7/107 9/103 27.9 0.73 (0.27 to 2.03)compared with placebo, reported that, although aspirin was Total (95% CI) 25/251 40/247 100.0 0.55 (0.32 to 0.95)associated with a 12% reduction in the incidence of Test for hetergeneity χ2=5.97, df=4, P=0.2pre-eclampsia, this was not significant nor was there any Test for overall effect z=-2.16, P=0.03substantial impact on intrauterine growth retardation, stillbirth,or neonatal death. Thus, routine use of low dose aspirin is not Effect of aspirin in preventing pre-eclampsia: meta-analysis of randomisedrecommended. However, some experts recommend its use in trials showing numbers of cases of pre-eclampsiapatients who are liable to develop early onset (before 32 weeks)pre-eclampsia or in high risk groups for pre-eclampsia, such aswomen with type 1 diabetes, chronic hypertension, multiple Virchow’s triad* in cancerpregnancies, or previous pre-eclampsia. However, the safety of Abnormal blood flowhigher doses of aspirin and aspirin ingestion during the first x Increased viscosity and turbulencetrimester remains uncertain. x Increased stasis from immobility Abnormal blood constituents x Increased platelet activation and aggregationAntithrombotic therapy in cancer x Increased procoagulant factors x Decreased anticoagulant and fibrinolytic factorsVenous thromboembolism is a frequent complication in Abnormal blood vessel wallpatients with cancer, and it is a common clinical problem. It can x Damaged or dysfunctional endotheliumeven precede the diagnosis of cancer by months or years. x Loss of anticoagulant naturePatients with cancer are nearly twice as likely to die from x Possibly angiogenesispulmonary embolism in hospital as those with benign disease, *For thrombogenesis (thrombus formation) there needs toand about 60% of these deaths occur prematurely. be a triad of abnormalities (abnormal blood flow, abnormal blood constituents, and abnormal blood vessel wall)Thromboembolism seems to be particularly predominant inpatients with mucinous carcinoma of the pancreas, lung, orgastrointestinal tract. This may be because cancer can beassociated with raised levels of procoagulants such as Risk factors for thromboembolism infibrinogen, von Willebrand factor, and tissue factor, as well as patients with cancerexcess platelet activity. Raised levels of plasminogen activator x Prolonged immobility x Surgical proceduresinhibitor are often present, and this will impair fibrinolysis. x Chemotherapy x Indwelling vascularTherapeutic interventions in patients with cancer, such as catheterssurgery, standard chemotherapy, or hormone based treatment(such as oestrogens for prostatic cancer), further increase therisk for thrombosis. One reason for this may be that certaintypes of chemotherapy impair the natural anticoagulant Activationproperties of the endothelium, thus promoting a procoagulantstate. Unfortunately, no standardised protocols exist for the VII Plateletmanagement of patients with cancer and the approaches vary. TF Monocyte Clotting VIIa cascade ProthrombinPrimary prophylaxis ATIII Xa ActivatedIn patients with cancer who are confined to bed or having low Va platelet Thrombinrisk surgical procedures a low dose of unfractionated heparin Fibrinogen Fibrinor low molecular weight heparin is administeredsubcutaneously, along with physical measures, as primary TFPI Plasmin Plasminogenprophylaxis to reduce thromboembolic risk. Patients having VEGF PAImajor abdominal or pelvic surgery for cancer are F1 + 2 uPA Angiostatin TSP1/2 PDGF tPA PF4recommended to receive adjusted dose heparin, low molecularweight heparin, or oral anticoagulants (therapeutic TFinternational normalised ratio (INR) 2.0-3.0) similar to those for Endothelial cellmajor orthopaedic surgery. A low dose warfarin regimen is recommended for patientsreceiving chemotherapy or those with indwelling venouscatheters to decrease the incidence of thromboembolism. For Overview of coagulation, fibrinolysis, and angiogenesis in cancer. The activation of platelets leads to their swelling and the release of angiogenicexample, one double blind randomised study of patients with factors. These affect the vascular endothelia of healing and tumour tissues.metastatic breast cancer receiving chemotherapy showed that The blue arrows facilitate angiogenesis and the red arrows are inhibitorya very low dose (1 mg/day) of warfarin for six weeks followed (ATIII=antithrombin III, F1 + 2=prothrombin fragments, PAI=plasminogenby a dose to maintain the INR at 1.3-1.9 was effective. Low activator inhibitor, PDGF=platelet derived growth factor, PF4=platelet factor 4, TF=tissue factor, TFPI=tissue factor pathway inhibitor, TSP1/dose low molecular weight heparin (for example, daltaparin 2=thrombospondin 1 and 2, tPA=tissue type plasminogen activator,2500 IU/day) is an alternative for patients with indwelling uPA=urokinase type plasminogen activator, VEGF=vascular endothelialvenous catheters. growth factor) 53
  • 61. ABC of Antithrombotic TherapyTreatment and secondary preventionPatients with cancer who develop a thromboembolism should Concerns about antithrombotic therapy inbe treated in a similar manner to patients without cancer. An cancerinitial period of therapeutic unfractionated heparin or low x Recurrent venous thromboembolismmolecular weight heparin which is overlapped and followed by x Increased tendency for minor and major bleeds x Inconsistency in therapeutic anticoagulant levelswarfarin for a minimum of three months is recommended. x Procoagulant effects of chemotherapy (forAnticoagulation should be continued in patients who have example, endothelial cell dysfuntion)active disease or who receive chemotherapy while these riskfactors last. The dose should maintain an INR of between2.0 and 3.0.Risk of haemorrhage Further readingPatients with cancer who are receiving antithrombotic therapy x Barbour LA. Current concepts of anticoagulation therapy inare thought to be at higher risk of bleeding than patients pregnancy. Obstet Gynecol Clin North Am 1997;24:499-521without cancer. This assumption has been disputed, however, in x CLASP (Collaborative Low-dose Aspirin Study in Pregnancy)light of the evidence from some studies in which the risk of Collaborative Group. CLASP: a randomised trial of low-dosemajor bleeding did not differ greatly between the two groups of aspirin for the prevention and treatment of pre-eclampsia amongpatients. For practical purposes, the recommended therapeutic 9364 pregnant women. Lancet 1994;343:619-29 x Cumming AM, Shiach CR. The investigation and management oflevels of anticoagulation remain the same (for example, if inherited thrombophilia. Clin Lab Haem 1999;21:77-92warfarin, then INR 2.0-3.0) as long as patients are educated x Coomarasamy A, Papaioannou S, Gee H, Khan KS. Aspirin for theabout the risks and the anticoagulation levels are strictly prevention of preeclampsia in women with abnormal uterine arterymonitored. The propensity for chemotherapy to be given in Doppler: a meta-analysis. Obstet Gynecol 2001;98:861-6cycles or boluses, followed by periods free of chemotherapy, x Cotrufo M, De Feo M, De Santo LS, Romano G, Della Corte A,seems likely to frustrate attempts to maintain the INR within its Renzilli A, et al. Risk of warfarin during pregnancy with mechanical valve prostheses. Obstet Gynecol 2002;99:35-40target range. x Ginsberg JS, Greer I, Hirsh J. Use of antithrombotic agents during Definite conclusions cannot be drawn about the safety of pregnancy. Chest 2001:119;S122-31antithrombotic therapy in patients with primary or secondary x Farquarson RG, Quenby S, Greaves M. Antiphospholipid syndromebrain malignancy. Some small studies report that it is probably in pregnancy: a randomized, controlled trial of treatment. Obstetsafe to give these patients anticoagulants. However, definite Gynecol 2002;100:408-13decisions about anticoagulation in such patients have to be x Letai A, Kuter DJ. Cancer, coagulation, and anticoagulation. Oncologist 1999;4:443-9individualised and carefully considered. Anticoagulation should x Levine M, Hirsh J, Gent M, Arnold A, Warr D, Falanga A, et al.probably be avoided in patients with brain metastasis because of Double-blind randomised trial of a very-low-dose warfarin forthe chances of renal cell carcinoma or melanoma, as these prevention of thromboembolism in stage IV breast cancer. Lancettumours are highly vascular. 