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New Oral anticoagulants: An Updated Review of Target-Specific Oral Anticoagulants Used in Stroke Prevention in Atrial Fibrillation.

New Oral anticoagulants: An Updated Review of Target-Specific Oral Anticoagulants Used in Stroke Prevention in Atrial Fibrillation.

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  • JAMA. 2001 May 9;285(18):2370-5.Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE.Source Division of Research, Kaiser Permanente of Northern California, 3505 Broadway, 12th Floor, Oakland, CA 94611, USA. axg@dor.kaiser.orgCONTEXT: Atrial fibrillation is the most common arrhythmia in elderly persons and a potent risk factor for stroke. However, recent prevalence and projected future numbers of persons with atrial fibrillation are not well described.OBJECTIVE: To estimate prevalence of atrial fibrillation and US national projections of the numbers of persons with atrial fibrillation through the year 2050.DESIGN, SETTING, AND PATIENTS: Cross-sectional study of adults aged 20 years or older who were enrolled in a large health maintenance organization in California and who had atrial fibrillation diagnosed between July 1, 1996, and December 31, 1997.MAIN OUTCOME MEASURES: Prevalence of atrial fibrillation in the study population of 1.89 million; projected number of persons in the United States with atrial fibrillation between 1995-2050.RESULTS: A total of 17 974 adults with diagnosed atrial fibrillation were identified during the study period; 45% were aged 75 years or older. The prevalence of atrial fibrillation was 0.95% (95% confidence interval, 0.94%-0.96%). Atrial fibrillation was more common in men than in women (1.1% vs 0.8%; P<.001). We estimate approximately 2.3 million US adults currently have atrial fibrillation. We project that this will increase to more than 5.6 million (lower bound, 5.0; upper bound, 6.3) by the year 2050, with more than 50% of affected individuals aged 80 years or older.CONCLUSIONS: Our study confirms that atrial fibrillation is common among older adults and provides a contemporary basis for estimates of prevalence in the United States. The number of patients with atrial fibrillation is likely to increase 2.5-fold during the next 50 years, reflecting the growing proportion of elderly individuals. Coordinated efforts are needed to face the increasing challenge of optimal stroke prevention and rhythm management in patients with atrial fibrillation.PMID: 11343485 
  • Lifetime risk for development of atrial fibrillation: the Framingham Heart Study.Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, D'Agostino RB, Massaro JM, Beiser A, Wolf PA, Benjamin EJ. Circulation. 2004 Aug 31;110(9):1042-6. Epub 2004 Aug 16.PMID: 15313941 Circulation. 2004 Aug 31;110(9):1042-6. Epub 2004 Aug 16. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, D'Agostino RB, Massaro JM, Beiser A, Wolf PA, Benjamin EJ.Source Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University Feinberg School of Medicine, 680 N Lake Shore Drive, Suite 1102, Chicago, IL, 60611, USA. dlj@northwestern.eduBACKGROUND: Atrial fibrillation (AF) is the most common cardiac dysrhythmia and a source of considerable morbidity and mortality, but lifetime risk for AF has not been estimated.METHODS AND RESULTS: We included all participants in the Framingham Heart Study who were free of AF at index ages of 40 years and older. We estimated lifetime risks for AF (including atrial flutter) to age 95 years, with death free of AF as a competing event. We followed 3999 men and 4726 women from 1968 to 1999 (176 166 person-years); 936 participants had development of AF and 2621 died without prior AF. At age 40 years, lifetime risks for AF were 26.0% (95% CI, 24.0% to 27.0%) for men and 23.0% (21.0% to 24.0%) for women. Lifetime risks did not change substantially with increasing index age despite decreasing remaining years of life because AF incidence rose rapidly with advancing age. At age 80 years, lifetime risks for AF were 22.7% (20.1% to 24.1%) in men and 21.6% (19.3% to 22.7%) in women. In further analyses, counting only those who had development of AF without prior or concurrent congestive heart failure or myocardial infarction, lifetime risks for AF were approximately 16%.CONCLUSIONS: Lifetime risks for development of AF are 1 in 4 for men and women 40 years of age and older. Lifetime risks for AF are high (1 in 6), even in the absence of antecedent congestive heart failure or myocardial infarction. These substantial lifetime risks underscore the major public health burden posed by AF and the need for further investigation into predisposing conditions, preventive strategies, and more effective therapies.
