Old Agent, New Agent or No Agent? The Decision to Anticoagulate Patients with Atrial Fibrillation. Daniel E. Singer, MD

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1 AHA International Stroke Conference, Pre-Con Symposium, February 5, 2013 Old Agent, New Agent or No Agent? The Decision to Anticoagulate Patients with Atrial Fibrillation Daniel E. Singer, MD Massachusetts General Hospital Harvard Medical School

2 Status of Oral Anticoagulants for AF, approved NOACs; 1 pivotal RCT left New indications, contraindications Multiple secondary studies from pivotal trials Accumulating clinical experience, particularly with dabigatran; FDA reports Main message: The novel anticoagulants look very good. But well-controlled warfarin remains a good choice, as well. 2

3 Stroke Prevention in AF: Core Facts 1. AF is the most common significant arrhythmia 2. AF prevalence strongly age-dependent 10% of age 80+ years 3. RR for stroke = 5; AF accounts for 15+% of all strokes in U.S. 4. Multiple RCTs: Warfarin reduces the risk of ischemic stroke by 68% (ITT). In primary prevention, the tradeoff: 15 ischemic strokes for 1 ICH. 5. ASA s effect is negligible to small.

4 The Optimal INR for AF Circ Cardiovasc Qual Outcomes 2009;2:

5 Anticoagulation for AF: For Whom? Guideline perspective: Anticoagulate AF patients whose risk of stroke is high enough to merit the burden and risk of warfarin therapy. ASA or no antithrombotic for others.

6 CHADS 2 Scoring System* Risk Factor Score Congestive heart failure (LV dysfunction) 1 Hypertension 1 Age 75 1 Diabetes mellitus 1 Stroke, TIA, thromboembolism 2 Range 0-6 N.B: Applies to paroxysmal AF (PAF), as well *Gage, et al. JAMA 2001; 285(22):

7 CHA 2 DS 2 -VASc Scoring System Risk Factor Score Congestive heart failure/lv dysfunction 1 Hypertension 1 Age 75 2 Diabetes mellitus 1 Stroke, TIA, thromboembolism 2 Vascular disease 1 Age Sex category (i.e. female sex) 1 Maximum score 9 Note: Maximum score is 9 since age may contribute 0, 1 or 2 points. Eur Heart J Oct;31(19): Epub 2010 Aug 29.

8 AT9 Stroke Prevention Guidelines* Clinical Profile (Applies to PAF, as well) CHADS non-stroke/tia RF: CHADS 2 =1 0 RF: CHADS 2 =0 Treatment Recommendation OAC, Warf., INR 2-3, vs no Rx: 1A OAC >(C+A)>ASA: 1B OAC, Warfarin, INR 2-3: 2B No AT Rx: 2B Other RFs to consider: age 65-74, female; renal dysfn, e.g., egfr <60 * ACCP 9 (Chest 2012; 141 (2)(Suppl):e531S-e575S);

9 Warfarin works, but there are many problems with achieving high quality warfarin anticoagulation.

10 Clotting Cascade and Drug Antagonists Nature 2009;45:

11 Novel Anticoagulants Direct thrombin or factor Xa inhibitors Where warfarin blocks the synthesis of functional clotting factors (II, VII, IX, X), the new anticoagulants competitively inhibit single key activated factors in the bloodstream and site of thrombus. Anticoagulant effect: rapid onset and offset; warfarin effect is slow and steady.

12 Rivaroxaban Pharmacokinetics Eur J Clin Pharmacol 2005;61:

13 Dabigatran DTI for AF: The RE-LY Trial: Fast-acting (~2 hr), specific competitive direct thrombin inhibitor (DTI) No dose adjustment, no regular monitoring 80% excreted by kidney Half-life of hours Clin Pharmacokinet 2008;47: ; N Engl J Med 2009;361(12):

14 Design of RE-LY Atrial Fibrillation 1 Risk Factor Absence of contraindications 951 centers in 44 countries R Open** Warfarin (INR ) N=6000 Dabigatran Etexilate 110 mg BID N=6000 Dabigatran Etexilate 150 mg BID N=6000 Primary efficacy outcome = all stroke or systemic embolism Primary safety outcome = major bleeding Non-inferiority margin: RR of 1.46

