All About…AnticoagulationCroydon Hilton28th November 2012
Speakers• Dr Phil Moore GP and Kingston CCG Deputy Chair (clinical) and Joint Associate Medical Director• Dr Raj Patel Consultant Haematologist Kings Thrombosis Exemplar Centre• Helen Williams Consultant Pharmacist for CV Disease South London Cardiac and Stroke Network 2
Aims for the evening……• Discuss the indications for anticoagulation• Consider the benefits and risks of anticoagulation – focusing on anticoagulation for specific patients and conditions – Consider difficult clinical decisions – discuss strategies to minimise bleeding risk and what to do if bleeding does occur• Introduce the novel oral anticoagulants and the current South London guidelines
Cardiomyopathy• Cardiomyopathy is a disease of the heart muscle• Muscle becomes enlarged, thick or rigid• Heart becomes weak and is less able to pump and maintain a normal electric rhythm• 25-30% of patients with cardiomyopathy also have AF• Stroke risk mainly associated with cardiomyopathy in the presence of AF• Anticoagulation can also be considered in the absence of AF
Mechanical Valve Replacement• Risk = systemic embolisation• Most cases are cerebrovascular events• Risk is higher than tissue valve hence target INR range is also higher• Risk higher in patients – with a hx of embolisation – with co-existing AF
Coagulation Disorders Thrombophillias Antiphospholipid syndrome• Generic term describing • Autoimmune, increased tendency to hypercoagulable state thrombosis caused by antibodies – Factor V Leiden 5% of UK against cell membrane population – 20-40% of VTED – Antithrombin & protein C and S phospholipids deficiency -2-10% of VTED • Provoked blood clots in – Prothrombin G20210A - 1% of UK arteries and veins population – 10% of VTED – Hyperhomocysteinaemia - arterial & venous thrombi
VTE: the burden of disease• Acute VTE = DVT / PE• In-hospital mortality 6-15% after PE• Risk of recurrence• Post-thrombotic syndrome• Pulmonary hypertension
Current DVT treatment• LMWH / Fondaparinux / UFH – Continue for at least 5 days or until INR>2 for at least 24hrs (whichever longer) – LMWH for 6 months in active cancer, reassess risk/benefit at 6 months• Warfarin for 3 months in provoked proximal DVT• Warfarin beyond 3 months in unprovoked proximal DVT if recurrence risk high and no 9additional bleeding risk
WarfarinMost commonly used anticoagulant worldwideHighly effective oral anticoagulantBut it has its limitations….
Target INR rangesIndication Target INRDVT / PE (VTE) 2-3Atrial Fibrillation 2-3Cardiomyopathy 2-3Antiphospholipid syndrome (APLS) 3-4Recurrence of VTE whilst on anticoag 3-4Mechanical heart valves 3-4 British Committee for Standards in Haematology. Br J Haemat 1998; 101: 374-387
AF and stroke risk % of strokes• AF is the leading cause of attributable to AF embolic stroke 25• Risk increases with age 20• Without preventive 15 treatment, approximately 1 % in 20 patients (5%) with AF 10 will have a stroke each year 5• AF related strokes are associated with higher 0 50-59 60-69 70-79 80-89 mortality and more disability Age (years) Kannel WB et al. Am J Cardiol 1998; 82 (8A): 2N–9N.
How does AF lead to stroke? Blood pools in the atria Blood clot forms Whole or part of the blood clot breaks off Blood clot travels to the brain and closes a cerebral artery causing a stroke
CHADS2 CHADS2 is a points-based system for predicting risk of stroke in AF based on key risk factors1 Congestive heart failure 1 point Hypertension 1 point Age >75 years 1 point Diabetes mellitus 1 point Stroke or TIA 2 points The greater the number of points, the greater the risk and need for anti-thrombotic therapy Number of points Recommendation 0 Antiplatelet therapy or nothing 1 Anti-coagulant therapy (or antiplatelet) 2 Oral anticoagulant therapy, such as warfarin1. Gage BF, et al. JAMA 2001; 285: 2864–70; 2. NICE Clinical Guideline 36. Available at: www.nice.org.uk/CG036
*The adjusted stroke rate was derived from multivariate analysis assuming no aspirin usage.Adapted from Gage BF, et al. Validation of clinical classification schemes for predicting stroke: resultsfrom the National Registry of Atrial Fibrillation JAMA.2001;285:2864-2870.