  • Chest. 2010 Feb;137(2):263-72. Epub 2009 Sep 17.Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ.Source University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK. g.y.h.lip@bham.ac.ukBACKGROUND: Contemporary clinical risk stratification schemata for predicting stroke and thromboembolism (TE) in patients with atrial fibrillation (AF) are largely derived from risk factors identified from trial cohorts. Thus, many potential risk factors have not been included.METHODS: We refined the 2006 Birmingham/National Institute for Health and Clinical Excellence (NICE) stroke risk stratification schema into a risk factor-based approach by reclassifying and/or incorporating additional new risk factors where relevant. This schema was then compared with existing stroke risk stratification schema in a real-world cohort of patients with AF (n = 1,084) from the Euro Heart Survey for AF.RESULTS: Risk categorization differed widely between the different schemes compared. Patients classified as high risk ranged from 10.2% with the Framingham schema to 75.7% with the Birmingham 2009 schema. The classic CHADS(2) (Congestive heart failure, Hypertension, Age > 75, Diabetes, prior Stroke/transient ischemic attack) schema categorized the largest proportion (61.9%) into the intermediate-risk strata, whereas the Birmingham 2009 schema classified 15.1% into this category. The Birmingham 2009 schema classified only 9.2% as low risk, whereas the Framingham scheme categorized 48.3% as low risk. Calculated C-statistics suggested modest predictive value of all schema for TE. The Birmingham 2009 schema fared marginally better (C-statistic, 0.606) than CHADS(2). However, those classified as low risk by the Birmingham 2009 and NICE schema were truly low risk with no TE events recorded, whereas TE events occurred in 1.4% of low-risk CHADS(2) subjects. When expressed as a scoring system, the Birmingham 2009 schema (CHA(2)DS(2)-VASc acronym) showed an increase in TE rate with increasing scores (P value for trend = .003).CONCLUSIONS: Our novel, simple stroke risk stratification schema, based on a risk factor approach, provides some improvement in predictive value for TE over the CHADS(2) schema, with low event rates in low-risk subjects and the classification of only a small proportion of subjects into the intermediate-risk category. This schema could improve our approach to stroke risk stratification in patients with AF.Comment inCHA2DS2-VASc risk scheme: not ready for clinical use. [Chest. 2010]Obstructive sleep apnea is a risk factor for stroke and atrial fibrillation. [Chest. 2010]
  • SOURCE GIVEN IN ORIGINAL SLIDE SET: Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. J Am Coll Cardiol. 2012 Jul 24. [Epub ahead of print] PMID: 22858389Am Coll Cardiol. 2012 Jul 24. [Epub ahead of print]Performance of the HEMORR(2)HAGES, ATRIA, and HAS-BLED Bleeding Risk-Prediction Scores in Patients With Atrial Fibrillation Undergoing Anticoagulation: The AMADEUS (Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation) Study.Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY.Source University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom.OBJECTIVES:The objective of this study was to compare the predictive performance of bleeding risk-estimation tools in a cohort of patients with atrial fibrillation (AF) undergoing anticoagulation.BACKGROUND:Three bleeding risk-prediction schemes have been derived for and validated in patients with AF: HEMORR(2)HAGES (Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-Bleeding, Hypertension, Anemia, Genetic Factors, Excessive Fall Risk and Stroke), ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation), and HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio, Elderly, Drugs/Alcohol). Τhe relative predictive values of these bleeding scores have not previously been compared.METHODS:We analyzed the dataset from the AMADEUS (Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation) trial, a multicenter, randomized, open-label