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JOURNAL REVIEW Newer Antithrombotics in AF

JOURNAL REVIEW Newer Antithrombotics in AF. Dr Ranjith MP Senior Resident Department of Cardiology Government Medical college Kozhikode. Introduction. A trial fibrillation is associated with a five-fold risk of stroke 1

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JOURNAL REVIEW Newer Antithrombotics in AF

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  1. JOURNAL REVIEWNewer Antithromboticsin AF Dr Ranjith MP Senior Resident Department of Cardiology Government Medical college Kozhikode

  2. Introduction • Atrial fibrillation is associated with a five-fold risk of stroke1 • The increase in risk of stroke is similar for paroxysmal, persistent and permanent AF2 • Strokes associated with AF are usually more severe than those from other causes, conferring an increased risk of morbidity, mortality and poor functional outcome1 1. Savelieva et al. Ann Med 2007;39:371–391 2. Hart R et al. JACC 2000; 35:183-187

  3. Introduction Warfarin Better Control Better • Warfarin -most effective treatment to prevent stroke in patients with AF & it reduces the risk by about two thirds compared with placebo AFASAK SPAF BAATAF CAFA SPINAF EAFT Aggregate -100% 50% -50% 100% 0 Hart R, et al. Ann Intern Med 1999;131:492

  4. Limitations of vitamin K antagonists • Slow onset and offset of action • Considerable variability in dose response among individuals • Multiple food and drug interactions • Narrow therapeutic window & considerable risk of hemorrhage • Even with careful laboratory monitoring, major bleeding occurs in 1% to 3% per year

  5. Introduction • Therefore, there is a need for novel approaches to stroke prevention in AF with new antithrombotic agents • The Newer Antithrombotics for stroke prevention in AF fall into two classes: • Oral direct thrombin inhibitors (e.g. dabigatran) • Oral direct factor Xa inhibitors (e.g. rivaroxaban, apixaban)

  6. Pharmacology of newer Antithrombotics

  7. Advantages of direct thrombin inhibitorsover indirect inhibitors • Advantage Mechanism Better suppression of thrombus Inhibit free and bound growth thrombin Retain activity in presence Do not bind PF4 or Vwf of platelet-rich thrombi Predictable anticoagulant Do not bind plasma proteins response No risk of HIT Do not bind PF4

  8. Trials with new agents vs warfarin in AF (aim INR 2.0-3.0)

  9. Ximelagatran • First oral direct thrombin inhibitor • As effective as warfarin for prevention of stroke and systemic embolic events in patients with atrial fibrillation1 • Prolonged administration (35 days) of ximelagratan was associated with a risk of liver toxicity, which led to withdrawal of the drug from the market2 1Testa L et al. Expert Opin Drug Saf. 2007;6(4):397-406 2Agnelli G et al. Thromb Res. 2008

  10. N Engl J Med 2009;361:1139-51.

  11. The RE-LY Study:Randomized Evaluation of Long-term anticoagulant therapy Atrial fibrillation ≥ 1 risk factor Absence of contraindications 951 centers/44 countries • Dabigatran Compared to Warfarin in 18,113 Patients with AF at Risk of Stroke Blinded Event Adjudication R Open Blinded Dabigatran Etexilate 150 mg BID n = 6076 Warfarin adjusted (INR 2.0-3.0) n = 6022 Dabigatran Etexilate 110 mg BID n = 6015 Connolly, SJ. et al. N Engl J Med 2009;361:1139-1151.

  12. RE-LY: Baseline Characteristics Connolly, SJ. et al. N Engl J Med 2009;361:1139-1151.

  13. RE-LY: Primary Outcome Connolly, SJ. et al. N Engl J Med 2009;361:1139-1151.

  14. RE-LY: Summary of Results Connolly, SJ. et al. N Engl J Med 2009;361:1139-1151.

  15. RE-LY: Stroke or Systemic Embolism 0.05 .. 0.04 Warfarin Dabigatran 110 mg 0.03 Cumulative Hazard Rates 0.02 Dabigatran 150 mg 0.01 0.0 0 0.5 1.0 1.5 2.0 2.5 Years of follow-up Connolly, SJ. et al. N Engl J Med 2009;361:1139-1151.

  16. RE-LY: Drug Discontinuation a. Rates of discontinuation at 1 and 2 years were higher with dabigatran than with warfarin (P < .001). Rates are based on Kaplan-Meier estimates Connolly, SJ. et al. N Engl J Med 2009;361:1139-1151.

