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Anticoagulation for Atrial Fibrillation: Who, When, and How? August 17, 2013 Elaine M. Hylek, MD, MPH Boston University School of Medicine.

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Presentation on theme: "Anticoagulation for Atrial Fibrillation: Who, When, and How? August 17, 2013 Elaine M. Hylek, MD, MPH Boston University School of Medicine."— Presentation transcript:

1 Anticoagulation for Atrial Fibrillation: Who, When, and How? August 17, 2013 Elaine M. Hylek, MD, MPH Boston University School of Medicine

2 Disclosures EmploymentNo conflict of interest to disclose Research supportNIH/NINDS, NIH/NHLBI; Bristol-Myers Squibb- Executive Steering Committee; ARISTOTLE trial; Janssen-Executive Steering Committee; ORBIT- AF Registry Scientific advisory boardBayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Pfizer ConsultancyNo conflict of interest to disclose Speakers bureauNo conflict of interest to disclose Major stockholderNo conflict of interest to disclose PatentsNo conflict of interest to disclose HonorariaBayer, Boehringer-Ingelheim, Pfizer Travel supportNo conflict of interest to disclose OtherNo conflict of interest to disclose Disclosures of Elaine Hylek

3 Hesse, B. et al. Circulation 2006;113:e e TEE depicting a large LAA thrombus attached to the lateral wall

4 Stanford Stroke Center, Albers G

5

6 Prevalence of AF by Age Feinberg WM. Arch Intern Med. 1995;155(5):469–473

7 HAZARDS OF WARFARIN Budnitz D et al. N Engl J Med 2011;365:2002–12

8 HAZARDS OF WARFARIN Budnitz D et al. N Engl J Med 2011;365:2002–12

9 Efficacy and Safety Data for Target-Specific Oral Anticoagulants

10 Cumulative hazard rates RR 0.91 (95% CI: 0.74–1.11) p<0.001 ( noninferiority ) p=0.34 ( superiority ) RR 0.66 (95% CI: 0.53–0.82) p<0.001 ( superiority ) Years Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg RE-LY: Time to First Stroke/SEE Connolly SJ et al. N Engl J Med 2009; 361:1139–51 RRR 34% 1.11% 1.69% 1.53%

11 RE-LY Primary Efficacy Outcome Stroke and non-CNS Embolism Connolly SJ., et al. NEJM Aug 30th DOI /NEJMoa

12 RR 0.26 (95% CI: 0.14–0.49) p<0.001 (sup) Hemorrhagic stroke Connolly SJ., et al. NEJM published online on Aug 30th DOI /NEJMoa RR 0.31 (95% CI: 0.17–0.56) p<0.001 (sup) Number of events 6,0156,0766, D110 mg BIDD150 mg BIDWarfarin 0.10% 0.38% RRR 69% RRR 74% 0.12%

13 Dabigatran Etexilate vs Warfarin (RE-LY) October 19, 2010 FDA Approves Pradaxa to Reduce the Risk of Stroke in Patients with Non-Valvular Atrial Fibrillation PRADAXA 150 mg BID-higher rate of major (GI) bleeds and any GI bleeds compared to warfarin. In patients ≥75 years of age, the risk of major bleeding may be greater with PRADAXA than with warfarin.

14 RivaroxabanWarfarin Event Rate HR (95% CI) P-value On Treatment N= 14, (0.65,0.95) ITT N= 14, (0.74,1.03) Rivaroxaban better Warfarin better ROCKET-AF Primary Efficacy Outcome Stroke and non-CNS Embolism Event Rates are per 100 Patient-years Based on Safety on Treatment or Intention-to-Treat thru Site Notification Populations Patel et al. NEJM 2011;365:883-91