noninferiority study that compared fixed-dose idraparinux with adjustable-dose oral vitamin K antagonist therapy in patients with AF. The principal safety outcome was any clinically relevant bleeding event, which was a composite of major bleeding plus clinically relevant nonmajor bleeding.RESULTS:The HAS-BLED score performed best in predicting any clinically relevant bleeding, reflected both in net reclassification improvement (10.3% and 13% improvement compared with HEMORR(2)HAGES and ATRIA, respectively) and receiver-operating characteristic (ROC) analyses (c-indexes: 0.60 vs. 0.55 and 0.50 for HAS-BLED vs. HEMORR(2)AGES and ATRIA, respectively). Using decision-curve analysis, the HAS-BLED score demonstrated superior performance compared with ATRIA and HEMORR(2)HAGES at any threshold probability for clinically relevant bleeding. HAS-BLED was the only score that demonstrated a significant predictive performance for intracranial hemorrhage (c-index: 0.75; p = 0.03). An ATRIA score >3 was not significantly associated with the risk for any clinically relevant bleeding on Cox regression or on ROC analysis (c-index: 0.50; p = 0.87).CONCLUSIONS:All 3 tested bleeding risk-prediction scores demonstrated only modest performance in predicting any clinically relevant bleeding, although the HAS-BLED score performed better than the HEMORR(2)HAGES and ATRIA scores, as reflected by ROC analysis, reclassification analysis, and decision-curve analysis. Only HAS-BLED demonstrated a significant predictive performance for intracranial hemorrhage. Given its simplicity, the HAS-BLED score may be an attractive method for the estimation of oral anticoagulant-related bleeding risk for use in clinical practice, supporting recommendations in international guidelines.Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
  • Let us see which of our anticoagulants both contemporary and newer, who can come even close to these……
  • Am J Cardiol. 2012 Aug 1;110(3):453-60. Epub 2012 Apr 24.Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation.Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ.SourceDivision of Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada; Faculty of Medicine, McGill University, Montreal, Quebec, Canada.AbstractNew oral anticoagulants, including apixaban, dabigatran, and rivaroxaban, have been developed as alternatives to warfarin, the standard oral anticoagulation therapy for patients with atrial fibrillation (AF). A systematic review and meta-analysis of randomized controlled trials was performed to compare the efficacy and safety of new oral anticoagulants to those of warfarin in patients with AF. The published research was systematically searched for randomized controlled trials of >1 year in duration that compared new oral anticoagulants to warfarin in patients with AF. Random-effects models were used to pool efficacy and safety data across randomized controlled trials. Three studies, including 44,563 patients, were identified. Patients randomized to new oral anticoagulants had a decreased risk for all-cause stroke and systemic embolism (relative risk [RR] 0.78, 95% confidence interval [CI] 0.67 to 0.92), ischemic and unidentified stroke (RR 0.87, 95% CI 0.77 to 0.99), hemorrhagic stroke (RR 0.45, 95% CI 0.31 to 0.68), all-cause mortality (RR 0.88, 95% CI 0.82 to 0.95), and vascular mortality (RR 0.87, 95% CI 0.77 to 0.98). Randomization to a new oral anticoagulant was associated with a lower risk for intracranial bleeding (RR 0.49, 95% CI 0.36 to 0.66). Data regarding the risks for major bleeding (RR 0.88, 95% CI 0.71 to 1.09) and gastrointestinal bleeding (RR 1.25, 95% CI 0.91 to 1.72) were inconclusive. In conclusion, the new oral anticoagulants are more efficacious than warfarin for the prevention of stroke and systemic embolism in patients with AF. With a decreased risk for intracranial bleeding, they appear to have a favorable safety profile, making them promising alternatives to warfarin.Copyright © 2012 Elsevier Inc. All rights reserved.