1994;343:886-9 x Lip GYH, Chin BSP, Blann AD. Cancer and the prothromboticRecurrent venous thromboembolism state. Lancet Oncol 2002;3:27-34Patients with cancer are at a higher risk than non-cancer x Prandoni P. Antithrombotic strategies in patients with cancer. Thromb Haemost 1997;78:141-4patients of recurrence of thromboembolism despite adequate x Sanson BJ, Lensing AW, Prins MH, Ginsberg JS, Barkagan ZS,anticoagulation. Again, no strict evidence based guidelines exist Lavanne-Pardlonge E, et al. Safety of low-molecular-weight heparinfor the management of these patients. The recommended in pregnancy: a systematic review. Thromb Haemost 1999;81:668-72options include maintenance of a higher level of x Chan W-S, Ginsberg JS. Diagnosis of deep vein thrombosis andanticoagulation (INR 3.0 to 4.5), substitution with adjusted dose pulmonary embolism in pregnancy. Thromb Res 2002;107:85-91heparin or low molecular weight heparin (some evidencesuggests heparin is probably better in this situation), andplacement of inferior venacaval filters with or withoutanticoagulation.The figure showing diagnosis of deep vein thrombosis is adapted fromChan W-S et al, Thromb Res 2002;107:85-91. The table showing the resultsof aspirin v aspirin plus heparin in treating antiphospholipid syndrome inpregnancy is adapted from Farquharson RG et al, Obstet Gynecol2002;100:408-13. The table showing Virchow’s triad in cancer is adaptedfrom Lip GYH et al, Lancet Oncol 2002;3:27-34. The histogram showingdistribution of warfarin dose and poor outcome according to order ofpregnancy is adapted from Cotrufo M et al, Obstet Gynecol 2002;99:35-40.The meta-analysis showing the effect of aspirin in preventingpre-eclampsia is adapted from Coomarasamy A et al, Obstet Gynecol2001;98:861-6. The figure showing the overview of coagulation,fibrinolysis, and angiogenesis in cancer is adapted from Nash G et al,Lancet Oncol 2001;2:608-13.54
  • 62. 15 Antithrombotic therapy in special circumstances.II—children, thrombophilia, and miscellaneousconditionsBernd Jilma, Sridhar Kamath, Gregory Y H LipTreatments for children Indications for antithrombotic therapy in childrenMost of the recommendations on antithrombotic therapy inchildren are based on the extrapolation of results fromrandomised studies of adults or from small cross sectional, andmainly retrospective, clinical studies of children. Although Treatment Prophylaxisantithrombotic therapy in children usually follows the same Definite Definiteindications as in adults, the distribution of diseases requiring • Venous thromboembolism • Prosthetic heart valvesantithrombotic therapy differs in the paediatric population. For • Arterial thromboembolism • Cardiac catheterisation • Complications of each • Central arterial cathetersexample, some predisposing factors for thromboembolism areencountered only in paediatric populations. Most of the Probable Probableindications for antithrombotic therapy in children arise because • Myocardial infarction • Endovascular stentsof an underlying medical disorder or an intervention for the • Stroke • Blalock-Taussig shunts • Atrial fibrillation • Central venous cathetersmanagement of the disorder. Management of antithrombotic • Fontanstherapy in children differs from that in adults because ofongoing changes in physiology that may alter the thromboticprocess and potentially influence the response of the body to Possible indicationsantithrombotic therapy. • Kawasaki disease • Cardiopulmonary bypass • Extracorporeal membrane oxygenationDrug treatments • HaemodialysisAntiplatelet treatment • Continuous venovenous haemoperfusionAspirin, dipyramidole, and indomethacin are probably the mostused antiplatelet treatments among children. Low doses of Indications for antithrombotic therapy in childrenaspirin (antiplatelet doses) usually have minimal side effects inchildren, but in general aspirin should not be prescribed tochildren aged < 16 years unless there are compelling clinicalindications. The particular concerns about Reye’s syndromeusually seem to be related to higher doses of aspirin( > 40 mg/kg).HeparinHeparin is probably the most commonly used antithromboticdrug in children. Varying concentrations of antithrombin in the Adjusting low molecular weight heparin in childrenbody during different developmental stages mean that thetherapeutic concentration of heparin in children has to be Anti-Xa level Hold next Repeat anti-Xa (U/ml) dose? Dose change? measurementmaintained by regular checks of the activated partialthromboplastin time (APTT) or anti-Xa concentrations. The < 0.35 No Increase by 25% 4 hours after next doserecommended therapeutic level of APTT is the one which 0.35-0.49 No Increase by 10% 4 hours after nextcorresponds to a heparin concentration of 0.2-0.4 U/ml or an doseanti-Xa concentration of 0.3-0.7 U/ml. 0.5-1.0 No No Next day, then 1 week In children, the advantages of low molecular weight heparin later, and monthlyover unfractionated heparin are similar to those in adults. In thereafter whileaddition, low molecular weight heparin may be preferred for receiving reviparin-Nachildren with difficult venous access because regular blood treatment (4 hourschecks to monitor the therapeutic levels are not mandatory. The after morning dose)recommended therapeutic dose of a low molecular weight 1.1-1.5 No Decrease by 20% Before next doseheparin is the one that reflects the plasma anti-Xa 1.6-2.0 3 hours Decrease by 30% Before next dose thenconcentrations of 0.5-1.0 U/ml four to six hours after injection. 4 hours after next dose > 2.0 Until Decrease by 40% Before next dose,Oral anticoagulants anti-Xa then every 12 hoursCertain problems are associated with the use of oral 0.5 U/ml until anti-Xa levelanticoagulants in children. Sensitivity to oral anticoagulants < 0.5 U/mlchanges during different phases of life, especially during infancy,because of varying concentrations of vitamin K and vitamin Kdependent proteins in the body. Neonates (during the first month 55
  • 63. ABC of Antithrombotic Therapyof life) are especially sensitive because of their relative deficiencyof vitamin K, and therefore warfarin should be avoided in suchpatients if possible. However, formula fed infants are resistant tooral anticoagulants because of a high concentration of vitamin Kin their diet. In general, young children need more oralanticoagulation for each kilogram of body weight than olderchildren and adults. Poor venous access (for internationalnormalised ratio (INR) checks) and non-compliance are addedproblems of anticoagulation in children. Recommended therapeutic ranges and duration ofanticoagulation for a variety of disorders in children are usuallysimilar to those for adults.Thrombolytic treatment Effect of age on dose of warfarin needed to sustain an internationalThrombolytic treatment is used primarily for maintaining normalised ratio (INR) of 2.0-3.0 in 262 children. Younger children required significantly more warfarin than older children (P<0.001)catheter patency and in the management of thromboembolismthat threatens the viability of the affected organ. Thrombolyticdrugs are used locally or systemically and their concentrationcan be monitored with plasma fibrinogen levels or total clottingtime. Decreased plasma plasminogen levels in newborns mayreduce the thrombolytic actions of the drugs. Thrombolytic Day 1drugs pose similar risks to children as to adults. If baseline INR is Action: 1.0-1.3 Warfarin dose 0.2 mg/kgVenous thromboembolismVenous thromboembolism in children usually occurs secondaryto an underlying disorder, such as in the upper arm secondary Loading (days 2-4)to a central venous line being inserted. Such lines are usuallyplaced for intensive care management and treatment of cancer. If INR is Action:The patency of these lines is traditionally maintained through 1.1-1.3 Repeat