15 Key Secondary Efficacy Outcomes RivaroxabanWarfarin Event Rate HR (95% CI)P-value Vascular Death, Stroke, Embolism (0.74, 0.99)0.034 Stroke Type Hemorrhagic Ischemic Unknown Type (0.37, 0.93) 0.94 (0.75, 1.17) 0.65 (0.25, 1.67) Non-CNS Embolism (0.09, 0.61)0.003 Myocardial Infarction (0.63, 1.06)0.121 All Cause Mortality Vascular Non-vascular Unknown Cause (0.70, 1.02) 0.89 (0.73, 1.10) 0.63 (0.36, 1.08) 0.75 (0.40, 1.41) Patel et al. NEJM 2011;365:883-91

16 RivaroxabanWarfarin Event Rate or N (Rate) HR (95% CI) P- value Major >2 g/dL Hgb drop Transfusion (> 2 units) Critical organ bleeding Bleeding causing death (0.90, 1.20) 1.22 (1.03, 1.44) 1.25 (1.01, 1.55) 0.69 (0.53, 0.91) 0.50 (0.31, 0.79) Intracranial Hemorrhage55 (0.49)84 (0.74)0.67 (0.47, 0.94) Intraparenchymal37 (0.33)56 (0.49)0.67 (0.44, 1.02) Intraventricular2 (0.02)4 (0.04) Subdural14 (0.13)27 (0.27)0.53 (0.28, 1.00) Subarachnoid4 (0.04)1 (0.01) Event Rates are per 100 patient-years Based on Safety on Treatment Population Safety Outcomes Rivaroxaban

17 Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, 0.66–0.95); P (superiority)=0.011 No. at Risk Apixaban Warfarin P (non-inferiority)< % RRR Granger C et al. NEJM 2011;365:981–92

18 Efficacy Outcomes Outcome Apixaban (N=9120) Warfarin (N=9081) HR (95% CI) P Value Event Rate (%/yr) Event Rate (%/yr) Stroke or systemic embolism* (0.66, 0.95)0.011 Stroke (0.65, 0.95)0.012 Ischemic or uncertain (0.74, 1.13)0.42 Hemorrhagic (0.35, 0.75)<0.001 Systemic embolism (SE) (0.44, 1.75)0.70 All-cause death* (0.80, 0.998)0.047 Stroke, SE, or all-cause death (0.81, 0.98)0.019 Myocardial infarction (0.66, 1.17)0.37 * Part of sequential testing sequence preserving the overall type I error Granger C et al. NEJM 2011;365:981–92

19 Bleeding Outcomes Outcome Apixaban (N=9088) Warfarin (N=9052) HR (95% CI)P Value Event Rate (%/yr) Event Rate (%/yr) Primary safety outcome: ISTH major bleeding* (0.60, 0.80)<0.001 Intracranial (0.30, 0.58)<0.001 Gastrointestinal (0.70, 1.15)0.37 Major or clinically relevant non-major bleeding (0.61, 0.75)<0.001 GUSTO severe bleeding (0.35, 0.60)<0.001 TIMI major bleeding (0.46, 0.70)<0.001 Any bleeding (0.68, 0.75)<0.001 * Part of sequential testing sequence preserving the overall type I error

20 CHADS 2 score = 0 No therapy rather than antithrombotic therapy (Grade 2B) CHADS 2 score = 1 Oral anticoagulation rather than no therapy or antiplatelet therapy (Grade 1B) CHADS 2 score = 2 Oral anticoagulation rather than no therapy or other therapies (Grade 1A) For recommendations in favor of oral AC, we suggest dabigatran 150 mg twice daily rather than VKA therapy (Grade 2B) You JJ et al. Chest 2012;141(2 Suppl):e531S-75S. PMID: ACCP Recommendations for Stroke Prevention Therapy