15 RE-LY: Trial Execution Median CHADS 2 = 2 Median follow-up of 2.0 years Mean TTR = 64% (patients on warfarin)

16 Cumulative incidence RE-LY Efficacy Outcomes: All Stroke and Systemic Embolism months N Engl J Med 2009;361(12):

17 RE-LY: Primary Outcomes D 110 mg* D 150 mg* Warfarin D 110* mg vs. warfarin D 150* mg vs. warfarin Stroke or systemic embolism Rate/yr Rate/yr Rate/yr RR 95% CI p 1.54 % 1.11 % 1.71 % RR 95% CI p <0.001 Hemorrhagic stroke 0.12 % 0.10 % 0.38 % 0.31 < <0.001 Ischemic stroke and NK Death, All cause 1.34 % 0.92 % 1.21 % % 3.64 % 4.13 % Numbers are from the revised table: Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L. Newly identified events in the RE-LY trial. N Engl J Med.363(19): and the appendix cited there.

18 RE-LY: Major Bleeding and ICH D 150 mg Annual Rate Warfarin Annual Rate D 150 mg vs. warfarin RR 95% CI p Major Bleed 3.32% 3.57% Intracranial (ICH) 0.32% 0.76% <0.001 GI Bleed 1.51% 1.02% Analyses are based on time to 1st event. P-values are for superiority. Results are according to randomized treatment group (ITT). Numbers are from the revised table: Connolly SJ, et al. Newly identified events in the RE-LY trial. N Engl J Med.363(19): and the appendix cited there.

19 RE-LY Trial Bullet Points As good or better in preventing stroke Substantially less risk of ICH (4-5 per 1000/yr) More GI bleeding on 150mg dose (+5 per 1000/yr) 6% more with dyspepsia +2 MI per 1000/yr (ns)

20 Pradaxa (dabigatran) Ad FDA approval Oct 19, 2010 U.S: 150 mg bid no 110 mg dose 75 mg bid for CrCl Canada: 150 mg bid 110 mg bid for >80 y or at high risk for bleeding

21 RE-LY: Bleeding by Age, CrCl, ASA GI Bleed Dabi 110 bid Warfarin Dabi 150 bid Rate per 100 py Rate per 100 py Rate per 100 py Age< Age * ** ICH Age < Age Age interaction, p-value: *0.02, **0.06 CrCl <50: ~2-fold increase in major bleeding, no interaction ASA use: 40-50% increase in all major bleeding with addition of ASA (not randomized), no interaction Eikelboom et al. Circulation 2011;123:

22 Pradaxa: FDA Post-Marketing Concerns 12/07/11: Package insert update recommends frequent monitoring of renal function. 12/29/12: Contraindicated in patients with mechanical heart valves.

23 Pradaxa: FDA Drug Safety Communication: Update on the risk for serious bleeding, 11/02/12 October August 2012: ~3.7 million Pradaxa prescriptions ~ 725,000 patients from U.S. outpatient pharmacies. For new users: RR for ICH + GIB, warf/dabi RR for GIB; RR for ICH NB: unadjusted The results of this Mini-sentinel assessment indicate that bleeding rates associated with new use of Pradaxa do not appear to be higher than bleeding rates associated with new use of warfarin, which is consistent with observations from the large clinical trial used to approve Pradaxa (the RE-LY.trial).

24 Rivaroxaban, FXa-I, and the ROCKET AF RCT

25 Rivaroxaban for AF: The ROCKET AF Trial: Fast-acting (~2 hr), specific competitive direct factor Xa inhibitor No dose adjustment, no regular monitoring 80% bioavailability, 33% excreted by kidney Half-life of 8-15 hours Patel M, et al. Am Heart J 2010;159:

26 ROCKET AF RCT: Rivaroxaban vs Warfarin, INR 2-3 Double-blind, randomized, non-inferiority trial 14,264 AF patients at increased risk for stroke Rivaroxaban vs Dose-adjusted Warfarin: 20 mg daily for creatinine clearance 50ml/min 15 mg daily for creatinine clearance of 30 to 49 ml/min Patients with CrCl <30 ml/min excluded Warfarin arm: mean TTR=55% Patel et al. N Engl J Med 2011;365:

27 ROCKET: Baseline Patient Features Feature Rivaroxaban (N=7131) Warfarin (N=7133) Age, median Prior stroke, SE or TIA CHF Hypertension Mean CHADS 2 Score (+/-SD) 3.48 (+/- 0.94) 3.46 (+/- 0.95)

28 ROCKET AF Primary Efficacy End Point Per Protocol Intent to Treat Rivaroxaban Warfarin Rate, %/yr (n) 1.7 (188) 2.1 (269) Rate, %/yr (n) 2.2 (241) 2.4 (306) HR 0.79 ( ) 0.88 ( ) Both comparisons meet non-inferiority criterion. ITT superiority p value=0.12 Patel MR, et al. N Engl J Med 2011;365:

29 ROCKET AF Per Protocol vs. Intention to Treat Figure 1. Cumulative rates of the primary endpoint (stroke or systemic embolism) in the per-protocol population and in the intention-to-treat population Patel MR, et al. N Engl J Med 2011;365:

30 Components of Primary Efficacy Outcome Data from safety, on-treatment population Rivaroxaban (n=6958) Warfarin (n=7004) Rivaroxaban vs. Warfarin Rate per 100 pys Rate per 100 pys Hazard Ratio (95% CI) Stroke ( ) Hemorrhagic ( ) Ischemic ( ) MI ( ) p-value Death, All cause ( ) Patel MR, et al. N Engl J Med 2011;365: (Supplementary Appendix).

31 ROCKET AF: Safety Endpoints Rivaroxaban (n=7111) Warfarin (n=7125) Rate per 100 pys Rate per 100 pys HR p value Major bleed ( ) ICH ( ) Fatal bleed ( ) Patel MR, et al. N Engl J Med 2011;365:

32 Rocket AF Trial: Conclusions In this trial of high stroke risk patients, rivaroxaban was at least as effective as warfarin and safer re intracranial hemorrhage. TTR achieved in trial is a concern. FDA approval Nov. 4, 2011 for NVAF. FDA approval Nov. 2, 2012 for DVT/PE.

33 Rivaroxaban, as Xarelto, Approved by FDA for AF, Nov. 4, 2011

34 ROCKET AF: FDA Concern re Stroke Risk Following Discontinuation

35 ROCKET AF: Events post Completion 30d post d/c Riva: 22 events vs Warf: 6 events Patel MR, et al. N Engl J Med 2011;365: (Supplementary Appendix).

36 Xarelto: U.S. FDA Boxed Warning

37 Apixaban FXa-I for AF

38 Apixaban for AF: The AVERROES and ARISTOTLE Trials Fast-acting (~2 hr), specific competitive direct factor Xa inhibitor No dose adjustment, no regular monitoring 25% excreted by kidney Half-life of 9-14 hours

39 The ARISTOTLE Trial Apixaban vs. Warfarin in Patients with Atrial Fibrillation N Engl J Med 2011;365:

40 The ARISTOTLE Trial Randomized, double-blind trial Apixaban (oral factor Xa inhibitor) 5mg twice daily vs. warfarin with target INR mg bid for 2 of the following 3 features: 80 years old; Weight 60 kg; Creatinine mg/dl 18,201 patients with AF and at least one additional RF for stroke, mean CHADS2 score of yr median follow-up TTR mean of 62% in warfarin

41 ARISTOTLE: Primary Outcome Granger CB et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. NEJM 2011

42 ARISTOTLE: Efficacy Outcomes Outcome Primary outcome: stroke or SE Ischemic or uncertain type of stroke Apixaban (n=9120) Warfarin (n=9081) Event rate, %/yr Event rate, %/yr Hazard Ratio (95% CI) ( ) ( ) Hemorrhagic stroke ( ) Death from any cause Myocardial infarction ( ) ( ) Granger CB et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. NEJM 2011

43 ARISTOTLE: Safety Outcome Granger CB et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. NEJM 2011

44 ARISTOTLE: Sites of Bleeding Apixaban Group (n=9088) Warfarin Group (n=9052) Bleeding Event Event rate, %/yr. Event rate, %/yr Hazard Ratio (95% CI) Major bleeding (ISTH definition) ( ) Intracranial ( ) Other location ( ) Gastrointestinal ( ) Granger CB et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. NEJM 2011

45 The ARISTOTLE Trial Fewer strokes (mainly decreased hemorrhagic stroke) Fewer bleeds (~same as ASA per AVERROES RCT) Fewer intracranial hemorrhages Extremely positive results; FDA approval for AF, Dec 28, Black box re discontinuations.