  • Figure 3. Forest plot for (A) major bleeding, (B) intracranial bleeding, and (C) gastrointestinal bleeding, new oral anticoagulants (NOA) versus warfarin in patients with AF.Am J Cardiol. 2012 Aug 1;110(3):453-60. Epub 2012 Apr 24.Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ.Source Division of Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada; Faculty of Medicine, McGill University, Montreal, Quebec, Canada.Abstract New oral anticoagulants, including apixaban, dabigatran, and rivaroxaban, have been developed as alternatives to warfarin, the standard oral anticoagulation therapy for patients with atrial fibrillation (AF). A systematic review and meta-analysis of randomized controlled trials was performed to compare the efficacy and safety of new oral anticoagulants to those of warfarin in patients with AF. The published research was systematically searched for randomized controlled trials of >1 year in duration that compared new oral anticoagulants to warfarin in patients with AF. Random-effects models were used to pool efficacy and safety data across randomized controlled trials. Three studies, including 44,563 patients, were identified. Patients randomized to new oral anticoagulants had a decreased risk for all-cause stroke and systemic embolism (relative risk [RR] 0.78, 95% confidence interval [CI] 0.67 to 0.92), ischemic and unidentified stroke (RR 0.87, 95% CI 0.77 to 0.99), hemorrhagic stroke (RR 0.45, 95% CI 0.31 to 0.68), all-cause mortality (RR 0.88, 95% CI 0.82 to 0.95), and vascular mortality (RR 0.87, 95% CI 0.77 to 0.98). Randomization to a new oral anticoagulant was associated with a lower risk for intracranial bleeding (RR 0.49, 95% CI 0.36 to 0.66). Data regarding the risks for major bleeding (RR 0.88, 95% CI 0.71 to 1.09) and gastrointestinal bleeding (RR 1.25, 95% CI 0.91 to 1.72) were inconclusive. In conclusion, the new oral anticoagulants are more efficacious than warfarin for the prevention of stroke and systemic embolism in patients with AF. With a decreased risk for intracranial bleeding, they appear to have a favorable safety profile, making them promising alternatives to warfarin. Copyright © 2012 Elsevier Inc. All rights reserved.
  • Table III. Suggestions for Reversal of New Oral AnticoagulantsKaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, Chan AK, James A, Moll S, Ortel TL, Van Cott EM, Ansell J.Am J Hematol. 2012 May;87 Suppl 1:S141-5. doi: 10.1002/ajh.23202. Epub 2012 Apr 4. Review.PMID: 22473649Am J Hematol. 2012 May;87 Suppl 1:S141-5. doi: 10.1002/ajh.23202. Epub 2012 Apr 4.Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors.Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, Chan AK, James A, Moll S, Ortel TL, Van Cott EM, Ansell J.SourceDepartment of Medicine, Henry Ford Hospital, Detroit, Michigan 48202, USA. skaatz1@hfhs.org.AbstractThe new oral anticoagulants dabigatran, rivaroxaban and apixaban have advantages over warfarin which include no need for laboratory monitoring, less drug-drug interactions and less food-drug interactions. However, there is no established antidote for patients who are bleeding or require emergent surgery and there is a paucity of evidence to guide the clinical care during these situations. Members of thrombosis and anticoagulation groups participating in the Thrombosis and Hemostasis Summit of North America formulated expert opinion guidance for reversing the anticoagulant effect of the new oral anticoagulants and suggest: routine supportive care, activated charcoal if drug ingestion was within a couple of hours, and hemodialysis if feasible for dabigatran. Also, the pros and cons of the possible use of four factor prothrombin complex concentrate are discussed.Copyright © 2012 Wiley Periodicals, Inc.