21 ESC 2012 UPDATE GUIDELINES For ATRIAL FIBRILLATION Camm J et al. Eur Heart J 2012;33:2719–47

22 2011 ACCF/AHA/HRS Focused Update Dabigatran is useful as an alternative to warfarin for the prevention of stroke in patients with AF. Selection of patients with AF and ≥1 risk factor for stroke who could benefit from treatment with dabigatran as opposed to warfarin should consider individual clinical features, including the ability to comply with twice-daily dosing, availability of an anticoagulation management program, patient preferences, cost, and other factors Because of the twice-daily dosing and greater risk of non-hemorrhagic side effects with dabigatran, patients already taking warfarin with excellent INR control may have little to gain by switching to dabigatran. Wann LS et al. Heart Rhythm 2011;8:e1–e8

23 Hylek, EM. J Cardiovasc Med 2009;10:605-09

24 Effect of TTR on Primary Endpoints In RELY Wallentin, et al. Lancet

25 10% increase in center algorithm-consistent warfarin dosing predicted a 6.12% increase in TTR (95% CI %), and an 8% decrease in rate of the composite clinical outcome (HR 0.92, 95% CI ).

26 Translating the Results of Clinical Trials into Clinical Practice  Patient selection  Therapeutic implementation  Environment of the healthcare delivery system Nallamothu, et al. Circulation 2008;118:1294–303

27 Will we be able to translate trial results to real-world practice?

28 PropertyDabigatranRivaroxabanApixabanEdoxaban Route of admin OralOralOralOral TargetThrombinFXaFXaFXa Dosing Twice daily Once daily Twice daily Once daily Monitoring required NoNoNoNo Half-life (hrs) 12–179–128–158–11 Mode of elimination Renal 80% Renal ~36% Renal ~25% Renal ~35% New Oral Anticoagulants: Summary

29 Definitions: Chronic Kidney Disease and Renal Insufficiency I  MILD  I  MOD  I  SEVERE  I Renal Insufficiency Classification Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation Slide courtesy of C Cove

30 Randomized TrialAgeBaseline CrCl Exclusion CrCl ARISTOTLE Apixaban 5 mg bid7083% ≥50<25 ml/min Warfarin7083% ≥50 ROCKET AF Rivaroxaban 20 mg qd7367 (median)< 30 ml/min Warfarin7367 (median) RE-LY Dabigatran 150 mg bid7268 (median)<30 ml/min Warfarin7269 (median)

31 Pharmacokinetics with Varying Levels of Renal Dysfunction Kaatz S et al. Am J Hematol 2012 Suppl 1:S PMID: ApixabanDabigatranRivaroxaban Elimination half life with CrCl >80 ml/min 7.6 hr13.8 hr8.3 hr Elimination half life with CrCl 50–79 ml/min 7.3 hr16.6 hr8.7 hr Elimination half life with CrCl 30–49 ml/min 17.6 hr18.7 hr9.0 hr Elimination half life with CrCl <30 ml/min 17.3 hr27.5 hr9.5 hr

32 Periodically assess renal function as clinically indicated (i.e., more frequently in clinical situations that may be associated with a decline in renal function) and adjust therapy accordingly. Discontinue dabigatran in patients who develop acute renal failure and consider alternative therapy. In patients with moderate renal impairment (CrCl 30–50 mL/min), concomitant use of the P-gp inhibitor dronedarone or systemic ketoconazole can be expected to produce drug exposure similar to that observed in severe renal impairment. Consider reducing the dose. JANUARY 2012 UPDATE DABIGATRAN PACKAGE INSERT

33 PropertyDabigatranRivaroxabanApixabanEdoxaban Route of admin OralOralOralOral TargetThrombinFXaFXaFXa Dosing Twice daily Once daily Twice daily Once daily Monitoring required NoNoNoNo Half-life (hrs) 12–179–128–158–11 Mode of elimination Renal 80% Renal ~36% Renal ~25% Renal ~35% New Oral Anticoagulants: Summary

34 Polypharmacy and Non-adherence Strongest predictor of non-adherence is the # of medications Non-adherence rates estimated 25–50% Intentional about 75% of the time Changes in regimen made by patients to: –increase convenience –reduce adverse effects or –decrease refill expense

35

36 Recommended Structured Follow-up First month and subsequent 3 month intervals

37 Pradaxa (dabigatran etexilate mesylate): Drug Safety Communication – Safety Review of Post-Market Reports of Serious Bleeding Events UPDATED 11/02/2012. … 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). FDA is continuing to evaluate multiple sources of data in the ongoing safety review of this issue.