46 Other Novel Agents to Prevent Stroke in AF* Edoxaban/DU 176-b (ENGAGE-AF TIMI 48), FXa-I, high (60 mg qd) and low dose (30 mg qd) n=20,500, recruitment complete, in follow-up. *ClinicalTrials.gov

47 Novel Anticoagulants for AF: What have we learned? 1. In trials, novel anticoagulants are clearly as good as moderately controlled warfarin and probably are better. The reduction in ICH is an unexpected but crucially important benefit. 2. The initial analyses from clinical care indicate that dabigatran s safety is no worse than warfarin s. 3. However, it is not certain that patients on well-controlled warfarin (TTR ~75+%) have much to gain, other than convenience, by switching to NOAC.

48 AF Guidelines ACCF/AHA/HRS, 2011, Focused Update: Dabigatran is useful as an alternative to warfarin ESC, 2012, Focused Update: NOACs should be considered rather than adjusted dose VKA (INR 2-3) for most patients with nonvalvular AF ACCP 9, 2012: Dabigatran 150mg bid favored over warfarin Circ, epub Feb 14, 2011 Europace Oct;14(10): Chest 2012;141(2 Suppl):e531S-75S.

49 Potential Beneficial Impact of Novel Anticoagulants Enlarging the % AF patients well protected from ischemic stroke Attracting the warfarin-reluctant Lowering stroke risk threshold for anticoagulants Reducing intracranial hemorrhage

50 OAC for AF: Choice of Agent Patients at moderate to high stroke risk, i.e., CHADS2 1: OAC or NOAC TTR>75%: Warfarin remains OK Poor TTR in compliant patient: NOAC indicated New starts, willing to try new meds, and cost is acceptable: NOACs have advantages

51 OAC for AF: Choice of NOAC All appear worthy; no head-to-head comparisons No reversal agent; no quantitative monitoring test in US Dabigatran Particularly effective for ischemic stroke (150mg bid) Seems safe in clinical care Most sensitive to renal insufficiency Dyspepsia; higher extracranial bleed risk in elderly Apixaban Most impressive trial results, partic. very good bleed results Risk on discontinuation Rivaroxaban Once daily Effective in the highest risk patients DVT/PE Rx indication Risk on discontinuation

52 OAC to Prevent Stroke in AF: The Beginning of the NOAC Era Truly remarkable period; a success story for modern drug development and for our patients. Multiple options, including improved warfarin: Used properly, all OACs very effective and adequately safe. We need to accumulate more clinical experience with the NOACs to validate performance in usual care and better address multiple practical problems: management of interruptions, bleeds, strokes, concomitant meds, and generally optimizing match of patient with OAC agent.

53 END

54 Quality-Adjusted Life Expectancy ASA ASA New Safer Anticoagulant threshold 10 ASA Warfarin threshold New Safer Anticoagulant NO AC Annual Rate of Ischemic Stroke CHADS 2 Derivation Model CHADS 2 ATRIA Cohort Eckman et al. Circ CV Q&O 2010;4:14-21

55 NOACs: Practical Issues Real-world efficacy and safety Cost Acute bleed no reversal agent Emergency surgery no reversal agent Stroke or bleed on therapy: too little drug?, too much, is pt taking med? Peri-procedural management/discontinuations Drug interactions Older, frail pt Poor renal function CAD: add ASA? ACS: triple therapy? Cardioversion; ablation