initial loading dose 1.4-1.9 50% of initial loading dosetherapeutic local instillation of urokinase for blocked lines or 2.0-3.0 50% of initial loading doseprophylactic intermittent boluses of heparin (which have 3.1-3.5 25% of loading dosedoubtful efficacy). > 3.5 Hold until INR < 3.5, then restart at 50% less than Established venous thromboembolism requires removal of previous dosethe predisposing factor and anticoagulation similar to that inadults (standard heparin for five days followed by maintenancewith oral anticoagulation for at least three months). Oralanticoagulation can be started on the same day as heparin. Low Maintainance anticoagulationmolecular weight heparin is a useful option for maintaininganti-Xa level of 0.5-1.0 U/ml. Patients with a first recurrence of If INR is Action: 1.0-1.4 Increase by 20% of dosevenous thromboembolism or with an initial episode with 1.5-1.9 Increase by 10% of dosecontinuing risk factors either could be closely monitored for 2.0-3.0 No changeany early signs of thromboembolism or should be given 3.1-3.5 Decrease by 10% of dose > 3.5 Hold until INR < 3.5, thenanticoagulant drugs prophylactically after the period of initial restart at 20% less thantherapeutic anticoagulation for the episode. Patients with a previous dosesecond recurrence of venous thromboembolism or with a firstrecurrence with continuing risk factors should be givenanticoagulants for life, as in adults. Protocol for oral anticoagulation treatment to maintain an INR ratio of 2.0-3.0 for childrenArterial thromboembolismThe usual predisposing factors include placement of centraland peripheral arterial catheters for cardiac catheterisation and Commonly used drugs in children that affect INR valuesintensive care settings. A bolus of heparin (50-150 U/kg) at thetime of arterial puncture and continuous low dose heparin Drug Usual effect on INRinfusion are common methods for cardiac and umbilical artery Amiodarone Increasecatheterisation, respectively. Aspirin Increase or no change Amoxicillin Slight increase Cefaclor IncreaseProsthetic heart valves Carbamazepine DecreaseOral anticoagulation is needed in children with mechanical heart Phenytoin Decreasevalves. An INR of 2.5-3.5 is recommended as the target range. Phenobarbital DecreasePatients who are predisposed to high risk of thromboembolism Cloxacillin Increasedespite anticoagulation treatment and those with Prednisone Increasethromboembolism while taking warfarin could benefit from the Co-trimoxazole Increaseaddition of antiplatelet drugs, such as aspirin (6-20 mg/kg/day) Ranitidine Increaseor dipyridamole (2-5 mg/kg/day), to oral anticoagulation.56
  • 64. Antithrombotic therapy in special circumstances. II—children, thrombophilia, and miscellaneous conditionsOther cardiac disorders Common thrombophilic disordersNo universally accepted guidelines or randomised trials exist forthe antithrombotic therapy in patients undergoing operations Inherited x Antithrombin III deficiencywhere there is risk of thromboembolism (such as Blalock-Taussig x Protein C deficiencyshunts, Fontan operations, and endovascular stents). A variety of x Protein S deficiencyantithrombotic regimens have been used after these operations, x Activated protein C resistance (factor V Leiden mutation)including intraoperative heparin only and intraoperative heparin x Inherited hyperhomocysteinaemiafollowed by oral anticoagulation or aspirin. x Raised factor VIII levels x Prothrombin gene G20210 A variantHereditary prothrombotic states AcquiredDeficiencies of protein C, protein S, or antithrombin III and x Antiphospholipid syndromefactor V Leiden mutation can lead to thromboembolism x Acquired hyperhomocysteinaemiaespecially in the presence of a secondary risk factor.Homozygous deficiency of these proteins could lead to fatalpurpura fulminans in newborns, which is treated immediatelyby rapid replacement of these factors with fresh frozen plasmaor protein concentrates. This is followed by careful initiation oflifelong oral anticoagulation to maintain the INR at higherlevels of 3.0-4.5. Heterozygous patients could be givenprophylactic antithrombotic therapy during exposure tosecondary risk factors or be followed up with close observation. Guidelines for antithrombotic therapy in inherited thrombophilia*Antithrombotic therapy in Indication Treatment Primary prophylaxisthrombophilia and miscellaneous Any surgery Unfractionated heparinconditions subcutaneously 5000 IU three times dailyA detailed discussion of management of thrombophilic Malignancy or orthopaedic surgery Unfractionated heparindisorders is beyond the scope of this article. The guidelines on subcutaneously 5000 IU threethe management of these disorders are based on small and times daily, possibly withnon-controlled series of patients because of the paucity of replacement of deficient factorsrandomised trials (as reviewed by the Haemostasis and Pregnancy Unfractionated heparin subcutaneously 5000 IU threeThrombosis Task Force in 2001). times daily Inherited thrombophilic disorders are genetically Pregnancy in antithrombin III Therapeutic dose ofdetermined, and most of the affected patients are heterozygotes. deficiency unfractionated heparin toHomozygotes are extremely rare. Antithrombin III, protein C, prolong APTT or dose adjustedand protein S are produced in the liver and act by inactivating warfarin (INR 2.0-3.0), exceptcoagulation factors. Deficiency of these proteins could lead to during first trimester and latteruncontrolled activation of the coagulation cascade and part of third trimester, whentherefore thromboembolism. unfractionated heparin is used Activated protein C resistance is the commonest inherited Puerperium (for 4-6 weeks) Unfractionated heparin subcutaneously 5000 IU threethrombophilic disorder and accounts for 20-50% of cases. times daily or dose adjustedAntithrombin III deficiency is the rarest of the mentioned warfarin (INR 2.0-3.0)inherited thrombophilic disorders but carries the highest Secondary prophylaxisthrombogenic risk. High plasma concentration of homocysteineis linked to genetic enzyme deficiencies and low plasma First episode of thrombosis Dose adjusted warfarin for 6 monthsconcentrations of folate and vitamin B-6, and an investigation of First episode of life threatening Lifelong oral anticoagulationvitamin B-12 metabolism is warranted. thrombosis, multiple deficiencies, Though thrombophilic disorders predispose patients to continuing predisposing factorthromboembolism, the routine use of anticoagulation for Recurrent thrombosis Lifelong oral anticoagulationprimary prophylaxis entails greater risks than benefit (except Treatment of established thrombosisprobably in homozygotes). Therefore primary prophylaxis is Treatment of acute thrombosis Unfractionated heparin towarranted only in the presence of a second risk factor, and for prolong APTT followed by oralas long as the risk factor lasts. Common predisposing factors anticoagulation treatment,that require prophylaxis include surgery, immobilisation, possibly with replacement ofpregnancy and the puerperium, and oral contraception. the deficient factors Special caution is needed when giving anticoagulation to *For full guidelines see Haemostasis and Thrombosis Task Force, Br J Haematolpatients with protein C deficiency. Because protein C is a vitamin 2001;114:512-28K dependent factor, the administration of warfarin could lead to Low molecular weight heparins are increasingly used as alternatives to unfractionated heparinsudden decrease in protein C before any noticeable decrease incoagulation factors. This could cause enhanced thrombosis anddiffuse skin necrosis. This adverse response can be avoided bygradual initiation of oral anticoagulation with low doses ofwarfarin, preferably overlapped by adequate heparinisation.In cases of severe deficiency, replacement of protein C isindicated before starting warfarin. 57