New Oral anticoagulants New Oral anticoagulants Presentation Transcript

  • An Updated Review of Target-Specific Oral Anticoagulants Used in Stroke Prevention in Atrial Fibrillation Diya Saleh Registrar, BPT
  • Question #1 An 82 year old man. What is the chance he has atrial fibrillation? A. B. C. D. 1% 5% 10% 25%
  • Prevalence of Diagnosed AF Stratified by Age and Sex 12.0 10.0 Women Men 11.1 10.3 9.1 8.0 7.3 6.0 5.0 4.0 3.0 1.7 2.0 0.0 0.1 0.2 0.4 <55 0.9 7.2 5.0 x-axis = % y-axis = # of men/women 3.4 1.7 1.0 55-59 60-64 65-69 70-74 75-79 80-84 > 85 # Women 530 310 566 896 1498 1572 1291 1132 # Men 1529 634 934 1426 1907 1886 1374 759 Go AS, JAMA. 2001 May 9;285(18):2370-5. Pub Med PMID: 11343485
  • Question #2 A 46 year old. What is his lifetime risk of developing AF? A. B. C. D. 1% 5% 10% 25%
  • Incidence of AF Lifetime Risk for AF at Selected Index Ages by Sex Index Age, yrs Men Women 40 26.0% (24.0 – 27.0) 23.0% (21.0 – 24.0) 50 25.9% (23.9 – 27.0) 23.2% (21.3 – 24.3) 60 25.8% (23.7 – 26.9) 23.4% (21.4 – 24.4) 70 24.3% (22.1 – 25.5) 23.0% (20.9 – 24.1) 80 22.7% (20.1 – 24.1) 21.6% (19.3 – 22.7) 1 in 4 Men & women >40 Years will develop AF Lifetime risk if currently free of AF Lloyd-Jones DM, et al. Circulation. 2004 Aug 31;110(9):1042-6. Pub Med PMID: 15313941.
  • Question #3 68 year old female with atrial fibrillation and no other co-morbidities. How would you classify her stroke risk? A. Low B. Moderate C. High
  • CHA2DS2-VASc 2009 Birmingham Schema Expressed as a Point-Based Scoring System Risk Factor Congestive heart failure/LV dysfunction Hypertension Age ≥ 75 y Diabetes mellitus Stroke/TIA/TE Vascular disease (prior myocardial infarction, peripheral artery disease, or aortic plaque) Age 65-74 y Sex category (i.e. female gender) LV = left ventricular; TE = thromboembolism Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Chest. 2010 Feb;137(2):263-72. Pub Med PMID: 19762550. Score 1 1 2 1 2 1 1 1
  • Question #3 68 year old female with atrial fibrillation and no other co-morbidities. How would you classify her stroke rate per year? A. B. C. D. 1% 2% 3% 4%
  • Question #4 78 year old male with atrial fibrillation and hypertension (CHADS2 score = 2 [4% stroke rate per year]). What is his annual major bleeding rate? A. B. C. D. E. 1% 2% 3% 5% 10%
  • Bleeding Risk Scores in AF
  • Bleeding Risk Scores in AF ATRIA HAS-BLED HEMORR2HAGES Anemia1 3 Hypertension4 1 Hepatic10 or disease2 1 1 Severe renal disease2 3 Abnormal Renal5 or 1 1 Ethanol abuse 1 Age ≥75 yrs 2 Stroke 1 Malignancy 1 Any prior hemorrhage 1 Bleeding 1 Older Age (>75 yrs) 1 Hypertension3 1 Labile INR8 1 Reduced platelet number 1 Elderly (>65 yrs) 1 Rebleeding12 2 Drugs9 or 1 1 Hypertension4 1 Anemia13 1 Genetic factors14 1 Excessive fall risk15 1 Stroke 1 1. 2. 3. 4. 5. 6. 8. 9. 10. 11. 12. 13. 14. 15. Liver function6 Hemoglobin <13 g/dl men; <12 g/dl women Estimated glomerular filtration rate <30 ml/min or dialysis-dependent Diagnosed hypertension Systolic blood pressure >160 mmHg Presence of chronic dialysis or renal transplantation or serum creatinine ≥200 mmol/L Chronic hepatic disease (eg cirrhosis) or biochemical evidence of significant hepatic derangement (eg bilirubin 2 x upper limit of normal, in association with aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase >3 x upper limit normal, etc.) Unstable/high INRs or poor time in therapeutic range (eg <60%) Concomitant use of drugs, such as antiplatelet agents, non-steroidal anti-inflammatory drugs, or alcohol abuse etc. Cirrhosis, two-fold or greater elevation of AST or APT, or albumin <3.6 g/dl Platelets <75,000, use of antiplatelet therapy (eg daily aspirin) or NSAID therapy; or blood dyscrasia Prior hospitalization for bleeding Most recent hematocrit <30 or hemoglobin <10 g/dl CYP2C9*2 and/or CYP2C9*3 Alzheimer's dementia, Parkinson's disease, schizophrenia, or any condition predisposing to repeated falls Alcohol Renal or function11 Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. J Am Coll Cardiol 2012;60:000–000. 2012 Jul 24. [Epub ahead of print] Online Appendix. PMID: 22858389.