56 Pharmacological features of novel anticoagulants Drug Target Prodrug Bioavail- Ability, % Dosing Halflife Renal clearance, % Routine coagulation monitoring Drug interactions Dabigatran fiia Yes 6% Fixed, twice daily Rivaroxaban fxa No 80% Fixed, once daily Apixaban fxa No 60% Fixed, twice daily Edoxaban fxa No 50% Fixed, once daily 12-17h 80% No Quinidine, amiodarone, potent P-gp inhibitors 7-11h 66% No Potent inhibitors of CYP3A4 and P-gp 12h 25% No Potent inhibitors of CYP3A4 9-11h 35% No Potent inhibitors of CYP3A4 and P-gp Table adapted from: Eikelboom and Weitz, Circulation 2010;121:

57 HAS-BLED Bleeding Risk Score Letter Clinical Characteristic Points Awarded H Hypertension 1 A Abnormal renal and liver function (1 point each) 1 or 2 S Stroke 1 B Bleeding 1 L Labile INRs 1 E Elderly (e.g. age >65 years) 1 D Drugs or alcohol (1 point each) 1 or 2 Maximum 9 points Eur Heart J Oct;31(19): Epub 2010 Aug 29.

58 ATRIA Hemorrhage Risk Score Clinical Characteristic Points Awarded Anemia 3 Severe renal disease (egfr <30 ml/minute or dialysis-dependent) Age 75 years 2 Any prior hemorrhage diagnosis 1 Diagnosed hypertension 1 3 Maximum 10 points Fang MC et al. A New Risk Scheme to Predict Warfarin-Associated Hemorrhage. JACC 2011;58:

59 Observed Major Bleeding Rates by ATRIA Hemorrhage Risk Category ATRIA hemorrhage risk category Events per 100 personyears Low risk (score 0-3) 0.76 Intermediate risk (score 4) 2.62 High risk (score 5-10) 5.76 Fang MC et al. A New Risk Scheme to Predict Warfarin-Associated Hemorrhage. JACC 2011;58:

60 RE-LY Secondary Analyses: Patients with Prior Stroke/TIA 20% (~1200 per arm) of RE-LY patients HR estimates of effect and safety consistent with overall RE-LY results Patients with History of Stroke or TIA Event Dabi 110 Dabi 150 Warfarin Stroke + SE p=ns Hemorrhagic stroke p<0.05 All ICH p<0.05 Diener H-C, et al. Lancet Neurol 2010;9:

61 RE-LY Secondary Analyses: Renal Function Annualized rate of ischemic stroke and TE (%) CrCl ml/min (n=3505) (n=8766) 80 (n=5826) Dabi 110 Dabi 150 Warfarin No interaction by renal function Connolly,SJ et al. N Engl J Med 2009;9:

62 Dabigatran: Practical Considerations Delicate capsule Cardioversion: probably OK Pt taking med?: aptt Bleed: no clear antidote Dialyzable Circ 2011;123:

63 ACS Plus AF Stable CAD: consider no ASA ACS, no stent: CHADS2=2+: triple therapy for 3-6 mos, then VKA plus ASA or clopidogrel PCI/stent: CHADS2=2+: triple therapy, then VKA plus 1 antiplatelet; at 12 mos, VKA alone Adapted from ESC Guidelines. Europ Hrt J, epub Aug 29, 2010

64 Ideal Anticoagulant Efficacy Low bleed risk Fixed dosing, twice daily, w/o routine monitoring Good, consistent bioavailability No interaction with food, drugs Rapid onset Monitoring test available Antidote available Adapted from Steffel, Braunwald. Euro Heart J 2011: epub March 18, 2011

65 ICH Rates in Recent Trials ICH Hemorrhagic Stroke Non-stroke ICH Trial %/year (n) %/year (n) %/year (n) SPORTIF Ximelagatran 0.35 (20) 0.12 (7) 0.23 (13) Warfarin 0.42 (24) 0.19 (11) 0.23 (13) RE-LY Dabigatran 110 mg 0.23 (27) 0.12 (14) 0.11 (13) Dabigatran 150 mg 0.32 (38) 0.10 (12) 0.22 (26) Warfarin 0.76 (90) 0.38 (45) 0.38 (45) ARISTOTLE Apixaban 0.33 (52) 0.24 (40) 0.09 (12) Warfarin 0.80 (122) 0.47 (78) 0.33 (44) ROCKET Rivaroxaban 0.5 (55) (ITT) 0.26 (29) (on treatment) 0.24 (26) (on treatment) Warfarin 0.7 (84) (ITT) 0.44 (50) (on-treatment) 0.26 (34) (on-treatment)