  • 65. ABC of Antithrombotic Therapy Little evidence exists to support the use of antithrombotic Recommendations from the College of Americanagents in hyperhomocysteinaemia. Although replacement of Pathologists consensus conference XXXVI: diagnostic issuesfolic acid and vitamin B-6 has been shown to reduce plasma in thrombophiliahomocysteine levels, no study has found reduction inthromboembolic events with this intervention. x Patients, and especially asymptomatic family members, should provide informed consent before thrombophilia testing is performedAntiphospholipid syndrome x Individuals testing positive for a thrombophilia need counselling on:The long term prognosis for this syndrome is influenced by the Risks of thrombosis to themselves and their family membersrisk of recurrent thrombosis. As with other thrombophilic Importance of early recognition of the signs and symptoms of venousdisorders, primary prophylaxis is not indicated in the absence thromboembolism that would require immediate medicalof other risk factors. A patient with one episode of thrombosis is attentionat considerable risk of further thrombosis and should be given Risks and benefits of antithrombotic prophylaxis in situations in which their risk of thrombosis is increased, such as surgery orlifelong anticoagulation with warfarin as secondary prophylaxis. pregnancyThe target INR should be 2.0-3.0 (although some authorities x Laboratory testing for other inherited and acquired thrombophiliasadvocate a higher INR level (>3.0)). Patients with this syndrome should be considered even after the identification of a knownmay be relatively resistant to warfarin and so will need high thrombophilia because more than one thrombophilia could coexist,doses. However, some authorities believe that the compounding the risk for thrombosis in many casesantiphospholipid antibodies interfere with the generation of the x When available, World Health Organization (WHO) standards, or standards that can be linked to the WHO standard, should be usedINR and lead to spurious results. Consequently, other routes to to calibrate funtional and antigenic assaysmonitoring anticoagulation may be needed. x Effect of age and sex should always be taken into consideration Low molecular weight heparin is used increasingly in when interpreting the results of antigenic and functional assayspatients with various thrombophilia and seems to be safe and x Before concluding that a patient has an inherited thrombophilia,reliable. diagnostic assays for function or antigen should be repeated after excluding acquired aetiologies of the defectKawasaki diseaseAspirin continues to be used in Kawasaki disease despite a lackof unequivocal evidence from randomised trials of its benefit inreducing coronary artery aneurysm or thrombosis. Aspirin isused in anti-inflammatory doses (50-100 mg/kg/day) duringthe acute stage of the disease, followed by antiplatelet doses(1-5 mg/kg/day) for seven weeks or longer. Further readingThe figure showing effect of age on dose of warfarin in 262 children is x Cumming AM, Shiach CR. The investigation and management ofadapted from Streif W et al, Curr Opin Pediatr 1999;11:56-64. The diagram inherited thrombophilia. Clin Lab Haem 1999;21:77-92of protocol for oral anticoagulation for children and the tables showing x Monagle P, Michelson AD, Bovill E, Andrew M. Antithromboticadjustment of low molecular weight heparin in children and commonly therapy in children. Chest 2001;119:S344-70used drugs in children are adapted from Monagle P et al, Chest x Streif W, Mitchell LG, Andrew M. Antithrombotic therapy in2001;119:S344-70. The guidelines for antithrombotic therapy in inherited children. Curr Opin Pediatr 1999;11:56-64thrombophilia are adapted from the Haemostasis and Thrombosis Task x Haemostasis and Thrombosis Task Force, British Committee forForce, Br J Haemotol 2001;114:512-28. The box of recommendations from Standards in Haematology. Guideline: investigation andthe College of Amercian Pathologists consensus conference on diagnostic management of heritable thrombophilia. Br J Haematolissues in thrombophilia is adapted from Olson JD, Arch Pathol Lab Med 2001;114:512-282002;126:1277-80.58
  • 66. 16 Anticoagulation in hospitals and general practiceAndrew D Blann, David A Fitzmaurice, Gregory Y H LipService requirements for warfarin management includephlebotomy or finger pricking, accurate measurement of theinternational normalised ratio (INR) by a coagulometer (withassociated standards and quality control), interpretation of theresult, and advice on the warfarin dose. Clinical management ofthe complications of treatment (predominantly overdose) arealso required. Furthermore, almost any drug can interact withoral anticoagulants, and many (such as steroids and antibiotics)often increase the anticoagulant effect. When introducing a new drug, if the duration of treatmentis short (such as an antibiotic for less than five days), thenadjustment of dose is often not essential. If, however, thetreatment is to last more than five days, then the INR should be Warfarin tablets used routinely in the Unitedchecked after starting treatment with the new drug and the Kingdomwarfarin dose adjusted on the basis of the results.Starting treatment in hospitalinpatientsOnce the indications for anticoagulation have been confirmed Drug interactions with warfarin*(for example, for suspected deep vein thrombosis do venography Enhanced anticoagulant effect—Alcohol, allopurinol, anabolic steroids,or d-dimer measurement), the initial dose of oral anticoagulant analgesics (for example, paracetamol), antiarrhythmics (fordepends on a patient’s coagulation status, age, clinical situation, example, amiodarone), antidepressants (for example, selectiveand degree of heart failure (if present). In older patients, those serotonin reuptake inhibitors), antidiabetics, antimalarials,with impaired liver function, and those with congestive heart antiplatelets, anxiolytics, disulfiram, influenza vaccine, leukotriene antagonists, levothyroxine, lipid regulating agents, testosterone,failure oral anticoagulation should be started cautiously and the uricosuricsresulting INR checked often (every three to five days). The dose of Reduced anticoagulant effect—Oral contraceptives, raloxifene, retinoids,warfarin needed to maintain an INR at 2.0-3.0, for example, falls rowachol, vitamin K (possibly present in enteral feeds)with age and is greater in patients of Indo-Asian or African origin Variable effect—Antibiotics (but, generally, more likely to enhance),than in Europeans. Where possible, take routine blood samples colestyramine, antiepileptics, antifungals, barbiturates, cytotoxicsfor prothrombin time and activated partial thromboplastin time (for example, effect enhanced by ifosfamide but often reduced by azathioprine), hormone antagonists, ulcer healing drugs(APTT), platelet count, and liver function tests before starting *This list is not exhaustive or definitive but provides perspective: the effect oftreatment. Oral anticoagulation with warfarin should be started each particular agent should be observed on each particular patient.on day one, preferably in conjunction with heparin because the Considerable variation exists in different drugs within a single class (for example, antibiotics). Refer to the BNF for guidanceinitial period of treatment with warfarin may be associated with aprocoagulant state caused by a rapid reduction in protein Cconcentration (itself a vitamin K dependent protein). Heparinshould not be stopped until the INR has been in the therapeuticrange for two consecutive days. Patients at a high risk ofthrombosis and those with a large atrial thrombus may needlonger treatment with heparin. Similarly, a specific anticoagulant treatment chart thatcontains the treatment protocol, the results of coagulation tests(INR and APTT ratios), and the prescribed doses based on theresults should be the basis of treatment and is a useful way ofassessing and monitoring patients’ anticoagulation in the followup period. Daily INR measurement for at least four days isrecommended in patients needing rapid anticoagulation (forexample, in those with high risk of thrombosis). Adjustment ofthe oral anticoagulant loading dose may be necessary if baselinecoagulation results are abnormal. Some patients may beparticularly sensitive to warfarin, such as older people and thosewith liver disease, congestive cardiac failure, or who are Anticoagulation monitoring by fingerprick. Noterecieving drug treatment (such as antibiotics) likely to increase coagulometer in the backgroundthe effects of oral anticoagulants. Once the therapeutic INR range is achieved it should bemonitored weekly until control is stable. The British Society forHaematology’s guidelines suggest that thereafter blood testingcan be extended to fortnightly checks, then checks every four 59