  17. RE−LY Summary Dabigatran 150 mg superior to warfarin for stroke/systemic embolism; dabigatran 110 mg was non-inferior Stroke ↓ in dabigatran 150 mg arm (p < 0.001) Major bleeding was higher in warfarin arm compared with dabigatran 110 mg, but was similar to dabigatran 150 mg (p <0.001*, p = 0.34†) (p = 0.31*, p = 0.03†) Trial design: Patients with AF were randomized to either dabigatran 110 mg, 150 mg, or open-label warfarin. Patients were followed for a mean of 2 years. *Dabigatran 150 mg vs. warfarin; †Dabigatran 110 mg vs. warfarin Results 10 10 %/year 5 5 %/year Conclusions • Dabigatran 150 mg superior to warfarin in reducing stroke or systemic embolism, with a similar bleeding profile. The 110 mg dose was non-inferior for efficacy, associated with lower bleeding compared with warfarin 1.69 3.11 3.36 1.53 2.71 1.11 0 0 Stroke/systemic embolism Major bleeding Dabigatran 110 mg Dabigatran 150 mg Warfarin Connolly SJ, et al. N Engl J Med 2009;Aug 30:[Epub]

  18. N Engl J Med 2011;365:883-91.

  19. ROCKET AF: Study Design • Risk Factors, at least 2 of: • CHF • Hypertension • Age  75 • Diabetes • OR • Stroke, TIA or systemic embolus Atrial Fibrillation Rivaroxaban 20 mg daily (15 mg for Cr Cl 30-49 ml/min) Warfarin INR target: 2.5 (2.0-3.0 inclusive) Randomize Double Blind / Double Dummy (N= 14,264) Monthly Monitoring Adherence to standard of care guidelines Primary Endpoint: Stroke or non-CNS Systemic Embolism MR Patel et al.N Engl J Med 2011;365:883-91.

  20. ROCKET AF: Baseline Demographics MR Patel et al.N Engl J Med 2011;365:883-91.

  21. ROCKET AF: Primary Efficacy OutcomeStroke and non-CNS Embolism Event Rates are per 100 patient-years MR Patel et al.N Engl J Med 2011;365:883-91.

  22. ROCKET AF: Primary Safety Outcomes MR Patel et al.N Engl J Med 2011;365:883-91.

  23. ROCKET AF: Primary Safety Outcomes MR Patel et al.N Engl J Med 2011;365:883-91.

  24. ROCKET AF- Summary Stroke or non-CNS systemic embolism (per 100 patient-years): 1.7 with rivaroxaban vs. 2.2 with warfarin (p for noninferiority < 0.001, p for superiority = 0.12 by intention to treat analysis, p for superiority = 0.015 by on-treatment analysis) Major and nonmajor clinically relevant bleeding (per 100 patient-years): 14.9 vs. 14.5 (p = 0.44) Intracranial hemorrhage (per 100 patient-years): 0.5 vs. 0.7 (p = 0.019) Trial design: Patients with atrial fibrillation at increased risk for stroke were randomized to the direct factor Xa inhibitor rivaroxaban 20 mg oral daily (n = 7,131) vs. warfarin with target INR 2-3 (n = 7,133). Results (p for non-inferiority < 0.001) 2.2 1.7 Per 100 patient-years Conclusions • Among AF patients with high stroke risk, rivaroxaban was noninferior to warfarin • Rivaroxaban was associated with a reduced incidence of the primary outcome without an excess of major bleeding or intracranial hemorrhage Stroke or non-CNS systemic embolism Rivaroxaban, 20 mg daily Warfarin, INR 2-3 MR Patel et al.N Engl J Med 2011;365:883-91.

  25. N Engl J Med 2011;365:981-92.

  26. ARISTOTLE: Study Design • Risk Factors, at least 1 of: • CHF • Hypertension • Age  75 • Diabetes • OR • Stroke, TIA or systemic embolus Atrial Fibrillation Apixaban 5 mgbd (2.5-mg for- age≥80, Wt≤60kg 60 kg, or serum creatininelevel of 1.5mg%) Warfarin INR target: 2.0-3.0 Randomized Double Blind (N= 18,201) Monthly Monitoring Adherence to standard of care guidelines Primary Endpoint: ischemic or hemorrhagic stroke or systemic embolism Christopher B. G et al.N Engl J Med 2011;365:981-92.