66 ROCKET AF: Efficacy by Prior stroke/tia Hankey G, et al. Lancet Neurol 2012;11:

67 CHADS 2 and CHA 2 DS 2 -VASc distributions in Swedish AF population Piccini JP, Singer DE. Eur Heart J 2012;33:

68 NOACs : Quick Comparison Distinctive qualities: All 3 have hemorrhagic stroke and composite ICH Dabigatran: DTI; all stroke; ischemic strokes; dialyzable; open label RCT; twice daily; dyspepsia; extracranial bleed in elderly Rivaroxaban: FXa-I; effective in highest risk pts; blinded trial; once daily; take with food; NI, not superior efficacy; lowest TTR; TE risk on stopping Apixaban: FXa-I; all stroke; all bleed; safe in moderate renal insufficiency; blinded trial; twice daily; TE risk on stopping

69 RE-LY Secondary Analyses: ACS Event Dabi 110 Dabi 150 Warfarin MI p~0.10 Composite* *Composite: MI, unstable angina, cardiac arrest, cardiac death; Rates per 100 pys Patients with history of CAD/MI Event Dabi 110 Dabi 150 Warfarin Composite** **Composite: MI, UA, PCI, CABG, cardiac arrest, cardiac death Hohnloser SH, et al. Circulation 2012;125:

70 RE-LY Secondary Analyses: Periprocedural Bleeding Over 2 years, 25% had a procedure causing discontinuation of drug Most common (all ~8-10%): pacemaker/icd, dental, biopsy/other diagnostic, cataract, colonoscopy Most common major surgery (~6%): TKR/THR Rates of major bleeds and stroke were low in both warfarin and dabigatran arms Healey J, et al. Circulation 2012;126:

71 ROCKET AF Dose Adjustment* CrCl (Cockcroft-Gault) 50 ml/min Rivaroxaban dose 20 mg/day ml/min 15 mg/day <30 ml/min excluded *25% dose reduction to produce similar maximal serum concentrations

72 AT9 Stroke Prevention Guidelines* Clinical Profile (Applies to PAF, as well) Prior stroke/tia and/or 2 of the following RFs: CHF, HTN, age 75, DM CHADS non-stroke/tia RF: CHADS 2 =1 0 RF: CHADS 2 =0 Treatment Recommendation Warfarin, INR 2-3, vs no Rx: 1A Warfarin >(C+A)>ASA: 1B Dabigatran 150 bid > Warf: 2B Warfarin, INR 2-3, > (C+A) >ASA ( mg/d): 2B Dabigatran 150 bid > Warf: 2B No AT Rx: 2B * ACCP 9 (Chest 2012; 141 (2)(Suppl):e531S-e575S);

73 AF and Stroke: Framingham Study, 30-Year Follow-up* Strokes Strokes Age Prev AF per 1000py o per 1000py AF RR % % % * Wolf PA, Abbott RD, Kannel WB, Arch Intern Med 1987;147: ; adjusted for BP

74 Annual stroke rate (%) RCTs of VKA vs Control to Prevent Stroke in AF 14 Control 12 Warfarin 66%* %* 86%* 69%* 52% 79%* *p< AFASAK BAATAF SPAF-I CAFA SPINAF EAFT Go AS et al. Progr Cardiovasc Dis 2005;48:

75 Efficacy of Aspirin for AF Pooled 3 trials versus placebo: AFASAK 75 mg daily SPAF I 325 mg daily EAFT 300 mg daily Relative Risk Reduction: 21% (0-38%) No signif impact on severe/fatal stroke *JAMA 2002;288: (AFASAK I &II, EAFT, PATAF, SPAF I-III)

76 % Dispensed warfarin Warfarin use in AF Patients in MarketScan Database , n=64, % 80% 60% 40% 20% 62.8% 62.4% 56.2% 0% Low Risk Moderate Risk High Risk (CHADS 2 =0-1) (CHADS 2 =2-3) (CHADS 2 =4-6) Risk Category Casciano et al. Poster, AHA CV Qual and Outcomes meeting, 2011