38 HAS-BLED Bleeding Risk Score –Hypertension (SBP>160mmHg) –Abnormal renal/liver fxn (1 pt for each) –Stroke –Bleeding history or prone –Labile INR (if on warfarin) –Elderly (>65 years) –Drugs (ASA, NSAIDS)/alcohol (1 pt for each) Increasing score associated with ISTH major bleeding (C-index 0.72) Pisters R et al. Chest 2010;138:1093–100

39 Hemorrhage Thrombosis Optimizing Benefit and Reducing Risk AF stroke associated with a 30-day mortality of 24%.

40 Swedish AF Cohort; Circulation 2011; 125:

41 Dabigatran visits,% 2010 Q Q Q Q Q4 Atrial fibrillation Venous thromboembolism Hypertensive heart disease Coronary artery disease03936 CVA/TIA00033 Valvular disorders00030 Kirley K et al. Circ Cardiovasc Qual Outcomes 2012;5:615–21

42 Effective Use of TSOACs in Clinical Practice 1. Patient selection – ADHERENCE 2. Dose selection – creatinine clearance 3. Determine interval follow-up 4. Assess stability of renal function 5. Blood pressure control 6. Avoidance of concomitant antiplatelet therapy 7. Package insert – avoid potent drug interactions, guidance on transitions

43 Procedural Management based on Bleeding Risk of Surgery DABIGATRAN APIXABAN/ RIVAROXABAN

44 Novel Anticoagulants Dabigatran 150 mg BID reduced ischemic stroke 2.Dabigatran 80% renal clearance 3.Dabigatran is associated with small risk of MI, but reduced cardiovascular mortality 4.Dabigatran and rivaroxaban increase GI bleeding 5.Rivaroxaban is once per day and approved Rx for VTE 6.Apixaban reduced stroke, major hemorrhage, and mortality 7.Well-controlled warfarin is associated with low rate of adverse events

45 Gaps: Practical Considerations Translation across indication Atrial fibrillation and valvular heart disease Atrial fibrillation and ACS Atrial fibrillation and DVT or PE Select situations in which monitoring would be desirable Reversibility-trauma, urgent surgery, life- threatening hemorrhage

46 Guide to the Management of Bleeding in Patients Taking NOAC Hankey GJ and Eikelboom JW. Circulation. 2011; 123: Patients with bleeding on NOAC therapy Mild bleeding Moderate-Severe bleeding Life-threatening bleeding Delay next dose or discontinue treatment as appropriate Mechanical compression Surgical intervention Fluid replacement and hemodynamic support Blood product transfusion Oral charcoal Hemodialysis ? Prothrombin Complex Concentrate? (Circulation 2011;124:1573-9) Consideration of rFVIIa or PCC Charcoal filtration ? Prothrombin Complex Concentrate (Circulation 2011;124:1573-9)

47 47 WILL THERE BE A CONTINUING ROLE FOR WARFARIN? Mechanical heart valves 2. Cost 3. Pregnancy 4. Severe renal impairment 5. Drug Interactions 6. Lack of acceptance of no monitoring Reversal? Nonadherence 9. Intolerant of novel anticoagulant drug

48 Novel anticoagulants may be safer in the elderly population due to their wider therapeutic index, shorter t 1/2, lack of dietary interference, and fewer drug interactions. Older individuals with AF are at the highest risk of stroke, the highest risk of hemorrhage, and the highest risk of stopping therapy. Further research is needed to inform commonly encountered clinical situations to optimize the effectiveness of these novel agents in routine practice.


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