  • 67. ABC of Antithrombotic Therapyweeks, eight weeks, and 12 weeks (maximum). By this time, thechecks are most likely to be in the setting of an experiencedhospital outpatient clinic. At the time of discharge from hospital, follow up Requirement for daily dose of warfarin to maintain an INRarrangements for each patient should include sufficient tablets between 2.0 and 3.0 and 3.0 and 4.5to allow adequate cover until the general practitioner can Daily dose ofprovide a prescription (two to three weeks’ worth) and an Age (years) No of patients warfarin (mg)*appointment for further INR measurements, generally in an INR to be in range 2.0 to 3.0outpatient clinic. This period should not exceed seven days and 40-49 36 7.3 (6.21 to 8.39)should be detailed in the patient case notes and the yellow 50-59 76 5.5 (5.0 to 6.0)Department of Health anticoagulant booklets. Information in 60-69 209 4.3 (4.05 to 4.55)the yellow booklet should indicate the target INR range for 70-79 233 3.9 (3.68 to 4.12)each patient and other pertinent information, such as the >80 107 3.3 (3.01 to 3.59)presence of diabetes and indication for anticoagulation. INR to be in range 3.0 to 4.5 40-49 9 6.5 (5.23 to 7.77)Starting treatment in outpatients 50-59 20 6.0 (5.2 to 6.8) 60-69 45 5.9 (5.13 to 6.67)Without the benefit of the management procedures described 70-79 24 4.8 (4.15 to 5.45)above, starting anticoagulant treatment in outpatients can be >80 2 4.2 (2.65 to 5.75)difficult, especially if patients are referred without their notes or *Data are presented as mean (95% CI)adequate information (such as other drugs prescribed or reason Relationship between age and daily dose in INR range 2.0-3.0 is correlation coefficient r = − 0.45, P < 0.001, and for INR range 3.0-4.5 is correlationfor anticoagulation). Nevertheless, local conditions and coefficient r = − 0.23, P = 0.022guidelines will generally recommend a starting dose, and Data from Blann AD, et al, Br J Haematol 1999;107:207-9patients will need to be recalled weekly for INR managementuntil they are deemed to be stable. In many cases theintroduction of computer assisted dosing (an algorithmsoftware) is of immense benefit.Complications and reversal of oralanticoagulationBleeding complications while patients are receiving oralanticoagulants increase substantially when INR levels exceed5.0, and therapeutic decisions depend on the presence of minoror major bleeding. However, in those cases with evidence ofsevere bleeding or haemodynamic compromise, hospitalisation,intensive monitoring, and resuscitation with intravenous fluidsmay be needed. Sometimes the bleeding point can be treated(for example, endoscopic treatment of bleeding peptic ulcer).Fresh frozen plasma is recommended when quick reversal of Yellow Department of Health anticoagulant booklet.over-anticoagulation is needed. If plasma is unavailable then Columns are provided for the date of each visit, INR result, recommended daily dose, and signaturevitamin K, given by slow intravenous injection at doses of0.5-1.0 mg or orally at doses of 1-10 mg, may reduce the INRwithin six to eight hours without the risk of over-correction.However, the effects of vitamin K can last for a week and maydelay the restarting of warfarin treatment, although retesting(thus restarting with warfarin) after 48-72 hours is common. Treatment of excessive antithrombotic therapy effects Class Drug AntidoteMaintenance in hospital practice Oral anticoagulants Warfarin Oral or intravenousThe traditional model of care for patients taking oral vitamin K; clottinganticoagulants requires them to attend a hospital outpatient factors or fresh frozen plasma, or both;clinic so that the INR can be estimated. Capillary or venous recombinant factor VIIblood samples are used, with the result being available either Intravenous or Heparin Protamine; clottingimmediately or at a later stage. However, the INR derived from subdermal factors or fresh frozencapillary (finger prick) blood is likely to be different from that anticoagulants plasma, or bothobtained from plasma from a peripheral blood sample, and this Thrombolytics Streptokinase, tissue Transexamic acidshould be considered. If possible, it is preferable to use plasminogenconsistently either finger prick or venous blood. Rarely, activator (examples)phlebotomists will visit housebound patients and return avenous sample to the laboratory for INR management. WhereINR results are available with the patient present, dosingrecommendations are made and the patient is given a date forthe next appointment. When there is a delay in the INRestimation, patients receive dosing and recall advice through the60
  • 68. Anticoagulation in hospitals and general practicepost or by telephone. Although this service has beentraditionally led by a physician (usually a consultanthaematologist) or pathologist, more recently biomedical Factors affecting delivery of anticoagulationscientists, nurse specialists, and pharmacists have been taking therapyresponsibility for anticoagulant clinics. This model has been Hospital anticoagulation clinicswidely used in the United Kingdom but has come under more x Usually busy and congested x Congestion is an increasing problem caused bystrain because of increasing numbers of patients referred for the ageing population with more indications forwarfarin treatment, particularly for stroke prophylaxis in atrial warfarin (especially atrial fibrillation)fibrillation. However, in terms of INR control, adverse events, or x Inconvenientpatient satisfaction, long term oral anticoagulant care has Domiciliary anticoagulation servicetraditionally required patients to attend a hospital anticoagulant x Depends on resourcesclinic repeatedly because of the need for laboratory testing, x Limited availabilityspecialist interpretation of the result, and adjustment of x Useful for those who are immobile orwarfarin dose. housebound “Near patient” testing x Requires considerable resourcesAnticoagulation in general practice x Dependent on primary care, facilities, and trainingConcerns over general practice involvement in anticoagulationmonitoring have been expressed—namely, lack of resources(machines and reagents to generate the INR) and lack ofexpertise (experience and training), although these can beovercome. Despite various moves to decentralisation, no largescale development in a primary care setting has occurred.Understandably, general practitioners are anxious thatdecentralisation of anticoagulation care represents an additional, Potential levels of involvement in general practice forunwanted, and possibly dangerous burden. Local circumstances managing anticoagulation treatmentvary enormously so the process of decentralisation will need to x Phlebotomy in the practice (by practice or hospital staff), blood sentbe modified according to local needs and resources. (post or van) to the hospital laboratory with the result returned to The establishment of a local development group consisting the practice (telephone, fax, post, or email), dosing decisions beingof general practitioners and hospital clinicians responsible for made in the practice, then communicated to the patientthe anticoagulant clinic is one way of promoting x Phlebotomy in the practice, blood sent (post or van) to the hospital laboratory, dosing with INR estimation performed in the hospitaldecentralisation and identifying problem areas. There is and patient managed directly (telephone or post)increasing evidence that general practitioners or healthcare x Phlebotomy, INR