HAS-BLED score Clinical Characteristics Points H Hypertension 1 A Abnormal liver or renal function 1 or 2 S Stroke 1 B Bleeding 1 L Labile INR 1 E Elderly (age > 65) 1 D Drugs or alcohol 1 or 2 Maximum risk score 9Pisters, R., Lane, D.A., Nieuwlaat, R., De Vos, C.B. et al. (2010), A novel user-friendly score (HAS-BLED) to assess one-year risk of major bleeding in atrial fibrillationpatients: The Euro Heart Survey, Chest, 138(5), pp.1093-1100.
Balancing stroke risk vs. harmAre all bleeds equal? •Hb drop of ≥ 2g/dl •Transfusion of ≥ 2 U All bleeding events •Symptomatic bleeding in critical organ Major bleeding •Fatal haemorrhage •Intracranial haemorrhage Life threatening •Hb drop of ≥ 5g/dl bleeding •Transfusion of ≥ 4 U •Inotropic agent support •Surgery
Exercising Caution1. Address uncontrolled hypertension2. Review benefit/risk of concomitant aspirin: – Hypertensives, diabetics, CHD and no acute ischemic event or intervention in the last year Stop aspirin when INR in therapeutic range3. Risk of bleeding is greatest in first 90 days of OAC therapy • Caution : drug interactions and new drugs • Close or more frequent monitoring4. Review concomitant use of NSAIDS5. Consider a PPIHylek, E.M., Evans-Molina, C, Shea, C. et al. (2007), Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial 19fibrillation, Circulation, 115, 2689-2696.
AF and QOF 2012The percentage of patients with AF and CHADS2 score = 1 on anticoagulant or antiplatelet therapyFor patients with AF and CHADS2 score > 1; the percentage of patients who are receiving anticoagulants20
For my patient…… 87 year old man withhypertension
For my patient……ANTICOAGULATE! 87 year old man withhypertension
Warfarin for non-rheumatic AF Warfarin better Placebo better AFASAK SPAF BAATAF CAFA SPINAF EAFT RRR 64%*, ARR 2.7% All trials (95% CI: 49–74%) 100 50 0 –50 –100 RRR (%)† Aspirin RRR 19% 0.7% ARR Random effects model; Error bars = 95% CI; *p>0.2 for homogeneity;Hart RG et al. Ann Intern Med 2007;146:857–67. †Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic)
Warfarin is underused - Why?Patient factors• Refusal, perceived inconvenience• Responsibility associated with INR monitoring• Inadequate knowledgePhysician factors• Over-estimation of potential bleeding and falls risk• Safety factors/monitoring24
The GRASP-AF tool FREEWhat is it?• Series of searches of a GPs clinical system• It identifies patients with a history of AF• It looks for relevant medical history• And medication – warfarin, aspirin, Novel Oral Anticoagulants (NOACs)• It calculates CHADS2 and CHA2DS2-VASc score• Flags up contraindications to oral anticoaglants/other reasons for not taking• Gives a practice over view – Dashboard• Provides various patient lists depending on your chosen search• Gives a simple alert for those at high risk and not on warfarin or a NOACUses free / commonly used software It helps to improves the management of AF in primary care
The GRASP-AF audit tooldashboard view - CHADS2
GRASP data- warfarin prescribing First upload Latest upload (%) (%)South West London Cardiac and Stroke Network 57.29 57.35North of England Cardiovascular Network 57.98 61.34Cardiac and Stroke Networks in Cumbria and Lancashire 40.09 42.39Greater Manchester and Cheshire Cardiac Network 56.55 56.1South Central Vascular Networks 50.81 54.2Kent Cardiovascular Network 54.51 55.77Surrey Heart and Stroke Network 48.13 46.5Avon, Gloucestershire, Wiltshire & Somerset Cardiac and Stroke Network 53.87 56.59Dorset Cardiac and Stroke Network 46.58 50Peninsula Cardiac Managed Clinical Network 53.31 56.26Black Country Cardiovascular Network 47.06 50Herefordshire and Worcestershire Cardiac and Stroke Network 54.96 53.47Shropshire & Staffordshire Heart and Stroke Network 52.01 53.37North & East Yorkshire and Northern Lincolnshire Cardiac and Stroke Network 58.88 58.88West Yorkshire Cardiovascular Network 50.53 51.62National Value 52.74 54.74
Patient 2 66 year old British woman, newly registered patient AF (2009) on warfarin Hypertension
CHADS Vasc at aged 65yrs! But…….anticoagulate now!