  • Question #5 78 year old female with atrial fibrillation on warfarin, hypertension and CHF. How many times she needs to fall in a year for the calculated risk of subdural hematoma from falling to outweigh the stroke reduction benefit of warfarin? A. B. C. D. E. 10 times 30 times 100 times 300 times 600 times
  • Anticoagulation and Risk of Falls in the Elderly – Putting Matters in Perspective • The risk of a subdural hematoma from falling is so small. • A patient with a 5% annual stroke risk from AF would need to fall 300 times in a year for the calculated risk of subdural hematoma from falling to outweigh the stroke reduction benefit of warfarin. • • Man-Son-Hing M, Laupacis A. Anticoagulant-related bleeding in older persons with atrial fibrillation: physicians' fears often unfounded. Arch Intern Med 2003; 163:1580. Man-Son-Hing M, Nichol G, Lau A, Laupacis A. Choosing antithrombotic therapy for elderly patients with atrial fibrillation who are at risk for falls. Arch Intern Med 1999; 159:677. • Sellers MB, Newby LK. Atrial fibrillation, anticoagulation, fall risk, and outcomes in elderly patients. Am Heart J 2011; 161:241.
  • The Old Story of Warfarin
  • Warfarin the underdog! • Is NOT rat poison – Rats have evolved (and so should you…) • Advantages of warfarin – Active by the oral route – Once daily dosing – Can be monitored • • • • Surgeries Bleeding episodes Recurrent events Adherence – Rapidly-acting antidote available – Low cost
  • Problems with Warfarin • Food and drug interactions • Genetic variation in metabolism • dosage adjustments & freq. monitor with INR narrow therapeutic window overlap with parenteral drugs • slow onset of action
  • A Cardiologist’s Perspective: On The Shifting Role of Warfarin • Warfarin has important limitations that contribute to underutilization and poor INR control – 3 of 4 patients with AF are unprotected or poorly protected against stroke • Warfarin will continue to play an important role: – For other indications (e.g., prosthetic valves) – In patients with renal impairment (i.e., CrCl < 15 ml/min)
  • Novel Oral Anticoagulants: Breakthrough or Just Another Bleeding Mess? Are they better than what we have?
  • Both efficacy and safety are important, imbalance in efficacy and safety may result in patient harm
  • Thrombosis Optimal Safety and Efficacy Bleeding Dose (concentration) of Anticoagulant
  • Why Bother To Innovate? • It’s just too bad that • • • • You wouldn’t necessarily get there on time Comfort would be a significant problem Forget about “hands free” anything And who needs seat belts, automatic transmission, parking/lane change/braking assist, etc., anyway?