estimation (plus dosing) and management allprofessionals such as biomedical scientists, pharmacists, and performed in the practice with hospital equipment and by hospitalpractice nurses, with or without computer assisted dosing, are staffable to achieve high standards of anticoagulation care with x Phlebotomy, INR estimation plus dosing and management made by“near patient” testing. As the principle of near patient testing is the practice (that is, full near patient testing); minimal input fromwell developed in glucose monitoring by or for diabetic the hospitalpatients, it seems logical that it can be transferred to oralanticoagulation, provided that adequate levels of accuracy andsafety are achievable. In one of the more widespread models general practitionerstake a blood sample and dosing decisions are made by ahospital department, with patients receiving dosing informationthrough the post or by telephone. This model retains theexpertise and quality assurance of the laboratory process whiledecentralising at minimal cost to primary care. Patients can Therapeuticattend their (usually more convenient) general practitioner’s windowsurgery and a venous blood sample is sent to the central (Usuallylaboratory. INR is determined and information on dose and the INR 2.0-3.0) T hrnext appointment is sent to the patient. There are no clinically ic om agsignificant changes in the INR when analysis is delayed for up bo rh em orto three days, and the quality control with near patient sampling bo em lic Hais at least equal to that in a hospital based setting. This processrequires access to phlebotomy in general practice, and the cost Clinical eventsof testing and dosing remains in the central laboratory. General practices with limited access to hospital clinics aremore likely to undertake the second level of care and givedosing advice. General practitioners who do not have access to Intensity of anticoagulation (INR)computer assisted dosing seem to have similar success tohospital clinics in achieving optimum INR control. The therapeutic “window” is a balance between the best reduction in The third level of care uses near patient testing for INR thromboembolic events and increased risk of bleeding with higherestimation and computer assisted dosing for recommendation intensities of anticoagulation. Adapted from Hylek EM, et al. New Engl J Medof dose and recall. Anticoagulant clinics are managed by 1993;120:897-902practice nurses with support from the general practitioner andhospital laboratory. Liaison with the hospital laboratory is 61
  • 69. ABC of Antithrombotic Therapyparamount to the success of such a clinic as it needs to provide Contraindications to warfarin use andtraining and guidance on near patient testing technique, quality managementassurance, and health and safety issues. In a study byFitzmaurice, et al (2000), INR therapeutic range analyses as The patient x Comorbidity—including comorbid medicalpoint prevalence, proportion of tests in range, number of conditions, falls, frailty, exposure to traumaserious adverse events, and proportion of time in range all x Impaired cognitive functioncompared well with the hospital control patients. However, the x Possibly houseboundproportion of time spent in the INR range showed substantial x Poor complianceimprovement for patients in the intervention group. The doctor Computer assisted dosing aids interpretation of results, x Poor appreciation of drug interactionsalthough it can be over-ridden if the suggestion made is not x Inefficient organisation of INR monitoringclinically indicated. For an effective and reliable service it is The systemessential to ensure formal training and quality assurance x General practice v hospital facilities—for exampleprocedures for near patient testing at the initial stages of the remote location and poor communication andclinic development. This model of care gives an immediately support x Inadequate resources and facilities availableavailable result, and, with close liaison with a hospital laboratory,it offers patients a complete model of care that would be auseful alternative to traditional care. Another primary care model that has had limited Further readingevaluation is that of anticoagulant clinics that are managedentirely by scientists and pharmacists. These specialist x Baglin T, Luddington R. Reliability of delayed INR determination: implications for decentralised anticoagulant care with off-site bloodhealthcare professionals make use of their expertise in sampling. Br J Haematol 1997;96:431-4coagulation and pharmacology respectively. Secondary care x Blann AD, Hewitt J, Siddique F, Bareford D. Racial background is aanticoagulant clinics run by scientists and pharmacists have determinant of average warfarin dose required to maintain the INRexisted in the United Kingdom since 1979, and in terms of between 2.0 and 3.0. Br J Haematol 1999;107:207-9INR control they perform as well as clinics run by pathologists. x Fitzmaurice DA, Hobbs FDR, Delaney BC, Wilson S, McManus R.Patients also prefer general practice management and welcome Review of computerized decision support systems for oralreduced waiting times and travelling costs. Improved patient anticoagulation management. Br J Haematol 1998;102:907-9 x Fitzmaurice DA, Murray ET, Gee KM, Allan TF, Hobbs FD. Aunderstanding may also occur, which can help compliance. randomised controlled trial of patient self management of oralFurther clinics managed by scientists or pharmacists, or both, anticoagulation treatment compared with primary careare currently being evaluated. management. J Clin Pathol 2002;55:845-9 x Fitzmaurice DA, Hobbs FD, Murray ET, Holder RL, Allan TF, Rose PE. Oral anticoagulation management in primary care with the usePatient self monitoring and dosing of computerized decision support and near-patient testing: a randomized, controlled trial. Arch Intern Med 2000;160:2343-8Diabetic patients have long been able to use portable monitoring x Haemostasis and Thrombosis Task Force of the British Society formachines to check their own blood glucose concentrations and Haematology. Guidelines on anticoagulation: third edition. Br Jadminister insulin accordingly. As equivalent machines for Haematol 1998;101:374-87checking INR are now available, increased patient demand is x MacGregor SH, Hamley JG, Dunbar JA, Dodd TRP, Cromarty JA.likely to rise. The machine will appeal especially to those Evaluation of a primary care anticoagulation clinic managed by areceiving long term anticoagulation whose lifestyle is not suited pharmacist. BMJ 1996;312:560to the inconvenience of attending outpatient clinics. As with x Pell JP, McIver B, Stuart P, Malone DNS, Alcock J. Comparison of anticoagulant control among patients attending general practicediabetic patients, well trained and motivated patients can and a hospital anticoagulant clinic. Br J Gen Pract 1993;43:152-4probably attain a level of control of their own warfarin dose x Radley AS, Hall J, Farrow M, Carey PJ, Evaluation of anticoagulantsimilar to that of the hospital. As yet, there are no comparison control in a pharmacist operated anticoagulant clinic. J Clin Patholdata on the safety and reliability of such an approach, so great 1995;48:545-7caution is needed in offering (or even recommending) thisoption, which will be applicable to a well defined subset ofpatients. However, most pilot data suggest that patient selfmanagement is as safe as primary care management for aselected population, and further study is needed to show if thismodel of care is suitable for a larger population.ConclusionThe quality of anticoagulant care has improved in recent yearswith the development of clinical guidelines (for example, by thehaemostasis and thrombosis task force of the British Society forHaematology), adoption of the INR system, quality controlassurance, computerised decision support systems, and clinicalaudit. This allows a gradual movement of dosing from hospitalto general practice. New models of delivering care (such as nearpatient testing) are now being developed to meet the increasingdemand from an ageing population, such as from the growingnumber of patients with atrial fibrillation, whose risk of stroke ismarkedly reduced by anticoagulant therapy.62