Patient 4• 76 year old women with AF and prior stroke• With hypertension, heart failure (LVSD)
• Unfortunately she is bed bound and district nurses are struggling to bleed her…• What other options do we have? – NOACs – Aspirin instead of warfarin – Point of care INR testing – No antithrombotic therapy – Low molecular weight heparin• NB. This patient has a mechanical mitral valve!
• Unfortunately she is bed bound and district nurses are struggling to bleed her…• What other options do we have? – – – Point of care NOACs Aspirin instead of warfarin Point of care INR testing – – testing No antithrombotic therapy Low molecular weight heparin• NB. This patient has a mechanical mitral valve!
Challenging Issues• What about a 93 year old frail old lady with AF? How old is too old?• What about the 56 year old with a history of GI bleed?• Is aspirin treating the doctor or the patient?
Older AF patients less likely to get warfarin Younger Older Gallagher AM et al. J Thromb & Haem 2008;6:1500-1506
Falls – what is the risk? • Markov decision analytic model was used to determine the preferred treatment strategy in patients > 65 yrs/old • Patients need to fall >295 times per year for risk to outweigh benefit • Mean number of falls / year of elderly people who fall: 1.8 Man-Son-Hing et al Arch Intern Med. 1999;159:677-685
• “The decision to not resume warfarin therapy in the 90 days following a GIB event is associated with increased risk for thrombosis and death”• “For many patients who have experienced warfarin-associated GIB, the benefits of resuming anticoagulant therapy will outweigh the risks”
Birmingham Atrial Fibrillation • 2001–2004; 260 GPs in England Treatment of the Aged and Wales • 973 pts 75 years (81.5 ± 4.2) 100 24 (1.8%) • 72% CHADS2 2 Event free survival • 40% on warfarin, 42% on 75 Aspirin (A) Warfarin (W) 48 (3.8%) aspirin • Warfarin (target INR 2–3) or 50 RR = 0.48 Stroke: aspirin (75 mg per day) (0.28–0.80) 0.8% vs. 1.8% • 25 RR = 0.30 10 endpoint - fatal or disabling p = 0.0027 (0.13-0.63) stroke (ischaemic or haemo- p = 0.0004 0 rrhagic), other intracranial 0 1 2 3 4 5 6 haemorrhage, or clinically Years after randomisation significant arterial embolism Intra-cranial haemorrhage on W vs. A: 0.5% vs. 0.4% (RR 1.15, 0.29 – 4.77, n.s.) INR > 3.0: 14% of the time Extra-cranial haemorrhage: 1.4% vs. 1.6% (RR 0.87, 043 – 1.73, n.s.)Mant J et al. Lancet 2007; 370: 493–503.