77 ROCKET AF: Efficacy and Safety by Prior stroke/tia Stroke and SE No Prior Stroke/TIA (n=6796) Annualized rates (%) Yes Prior Stroke/TIA (n=7468) Riva Warf Riva Warf Major Bleed ICH Fatal bleed No signif interaction of effect by prior stroke/tia Hankey G, et al. Lancet Neurol 2012;11:

78 ARISTOTLE: Efficacy and Safety by Prior stroke/tia Stroke and SE No Prior Stroke/TIA (n=14765) Annualized rates (%) Yes Prior Stroke/TIA (n=3436) Apix Warf Apix Warf Major Bleed ICH GI bleed No signif interaction of effect by prior stroke/tia Easton et al. Lancet Neurol 2012;11:

79 Efficacy of Anticoagulation for AF Trial Target Ranges: INR ~ Relative Absolute Risk Reduction Risk Reduction Pooled 5 RCTs 68% (50-79%) 3.1% per year EAFT 66% (43-80%) 8.4% per year Arch Intern Med 1994;154: Lancet 1993;342:

80 Safety of Anticoagulation for AF: Pooled Primary Prevention RCTs Absolute Rates of Hemorrhage: Anticoagulation Control Intracranial 0.3% per yr 0.1% per yr (n=6) (n=2)

81 RE-LY Efficacy Subgroup Analyses, Forest Plot Pradaxa package insert,12/2012, Boehringer Ingelheim

82 ARISTOTLE: Efficacy Results by Subgroups Efficacy: No interaction. Relative effect of apixaban vs warfarin was consistent across multiple subgroups. Safety: Notable interaction for renal insufficiency. Eliquis Prescribing Information 2012.

83 Warfarin s Effect on Outcome of Ischemic Stroke and ICH: ATRIA Cohort Fang MC, et al. Stroke 2012;43:

84 ARISTOTLE: Efficacy and Safety by Prior stroke/tia Stroke and SE No Prior Stroke/TIA (n=14765) Annualized rates (%) Yes Prior Stroke/TIA (n=3436) Apix Warf Apix Warf Major Bleed ICH GI bleed No signif interaction of effect by prior stroke/tia Easton et al. Lancet Neurol 2012;11:

85 ROCKET AF: Efficacy and Safety by Prior stroke/tia Stroke and SE No Prior Stroke/TIA (n=6796) Annualized rates (%) Yes Prior Stroke/TIA (n=7468) Riva Warf Riva Warf Major Bleed ICH Fatal bleed No signif interaction of effect by prior stroke/tia Hankey G, et al. Lancet Neurol 2012;11:

86 Net Clinical Benefit of Warfarin for AF in Community Practice Annals Intern Med 2009;151:

87 Anticoagulant Use in AF: Kirley K. Circ CV Q&O;5: NB: Figure is AC for all indications

88 AVERROES Trial Apixaban, 5 mg bid, vs. aspirin, mg qd, in patients with AF who cannot or will not take a VKA. CHADS 2 =2.0/2.1 1 st interim analysis: study stopped with f/u=1.1 yr Stroke + SE: RRR=55% ~No increase in bleeding (ICH: 0.4%/yr in both arms) Am J Med 2010; 159:348-53; NEJM 2011; epub Feb 10, 2011

89 AVERROES: Efficacy Results: K-M Display

90 Problems with Warfarin Drug and diet interactions Narrow therapeutic index Much inter- and intra-individual variation in dosing. Monitoring is crucial (17 INRs/yr) Wide variation in quality of anticoagulation ~4 day lag in effect, both on and off Much physician and patient burden; significant discontinuation rates

91 Risk Factors for Stroke in AF: Additional Info Vasc : Independent effect is negligible to small Renal dysfunction, e.g., egfr <60 ml/min/1.73 m 2 : consistent, modest RF 91

92 RE-LY Secondary Analyses: Patients with Prior Stroke/TIA 20% (~1200 per arm) of RE-LY patients HR estimates of effect and safety consistent with overall RE-LY results Patients with History of Stroke or TIA Event Dabi 110 Dabi 150 Warfarin Stroke + SE p=ns Hemorrhagic stroke p<0.05 All ICH p<0.05 Diener H-C, et al. Lancet Neurol 2010;9:

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