  • 70. IndexPage numbers in bold type refer to figures; those in italic refer to tables or boxed material.abciximab 2 in acute stroke 27, 28–9 in acute coronary syndromes 39, 39, 42 in atrial fibrillation 16, 17 for percutaneous coronary interventions 44, 45 in children 55activated partial thromboplastin time (APTT) 3 for percutaneous coronary interventions 44, 44–5 in children 55 in peripheral vascular disease 25, 26, 26–7 in venous thromboembolism 13 postmyocardial infarction/stable angina 36–7activated protein C resistance 57 for stroke prevention 30, 30acute coronary syndromes 38–41, 42–3 in valvar heart disease/prosthetic heart valves 31, 32 antithrombotic therapy 38–41, 41, 43 see also aspirin; clopidogrel; dipyridamole; ticlopidine initial management 42, 42 antithrombin III 3, 57 pathogenesis 38, 38 deficiency 57 for percutaneous coronary intervention 43–5, 45 aortic valve disease 32 pros and cons of invasive therapy 43 aortic valvuloplasty 32 risk stratification 42, 43 aortofemoral bypass grafts 25, 26 subsequent management 42–3, 43 aortoiliac bypass grafts 25, 26ADP receptor antagonists argatroban 3 in acute coronary syndromes 38–9, 39 arterial occlusion 24, 25 see also clopidogrel; ticlopidine arterial thromboembolismage, bleeding risk and 6, 7, 7 in children 56alteplase see also systemic thromboembolism in acute myocardial infarction 36, 36 aspirin 1, 1 in pulmonary embolism 14 in acute coronary syndromes 38, 38, 39, 41, 42 see also recombinant tissue plasminogen activator in acute myocardial infarction 36, 36angina in acute stroke 21–2, 28–9, 29 stable 36–7 adverse effects 1, 7, 7 unstable see acute coronary syndromes in atrial fibrillation 16, 17, 17, 21–2angioplasty, percutaneous transluminal 26 in children 55angiotensin converting enzyme (ACE) inhibitors, in heart contraindications 1 failure 50 in heart failure 49–50anticoagulation 2–3 in Kawasaki disease 58 in acute coronary syndromes 40–1 for percutaneous coronary interventions 44, 44–5, 45 in acute myocardial infarction 36, 36 in peripheral vascular disease 24, 24, 25, 26–7 in acute stroke 29 postmyocardial infarction/stable angina 36–7 in atrial fibrillation 21–2 in pregnancy 34, 52, 52–3 in cancer 53–4 for stroke prevention 7, 7, 30, 30 for cardioversion in atrial fibrillation 19, 19, 22, 23 in valvar heart disease/prosthetic heart valves 31, 32, 34 in heart failure 48–9, 49 atrial fibrillation 16–19 in hospitals and general practice 59–62 acute, anticoagulation for 21 patient self monitoring and dosing 62 DC cardioversion see cardioversion, in atrial fibrillation for percutaneous coronary interventions 45, 45 indications for antithrombotic therapy 17–18, 18 in peripheral vascular disease 24–5 INR range 19 postmyocardial infarction/stable angina 36, 37 paroxysmal 16, 20 reversal of effects 60, 60 pathophysiology of thromboembolism 20, 20–1 for stroke prevention 30 presenting with acute stroke 21–2 therapeutic “window” 61 risk stratification 18, 18 in thrombophilias 57, 57, 58 stroke prevention 7, 7, 16, 16–17, 17, 21 venous thromboembolism therapy 13–14, 14 stroke risk 16, 17 see also heparin; oral anticoagulation; warfarin thrombus formation 16antiphospholipid syndrome 58 valvar heart disease with 20, 32, 33 in pregnancy 52, 52 atrial thrombus see intra-atrial thrombus venous thromboembolism therapy 14antiplatelet drugs 1, 1–2 Baker’s cyst, ruptured 9, 10 in acute coronary syndromes 38–9, 39 bleeding complications 5–8 in acute myocardial infarction 36, 36 management 60 63
  • 71. Index risk 7–8 dental surgery 33 in stroke prevention trials 17 diabetes 20, 24 warfarin 5–7, 49 dipyridamole 1–2, 26breastfeeding 51 in peripheral vascular disease 24, 26, 26, 27cancer 53–4 postmyocardial infarction/stable angina 37 haemorrhage risk 54 for stroke prevention 30, 30 recurrent venous thromboembolism 54 venous thromboembolism prophylaxis 12, 53 echocardiography venous thromboembolism risk 9, 53, 53, 53 in atrial fibrillation 18, 18 venous thromboembolism therapy 14, 53 transoesophageal see transoesophageal echocardiographyCAPRIE study 24, 30 elderlycardiac disorders anticoagulation in atrial fibrillation 17 in children 56–7 bleeding risks 7, 7 predisposing to stroke 29, 30 warfarin therapy 5, 7, 7, 8cardiomyopathy electrocardiography, in acute coronary syndromes 42 idiopathic dilated 48, 49 endoscopic procedures 33 ischaemic 48, 49 enoxaparin 3 peripartum 48 in acute coronary syndromes 40, 40, 42cardioversion, in atrial fibrillation 19, 21, 21, 22 venous thromboembolism prophylaxis 12, 12 anticoagulation for 19, 19, 22, 23 eptifibatide 2 guideline recommendations 19, 22, 23 in acute coronary syndromes 39, 39 thromboembolism/stroke risk after 20, 22, 22 for percutaneous coronary interventions 44 transoesophageal echocardiography guided 19, 19, 21, 22carotid endarterectomy 24, 27 factor V Leiden 57carotid stenosis 24, 26–7 femoral-popliteal bypass 25, 26cellulitis, infective 9, 10 fibrin D-dimers, plasma 10, 10, 11cerebrovascular disease 27, 28–30 fibrinolysis 4 bleeding complications and 6 fibrinolytic therapy see thrombolytic therapy see also stroke fondaparinux 11, 12children 55, 55–7cilostazol 24 gangrene 25, 25claudication, intermittent 24, 24–5 gastrointestinal bleeding 7clopidogrel 2 general practice, anticoagulation in 61, 61–2 in acute coronary syndromes 38–9, 39, 41, 42 glycoprotein IIb/IIIa receptor inhibitors 2 in heart failure 50 in acute coronary syndromes 39, 39, 41, 42 for percutaneous coronary interventions 44, 45 for percutaneous coronary interventions 44–5, 45 in peripheral vascular disease 24, 24, 26, 26, 27 postmyocardial infarction/stable angina 37 postmyocardial infarction/stable angina 37 glycoprotein IIb/IIIa receptors 2, 38 for stroke prevention 30coagulation cascade 2 haemorrhagic complications see bleeding complicationscompression elastic stockings 11, 12 heart failurecomputed tomography acute 50 in stroke 29 antithrombotic therapy 12, 12, 48–50, 49 in venous thromboembolism 10, 11 chronic 46–50coronary angiography 43 stroke and systemic embolism 46–8coronary angioplasty, in acute coronary syndromes 43–5, 44 see also left ventricular dysfunctioncoronary artery disease, stable 36–7 heparin 3coronary artery stenting 44, 44, 44, 45, 45 in acute myocardial infarction 36, 36coumarins adverse effects 3 in pregnancy 51 in cancer 53, 54 venous thromboembolism therapy 14 for cardioversion in atrial fibrillation 19, 19 see also oral anticoagulation; warfarin in children 55, 56critical ischaemia 24, 25, 25 low molecular weight see low molecular weightcyclo-oxygenase 1 heparin for percutaneous coronary interventions 45, 45dalteparin 3 postmyocardial infarction 37 in acute coronary syndromes 40, 40 in pregnancy 34 postmyocardial infarction 37 reversal of effects 60 thromboembolism prophylaxis 12 in stroke 29, 29danaparoid 12 unfractionated 3, 3D-dimers, plasma 10, 10, 11 in acute coronary syndromes 40, 42deep vein thrombosis 9, 13 in peripheral vascular disease 25 clinical presentation and diagnosis 9–10, 10, 10 in pregnancy 15, 51–2 in pregnancy 51, 51–2 thromboembolism prophylaxis 12, 12 treatment 13, 13–15 venous thromboembolism prophylaxis 11 see also venous thromboembolism venous thromboembolism therapy 13, 1364