OAC should not be denied to patientswith CHADS score 1 or more without seeking expert advice
Adverse EffectsBleeding is common… we are talking about anticoagulants….. Even if INR in range: GI/GU bleeds: INR often in range Soft tissue bleed: INR often supra-therapeutic Risk factors: • age >65 • Age >75 with AF (ICH) • Higher target INR range • Hx GI bleed, • Hx stroke, renal insufficiency
Signs and Symptoms of Bleeding• Epistaxis, gum bleeding, bleeding from cuts or scrapes or heavier than usual menstrual period• Severe worsening bruising not due to injury• Red or dark urine• Red or black bowel motions• Coughing blood• Dark or blood stained vomit• Severe headache or dizziness
Bleeding and referral? 1. Where is the source of the bleeding? 2. Intermittent or continuous?•Continuous bleeding •Minor bruising•Haematemesis •Intermittent epistaxis•Haemoptysis •Intermittent gum bleeding•Severe headache/dizziness •Transient haematuria•Malaena•Heavy menstrual bleeding•Continuous bleeding from cut/graze CLINICAL•Continuous haematuria JUDGEMENT A&E Reassure and consider early INR
Also, be aware of key drug interactionsDrug Effect ManagementAmiodarone Warfarin 30-50%Antifungals Avoid, monitor INRBroad-spectrum Avoid, monitor for signs ofantibiotics bleedingAspirin/NSAIDs Avoid, monitor INRMetronidazole Avoid, monitor INR. Will need dose if long-termPhenytoin / Monitor INR
Alcohol Interactions• Intermittent binge drinking can result in higher INR – Alcohol acts as a mild anticoagulant• Chronic alcohol intake can result in lower warfarin concentrations – Metabolic enzyme induction
When to take - Same time each dayAlcohol - May potentiate warfarin – moderation and no binges!Risk of bleeding – Avoid high risk sports! Advice on managing bleedsFollow up - Regular clinic attendanceAspirin - Only if prescribed, and avoid OTC anti-inflammatory drugsReason for taking - AF, DVT, PE, otherInteractions - Drugs – inc OTC; FoodsNotify - GP, Dentist, Pharmacist that takingINR – Target Range WarfarinSkipped dose - Don’t double up CounsellingEnd of course (if appropriate)Dose - 1mg brown 3mg blue 5mg pink
What about these patients…….• A 49 year old male with AF – Hypertension and brittle diabetes – frequent antibiotics for leg ulcers – Resulting in labile INR• A 63 year old female with AF – hair loss with all VKAs, – severe oesophagitis – wants once daily option
An Ideal Anticoagulant Properties BenefitOral, once daily dosing Ease of administration No need for overlapping parenteralRapid onset of action anticoagulantMinimal food or drug interactions Simplified dosingPredictable anticoagulant effect No coagulation monitoringExtra renal clearance Safe in patients with renal disease Simplifies management in case ofRapid offset in action bleeding or interventionAntidote For emergencies
Apixaban versus Aspirin Stroke or Systemic Embolism Major Bleeding • AVERROES trial (double-blind, n = 5,599) • Apixaban far more effective (SSE) than aspirin • Apixaban comparable safety (major bleeds) to aspirin • Apixaban better tolerated than aspirin (d/c 17.9% vs 20.5% per year) 60Granger C et al NEJM 2011
Apixaban versus Warfarin (ARISTOTLE) Stroke or Systemic Embolism 61Connolly S et al NEJM 2011
Novel oral anticoagulants SLCSN Positioning 2012/13 (1) An alternative to warfarin for SPAF in patients with CHADS2 ≥ 1 who:• have a warfarin allergy, warfarin specific- contraindication or are unable to tolerate warfarin therapy• are unable to comply with the specific monitoring requirements of warfarin• are unable to achieve a satisfactory INR after an adequate trial of warfarin• have had an ischaemic stroke whilst stable on warfarin therapy
SLCSN Positioning 2012/13 (2)• Warfarin remains the first-line option for most patients• Initiation by clinicians with ‘expertise in initiating anticoagulation’• Initiating clinician responsible for at least first 3 months of therapy: – Address side effects – Emphasise importance of adherence• Transfer to GP when ‘stable’ and in line with approved indications
For more information….. • Position statement • Prescribing guidance – dabigatran – rivaroxaban • Suggested pathway of care • Transfer of care guidance (TBC) • Patient info leaflet dabigatran vs warfarin • Frequently asked questions