  • Why Bother To Innovate? Safety and convenience are overrated and not worth the money; you’ll still get from point A to point B… Maybe... • If you are unlucky enough to crash you will probably survive • And while you are unlikely ever to be able to replace any broken parts, well… just get someone else to drive you the next time
  • AN “IDEAL” ANTI COAGULANT • • • • • „Fixed‟ „oral‟ dose No need for dose adjustment Wide therapeutic range Acceptable bleeding risks No need for monitoring
  • Target-Specific Oral Anticoagulants
  • Potential Limitations of New Anticoagulants • Antidotes – None of the newer agents has a specific antidote • • • • • • Monitoring Adverse Drug Events Compliance Cost Clinical Trials vs. Actual Clinical Practice Patient populations not even studied (i.e. Cancer)
  • No blood monitoring is an advantage of NOACs but it is also a major disadvantage…
  • Comparison of Warfarin With TargetSpecific Oral Anticoagulants
  • Non-Valvular Atrial Fibrillation Studies Trial RE-LY ARISTOTLE ROCKET-AF Design Randomized Open Label N=18,113 Randomized Double blind N=18,209 Randomized double blind & dummy N=14,000 Treatment Dabigatran 150 mg, BID 110 mg, BID Apixaban 5 mg, BID Rivaroxaban 20 mg, Qday Comparator Warfarin 2-3 (67% TTR) Warfarin 2-3 (66% TTR) Warfarin 2-3 (57.8% TTR) Mean CHADS2 2.1 2.1 3.5 Time Therapeutic Range = TTR Modified Ahrens I, et al Thromb Haemost 2011;105
  • Primary Endpoints Atrial Fibrillation Trials Study NOAC VKA Outcome RE-LY Dabigatran 1.1% Warfarin 1.7% RR 0.66 95% CI 0.53-0.82 P < 0.001 superiority ARISTOTLE Apixaban 1.3% Warfarin 1.6% HR 0.79 95% CI 0.66-0.95 P= < 0.001 Non- I P= 0.01 Superiority ROCKET-AF Rivaroxaban 1.7% Warfarin 2.2% HR 0.79 95% CI 0.66-0.96 P = <0.001 Non-Inferiority
  • Major Bleeding Atrial Fibrillation Trials Study NOAC VKA Outcome RE-LY Dabigatran 3.3% Warfarin 3.6% RR 0.93 95% CI 0.81-1.07 P = 0.31 ARISTOTLE Apixaban 2.1% Warfarin 3.1% HR 0.69 95% CI 0.60-0.8 P = < 0.001 ROCKET-AF Rivaroxaban 5.6% Warfarin 5.4% HR 1.04 95% CI 0.90-1.20 P = 0.58
  • Intracranial Hemorrhage Atrial Fibrillation Trials Study NOAC VKA Outcome RE-LY Dabigatran 0.3% Warfarin 0.7% RR 0.40 95% CI 0.27-0.60 P= <0.001 ARISTOTLE Apixaban 0.3% Warfarin 0.8% HR 0.42 95% CI 0.30-0.58 P = <0.001 ROCKET-AF Rivaroxaban 0.5% Warfarin 0.7% HR 0.67 95% CI 0.47-0.93 P = 0.02
  • Meta-analysis of Efficacy and Safety of New Oral Anticoagulants Dabigatran, Rivaroxaban, Apixaban vs. Warfarin in AF patients All cause stroke/SEE Ischemic and unspecified stroke Hemorrhagic stroke Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Am J Cardiol. 2012 Aug 1;110(3):453-60. Pub Med PMID: 22537354..
  • Meta-analysis of Efficacy and Safety of New Oral Anticoagulants Dabigatran, Rivaroxaban, Apixaban vs. Warfarin in AF patients Major bleeding Intracranial bleeding GI Bleeding Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Am J Cardiol. 2012 Aug 1;110(3):453-60. Pub Med PMID: 22537354.
