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Anticoagulation for Atrial Fibrillation: Who, When, and How?

Anticoagulation for Atrial Fibrillation: Who, When, and How?. August 17, 2013 Elaine M. Hylek , MD, MPH Boston University School of Medicine. Disclosures. Disclosures of Elaine Hylek. TEE depicting a large LAA thrombus attached to the lateral wall .

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Anticoagulation for Atrial Fibrillation: Who, When, and How?

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

  2. Disclosures • Disclosures of Elaine Hylek

  3. TEE depicting a large LAA thrombus attached to the lateral wall Hesse, B. et al. Circulation 2006;113:e456-457e

  4. Stanford Stroke Center, Albers G

  5. Stanford Stroke Center, Albers G

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

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

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

  9. Efficacy and Safety Data for Target-Specific Oral Anticoagulants

  10. RE-LY: Time to First Stroke/SEE RR 0.91 (95% CI: 0.74–1.11) p<0.001 (noninferiority) p=0.34 (superiority) 0.05 0.04 RRR 34% 1.69% Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg 0.03 Cumulative hazard rates 1.53% RR 0.66 (95% CI: 0.53–0.82) p<0.001 (superiority) 0.02 1.11% 0.01 0.0 0 0.5 1.0 1.5 2.0 2.5 Years Connolly SJ et al. N Engl J Med 2009; 361:1139–51

  11. RE-LY Primary Efficacy OutcomeStroke and non-CNS Embolism Connolly SJ., et al. NEJM Aug 30th 2009. DOI 10.1056/NEJMoa0905561

  12. Hemorrhagic stroke RR 0.31 (95% CI: 0.17–0.56) p<0.001 (sup) RR 0.26 (95% CI: 0.14–0.49) p<0.001 (sup) 50 Number of events 45 40 0.38% RRR 74% RRR 69% 30 20 14 10 12 0.12% 0.10% 0 D110 mg BID D150 mg BID Warfarin 6,015 6,076 6,022 Connolly SJ., et al. NEJM published online on Aug 30th 2009. DOI 10.1056/NEJMoa0905561

  13. DabigatranEtexilatevs Warfarin (RE-LY) October 19, 2010 FDA Approves Pradaxa to Reduce the Risk of Stroke in Patients with Non-ValvularAtrial 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. ROCKET-AF Primary Efficacy OutcomeStroke and non-CNS Embolism Rivaroxaban better Warfarinbetter 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 Patel et al. NEJM 2011;365:883-91

  16. Safety Outcomes Rivaroxaban Event Rates are per 100 patient-years Based on Safety on Treatment Population

  17. Primary OutcomeStroke (ischemic or hemorrhagic) or systemic embolism P (non-inferiority)<0.001 21% RRR 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 9120 8726 8440 6051 3464 1754 Warfarin 9081 8620 8301 5972 3405 1768 Granger C et al. NEJM 2011;365:981–92

  18. Efficacy Outcomes * Part of sequential testing sequence preserving the overall type I error Granger C et al. NEJM 2011;365:981–92

  19. Bleeding Outcomes * Part of sequential testing sequence preserving the overall type I error

  20. ACCP Recommendations for Stroke Prevention Therapy CHADS 2 score = 0 No therapy rather than antithrombotic therapy (Grade 2B) CHADS 2 score = 1 Oral anticoagulation rather than no therapy or antiplatelettherapy (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: 22315271

  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. WannLS 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 0.54 0.59 0.91 1.21 Wallentin, et al. Lancet 2010

  25. 10% increase in center algorithm-consistent warfarin dosing predicted a 6.12% increase in TTR (95% CI 5.65-6.59%), and an 8% decrease in rate of the composite clinical outcome (HR 0.92, 95% CI 0.85-1.00).

  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. New Oral Anticoagulants: Summary

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

  30. Pharmacokinetics with Varying Levels of Renal Dysfunction KaatzS et al. Am J Hematol2012 Suppl1:S141-5. PMID: 22473649

  31. JANUARY 2012 UPDATE DABIGATRAN PACKAGE INSERT 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 (CrCl30–50 mL/min), concomitant use of the P-gpinhibitor dronedarone or systemic ketoconazole can be expected to produce drug exposure similar to that observed in severe renal impairment. Consider reducing the dose.

  32. New Oral Anticoagulants: Summary

  33. 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

  34. Recommended Structured Follow-upFirst month and subsequent 3 month intervals

  35. Pradaxa (dabigatran etexilatemesylate): Drug Safety Communication – Safety Review of Post-Market Reports of Serious Bleeding EventsUPDATED 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.

  36. 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) PistersR et al. Chest2010;138:1093–100

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

  38. Swedish AF Cohort; Circulation 2011; 125: 2298-2307

  39. KirleyK et al. Circ CardiovascQualOutcomes 2012;5:615–21

  40. Effective Use of TSOACs in Clinical Practice • 1. Patient selection – ADHERENCE • Dose selection – creatinineclearance • Determine interval follow-up • Assess stability of renal function • Blood pressure control • Avoidance of concomitant antiplatelet therapy • Package insert – avoid potent drug interactions, • guidance on transitions

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

  42. Novel Anticoagulants • Dabigatran 150 mg BID reduced ischemic stroke • Dabigatran 80% renal clearance • Dabigatran is associated with small risk of MI, but • reduced cardiovascular mortality • Dabigatran and rivaroxaban increase GI bleeding • 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

  43. 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

  44. Guide to the Management ofBleeding in Patients Taking NOAC Patients with bleeding on NOAC therapy Mild bleeding Moderate-Severe bleeding Life-threatening bleeding • Consideration of rFVIIa or PCC • Charcoal filtration • ? Prothrombin Complex Concentrate (Circulation 2011;124:1573-9) • 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) Hankey GJ and Eikelboom JW. Circulation. 2011; 123: 1436-1450

  45. WILL THERE BE A CONTINUING ROLE FOR WARFARIN? 1. 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 47

  46. Novel anticoagulants may be safer in the elderly population due to their wider therapeutic index, shorter t1/2, 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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