  • 72. Index in valvar heart disease/prosthetic heart valves in stroke 29 31, 33, 34 in thrombophilia 58hirudin 3 in valvar heart disease/prosthetic heart valves 31 in acute coronary syndromes 40, 40 for venous thromboembolism prophylaxis 11, 12, 12 in acute myocardial infarction 36 for venous thromboembolism therapy 14, 14 after percutaneous coronary interventions 45 see also intra-atrial thrombus venous thromboembolism prophylaxis 11–12hirulog 3 melagatran 3, 40homocysteine, high plasma concentrations 57, 58 menorrhagia 5hospitals, anticoagulation practice 59–61 mitral regurgitation 32hypercoagulable state mitral stenosis 32 atrial fibrillation and 21 mitral valve venous thromboembolism therapy 14 prolapse 32hyperhomocysteinaemia 57, 58 repair 32hypersensitivity reactions, thrombolytic agents 4 mitral valvuloplasty 32hypertension 20 myocardial infarction 35–7, 36 acute 35–6, 36iloprost 1 thrombolytic therapy 35, 35–6immobility 9 see also acute coronary syndromesimpedance plethysmography 10 after 36, 36–7indobufen, in atrial fibrillation 16 in heart failure 46, 47inferior vena cava filters 12, 15, 15, 15 thromboembolism prophylaxis after 12, 12,infrainguinal bypass 24, 25, 26, 26 35, 36, 36 prosthetic 24, 26 with vein grafts 24, 26 nadroparin 3inpatients, starting anticoagulation 59–60 in acute coronary syndromes 40, 40INR see international normalised ratio thromboembolism prophylaxis 12intermittent claudication 24, 24–5 naftidrofuryl 24intermittent pneumatic compression 11, 12 near patient testing 61–2international normalised ratio (INR) 2, 5 neurosurgery 12, 12 bleeding risks and 6 in children 56, 56 oestrogens 9 excessively high 6–7, 60 oral anticoagulation general practice based management 61–2 in cancer 53 hospital based management 59–61 in children 55–6, 56, 56 near patient testing 61–2 in heart failure 46–7, 48–9, 49 patient self monitoring and dosing 62 in hospitals and general practice 59–62 in venous thromboembolism 13, 14 in pregnancy 15 warfarin dosing and 60 reversal 60, 60intra-atrial thrombus 18 risk : benefit assessment 5 in atrial fibrillation 20, 20, 21 in valvar heart disease/prosthetic heart valves 31, 32, in valvar heart disease 32 33, 33 , 34, 34intracranial haemorrhage 6 in venous thromboembolism 13, 14 warfarin-induced 6, 17, 49 see also warfarinintrauterine growth retardation 52–3 orthopaedic surgery 11–12, 12ischaemia, critical 24, 25, 25 outpatients, starting anticoagulation 60Kawasaki disease 58 percutaneous balloon valvuloplasty 32 percutaneous transluminal angioplasty 26left atrial appendage, thrombus in 16, 20, 20 percutaneous transluminal coronary angioplasty see also intra-atrial thrombus 43–5, 44left atrial enlargement 20 peripheral vascular disease 24, 24–7left ventricular aneurysm 37, 47–8 bleeding complications and 6left ventricular dysfunction revascularisation procedures 25–7 atrial fibrillation with 20 phenindione 2 stroke risk 18, 48 plasma, fresh frozen 60 see also heart failure polypharmacy 8left ventricular thrombus 37 pre-eclampsia 52–3, 53 in heart failure 47, 47, 47–8 pregnancy 51–3 risk factors 48, 48 antithrombotic therapy 51, 51–3low molecular weight heparin 3, 3, 3 valvar heart disease/prosthetic heart valves 34, 52 in acute coronary syndromes 40, 40, 41, 42 venous thromboembolism 15, 51, 51–2 in children 55, 55, 56 prosthetic heart valves 31, 31–4 for percutaneous coronary interventions 45 in children 56 in peripheral vascular disease 25–6 choice of antithrombotic agent 31–2 in pregnancy 15, 34, 51–2 guidelines for intensity of anticoagulation 33 65
  • 73. Index indications for antithrombotic therapy 32–3 systemic thromboembolism in pregnancy 34, 52 after cardioversion for atrial fibrillation 20, 22, 22 surgical procedures 33 after myocardial infarction 36, 37 thrombogenicity 31, 31 in children 56 types 31, 32, 32 in heart failure 46–8, 48protein C 57 prevention, after myocardial infarction 36 activated, resistance 57 risk factors 48, 48 deficiency 57 see also strokeprotein S 57 deficiency 57 tenecteplase 36, 36prothrombotic states, hereditary 57, 57 see also recombinant tissue plasminogen activatorpulmonary angiography 11 thrombin inhibitors, direct 3pulmonary embolectomy 15 in acute coronary syndromes 40, 40pulmonary embolism 9, 9 in atrial fibrillation 16–17 clinical presentation and diagnosis 10, 11, 11, 11 see also hirudin in heart failure 46, 47 thrombocytopenia, heparin induced 13 in pregnancy 51–2 thromboembolism see systemic thromboembolism; venous treatment 13–15, 14, 15 thromboembolismpulmonary endarterectomy 15 thrombolytic therapy 3–4 in acute coronary syndromes 41, 41recombinant tissue plasminogen activator 4, 4 in acute ischaemic stroke 29–30, 30 in acute myocardial infarction 36, 36 in acute myocardial infarction 35, 35–6 in stroke 29 in children 56 see also alteplase contraindications 4respiratory failure 12 in deep vein thrombosis 15rest pain 24, 25 in pulmonary embolism 14, 14–15reteplase 4, 36, 36 reversal of effects 60 see also recombinant tissue plasminogen activator thrombophilia 57, 57–8, 58revascularisation, peripheral artery 25–7 thrombus formation (thrombogenesis) 1, 1Reye’s syndrome 55 in atrial fibrillation 20, 20–1 in heart failure 47, 47, 47–8self monitoring, anticoagulation 62 ticlopidine 2spinal cord injuries 12, 12 for percutaneous coronary interventions 44, 44, 45stenting, coronary 44, 44, 44, 45, 45 in peripheral vascular disease 26streptokinase 4, 4 postmyocardial infarction/stable angina 37 in acute myocardial infarction 35–6 tinzaparin 12 in pulmonary embolism 14, 14–15 tirofiban in stroke 29 in acute coronary syndromes 39, 39stress testing, in acute coronary syndromes 42, 42 for percutaneous coronary interventions 44stroke 27, 28–30 tissue plasminogen activator 4 acute ischaemic 28–30 see also recombinant tissue plasminogen activator atrial fibrillation presenting with 21–2 transient ischaemic attack 27 haemorrhagic transformation risk 30 transoesophageal echocardiography guided cardioversion, in after cardioversion for atrial fibrillation 20, 22, 22 atrial fibrillation 19, 19, 21, 22 cardioembolic 28, 29, 30, 48, 48 trauma, multiple 12, 12 classification 28, 28 tricuspid valve disease 32 epidemiology 28, 46, 47 troponins haemorrhagic 28 in acute coronary syndromes 39, 42, 43, 43 in heart failure 46, 46–8, 48 after myocardial infarction 43 lacunar 28, 29 pathophysiology in atrial fibrillation 20, 20–1 ultrasonography, compression 10 prevention 30, 30 urokinase 4 in atrial fibrillation 7, 7, 16, 16–17, 17, 21 in pulmonary embolism 14, 14–15 risk factors 28, 28 risk in atrial fibrillation 16, 17 valvar heart disease 31–4 thromboembolism prophylaxis 12, 12 assessment 31, 31 see also systemic thromboembolism atrial fibrillation 20, 32, 33sudden cardiac death, in heart failure 47 choice of antithrombotic agent 31–2sulfinpyrazone 1 guidelines for intensity of anticoagulation 33surgery indications for antithrombotic therapy 32 in children 57 in pregnancy 34 for pulmonary embolism 15, 15 surgical procedures 33 thromboembolic risk stratification 11 valvuloplasty, percutaneous balloon 32 thromboembolism prophylaxis 11, 12 vascular surgery 24, 25–7 in valvar heart disease/prosthetic heart valves vasodilating agents 24 33, 34 vein grafts, in peripheral vascular disease 25, 2666
  • 74. Indexvenography 10 bleeding complications 5–7, 60venous obstruction 9 incidence 6venous thromboembolism 9–12 major bleeds 5–6 in cancer see under cancer minor bleeds 5 in children 56 risk factors 6, 6 clinical presentation and diagnosis 9–11, 10 in breastfeeding mothers 51 in heart failure 47, 50 in cancer 53 pathophysiology 9 for cardioversion in atrial fibrillation 19, 19 in pregnancy 15, 51, 51–2 in children 55–6, 56, 56 prevention 11–12, 12 contraindications 62 in cancer 53 drug interactions 2, 8, 59 postmyocardial infarction 12, 12, 36, 37 in elderly 5, 7, 7, 8 recurrent 14, 54 in heart failure 46–7, 48–9, 49 risk factors 9 in hospitals and general practice 59–62 treatment strategies 13–15 INR guided dosing 60 see also deep vein thrombosis; pulmonary embolism monitoring see international normalised ratioventilation-perfusion scan 11, 11 overanticoagulation 6–7, 60, 60Virchow’s triad 1, 1, 9 in peripheral artery revascularisation 25, 26, 27 in atrial fibrillation 20, 21 in peripheral vascular disease 24–5 in cancer 53 postmyocardial infarction 37 in heart failure 47 in pregnancy 34, 51, 52, 52vitamin K 2, 2 reversal of effects 7, 60, 60 in children 55–6 for stroke prevention 30 therapy 7, 60 thromboembolism prophylaxis 11, 12 in thrombophilia 58warfarin 2, 2, 59 in valvar heart disease/prosthetic heart valves 31, 32, 33, 33 , in acute coronary syndromes 40–1 34, 34 adverse effects 2 in venous thromboembolism 13, 14 after percutaneous coronary interventions 45 in atrial fibrillation 16, 16, 17, 17 ximelagatran 16–17, 40 with acute stroke 21 67