So, what should I do for….?• A 49 year old male with AF – Hypertension and brittle diabetes – frequent antibiotics for leg ulcers – Resulting in labile INR• Started dabigatran 150mg bd – Renal function annually – Assess for side effects (dyspepsia) – Reinforce adherence 65
So, what should I do for…• A 63 year old female with AF – hair loss with all VKAs, – severe oesophagitis – wants once daily option• Started rivaroxaban 20mg daily – Renal function annually – Assess for side effects (headache, syncope) – Reinforce adherence 66
Major bleeding rates• RE-LY: 3.36% warfarin versus 3.11% dabigatran 150mg bd / 2.71% dabigatran 110mg bd – Fewer life threatening bleeds with dabigatran (both doses) – Reduction in intra-cranial haemorrhage (both doses) – More GI bleeds (1.02% warfarin, 1.51% dabigatran 150mg bd / 1.12% dabigatran 110mg bd)• ROCKET-AF: 3.4% warfarin versus 3.6% rivaroxaban – Reduced intra-cranial haemorrhage and fatal bleeds with rivaroxaban – Increased transfusions with rivaroxaban – More GI bleeds (2.2% warfarin versus 3.2% rivaroxaban) 67
Bleeding and referral? 1. Where is the source of the bleeding? 2. Intermittent or continuous?•Continuous bleeding •Minor bruising•Haematemesis •Intermittent epistaxis•Haemoptysis •Intermittent gum bleeding•Severe headache/dizziness •Transient haematuria•Malaena•Heavy menstrual bleeding•Continuous bleeding from cut/graze CLINICAL•Continuous haematuria JUDGEMENT A&E Reassure and consider referral
Adherence• No way to know if the patient is complying• Not suitable as an alternative to warfarin if compliance is an issue• Need to reinforce adherence at every opportunity – Initiation – First prescription (NMS) – Subsequent clinical reviews – At each repeat prescription and supply69
Counselling• Reduces the chance of unwanted blood clots forming which helps prevent strokes• Take regularly - any time is ok – Forgotten doses • W – if before midnight • D – if within 6 hrs of next dose (miss) • R – take immediately, do not double within the same day• Like all medicines – unwanted side effects – If unusual bleeding, such as dark or bloody stools, urine or unexplained bruising tell your doctors – NSAIDs can’t be taken with anticoagulants – Specifics Dabigatran- indigestion; rivaroxaban- dizziness, headache
What about difficult to managepatients in VTE?• 27 year old African with DVT – warfarin requirement 35mg – difficult to maintain INR 2-3• 84 year old man PE 10 years ago – Was prescribed warfarin – Had a subdural and told never to have warfarin again – Creatinine clearance 46mls/min
EINSTEIN DVT: primary efficacy outcome 4.0 Cumulative event rate (%) Enoxaparin/VKA (n=1,718) 3.0 Rivaroxaban (n=1,731) 2.0 HR=0.68; p<0.001 1.0 0 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) Number of subjects at risk Rivaroxaban 1,731 1,668 1,648 1,621 1,424 1,412 1,220 400 369 363 345 309 266 Enoxaparin/ 1,718 1,616 1,581 1,553 1,368 1,358 1,186 380 362 337 325 297 264 VKAThe EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510
Issues in VTE management• Which patients? – Patients on long-term LMWH / patients in whom warfarin is unsuitable (as per AF guidance) – All patients?• Who should prescribe? – Acute vs primary care – Dose adjustment at 3 weeks – Duration – appropriate cessation at ??? months• Monitoring renal function• Adherence 76
Back to our patients with VTE• 27 year old African male with DVT – warfarin requirement 35mg – difficult to maintain INR between 2-3• Rivaroxaban 20mg daily
Back to our patients with VTE• 84 year old man PE 10 years ago – Was prescribed warfarin – Had a subdural and told never to have warfarin again – Creatinine clearance 46mls/min• Cautiously; rivaroxaban 15mg daily
In Summary: Oral AnticoagulationIndication Oral anticoagulant Warfarin Dabigatran Rivaroxaban INR rangeVTE prophylaxis following 2-3 220mg od 10mg odhip/knee replacement surgery 10-35 days 2-5 weeksPrevention of thromboembolic 2-3 150mg bd 20mg odevents in non valvular AF (110mg bd in (15mg od in selectedLong term selected patients) patients)Treatment of DVT 2-3 No license at 15mg bd for 3 weeks3-6 months present then 20mg od (15mg od)Prosthetic valves 2- 4 No license at No license at presentLong term (depending on present locations)