  • Reversal of NOACs Suggestions for Reversal of New Oral Anticoagulants Apixaban Dabigatran Rivaroxaban Oral activated charcoal Yes Yes Yes Hemodialysis No Yes No Hemoperfusion with activated charcoal Possible Yes Possible Fresh frozen plasma No No No Activated factor VIIa Unclear Unclear Unclear 3-factor PCC Unclear Unclear Unclear 4-factor PCC Possible Possible Possible PCC: prothrombin complex concentrate, PCCs with normal amounts of VII are known as 4-factor PCCs whilst the products without VII are 3-factor PCCs Kaatz S, et al. Am J Hematol. 2012 May;87 Suppl 1:S141-5. Pub Med PMID: 22473649.
  • Laboratory Testing New Oral Agents Lab Tests Useful Dabigatran Rivaroxaban Lab Test Strong ECT Chromogenic Anti-Xa TT Apixaban Chromogenic Anti -Xa aPTT, PT aPTT Weak PT / INR ECT: Ecarin clotting time Palladino M et al A J Hem 2012;87 Suppl:S127-S132
  • Optimal Candidates for New Drugs Patients who: •Find INR testing burdensome •Despite adherence to provider recommendations, have low ‘time-in-range’ •Can afford (or arrange to get) the new drugs •Have normal renal function
  • Optimal Candidates for Warfarin Patients who: •Have (borderline) renal insufficiency •Are taking stable dose of warfarin and do not find INR testing burdensome •Have access to self-testing machine •Are concerned about the lack of an evidencebased reversal strategy
  • Choice of Anticoagulant Based on Patient Characteristics? Characteristic Drug Choice Rationale Mechanical or valvular AF Warfarin New agents not studied Liver dysfunction with elevated INR Warfarin New agents require hepatic metabolism Poor compliance Warfarin or nothing Missed doses of greater consequence with shorter acting agents Stable on warfarin Warfarin Consider switching at patient request CrCl < 30 mL/min Warfarin Such patients were excluded from trials with new agents CrCl of 30-50 mL/min Rivaroxaban or Apixaban Oral Xa inhibitors are less affected by impaired renal function than dabigatran Dyspepsia or upper GI complaints Rivaroxaban or Apixaban Dyspepsia in up to 10% given dabigatran Recent GI bleed Apixaban More GI bleeding with dabigatran (150 mg BID) or rivaroxaban than with warfarin Recent ischemic stroke on Warfarin Dabigatran Dabigatran (150 mg BID) associated with lowest risk of ischemic stroke vs warfarin Recent acute coronary syndrome Rivaroxaban or Apixaban Small MI signal with dabigatran Poor compliance with BID regimen or desire for once daily Rivaroxaban Only oral agent that is currently once a day Adapted/modified from Weitz & Gross, Hematology 2012:536-40
  • A Cardiologist's Perspective: On The Evolving Treatment Paradigm for Stroke Prevention in AF • Compared with warfarin, each of the 3 new agents: – Are at least as effective in preventing stroke/systemic embolism – Are associated with less intracranial bleeding – Are associated with similar or less major bleeding – Offer greater ease of use
  • Some Final Insane Musings • Imagine if the novel anticoagulants had been established therapy for some 6 decades and a new drug appeared that: – Was unpredictable in terms of patient therapeutic response – Had slow therapeutic onset and offset – Had a narrow therapeutic window – Required close monitoring via frequent blood tests – Required frequent dose adjustment – Was plagued by drug-drug and drug-food interactions – Was associated with more intracranial haemorrhage – Resulted in a 10% increase in mortality Would anyone in their right mind think it had a chance of getting to market and, if it did, would anyone prescribe it?
  • • “HAD WARFARIN INTRODUCED INTO THE MARKET TODAY, THE US FDA WOULD HAVE REJECTED” -A FAMOUS CARDIOLOGIST DURING THE ESC “BUT STILL, WARFARIN REMAINS OUR POOR MAN‟S CHOICE”
  • Final Quiz Warfarin-induced Skin Necrosis
  • The Hope for Excellence
  • THANK YOU !!!