  27. ARISTOTLE : Baseline Characteristics Christopher B. G et al.N Engl J Med 2011;365:981-92.

  28. ARISTOTLE :Baseline Characteristics Christopher B. G et al.N Engl J Med 2011;365:981-92.

  29. ARISTOTLE :Primary OutcomeStroke or systemic embolism Christopher B. G et al.N Engl J Med 2011;365:981-92.

  30. ARISTOTLE :Primary OutcomeStroke or systemic embolism Christopher B. G et al.N Engl J Med 2011;365:981-92.

  31. ARISTOTLE :Major Bleeding Christopher B. G et al.N Engl J Med 2011;365:981-92.

  32. ARISTOTLE :Bleeding Outcomes Christopher B. G et al.N Engl J Med 2011;365:981-92.

  33. ARISTOTLE : Conclusion • Compared with warfarin, apixaban (over 1.8 years) prevented • 6 Strokes • 15 Major bleeds • 8 Deaths • Treatment with apixaban as compared to warfarin in patients with AF & at least one additional risk factor for stroke: • Reduces stroke and systemic embolism by 21% (p=0.01) • Reduces major bleeding by 31% (p<0.001) • Reduces mortality by 11% (p=0.047) Christopher B. G et al.N Engl J Med 2011;365:981-92.

  34. ARISTOTLE : Summary Primary efficacy outcome (stroke/systemic embolism) for apixaban vs. warfarin: 1.27%/year vs. 1.6%/year; pnoninferiority < 0.001, psuperiority = 0.01 All strokes:1.19%/year vs. 1.51%/year, p = 0.01; all-cause mortality: 3.52%/year vs. 3.94%/year, p = 0.047 Primary safety outcome (ISTH major bleeding): 2.13%/year vs. 3.09%/year, p < 0.001 (p < 0.001)* (p < 0.001) Trial design: Patients with atrial fibrillation (AF) and at least one additional risk factor for stroke were randomized to either apixaban 5 mg twice daily or dose-adjusted warfarin (titrated to a target INR of 2.0-3.0). Patients were followed for a median of 1.8 years. Results 10 10 % 5 % 5 3.09 2.13 Conclusions 1.6 1.27 • Landmark trial, demonstrates superiority of apixaban over warfarin in patients with AF for efficacy, with a significant reduction in bleeding • Apixaban is an oral anti-Xa agent that does not require routine blood monitoring 0 0 Primary efficacy outcome Primary safety outcome Apixaban (n = 9,120) Warfarin (n = 9,081) * For noninferiority Christopher B. G et al.N Engl J Med 2011;365:981-92.

  35. N Engl J Med 2011;364:806-17.

  36. AVERROES (Apixaban versus Acetylsalicylic Acid to Prevent Strokes): Study Design ≈ 1.6 years Patient characteristics Randomization Apixaban 2.5 mg bid or 5 mg bid • Aged 50 years • Atrial fibrillation • 1 additional risk factor for stroke • Not suitable for vitamin K antagonist N=5600 Aspirin 81-324 mg qd • Primary outcome measures: • Time to composite outcome of stroke or systemic embolism • Time to major bleeding Stuart JC et al.NEngl J Med 2011;364:806-17.

  37. AVERROES: Results (efficacy) • Apixaban significantly reduced risk of stroke or systemic embolic events by 54% • The trial was stopped early as interim analysis showed significant benefit with apixaban Primary and secondary end points Stuart JC et al.NEngl J Med 2011;364:806-17.

  38. AVERROES: Results (safety) • The risk of major bleeding increased by a statistically nonsignificant 14% • There was no increased risk of fatal or intracranial hemorrhage, two particular concerns with AF patients who receive anticoagulation therapy Bleeding events Stuart JC et al.NEngl J Med 2011;364:806-17.

  39. Am Heart J 2010:160:635-641.e2.

  40. ENGAGE-AF-TIMI 48; Study Design AF on ECG < 12 mos Intended oral A/C CHADS2 Score > 2 n~16,500 Randomization Strata: 1. CHADS2 2-3 vs 4-6 2. Drug clearance R Low Exposure Strategy DU-176b 30 mg QD (n=5500) High Exposure Strategy DU-176b 60 mg QD (n=5500) Active Control Warfarin (n=5500) Median Duration of Followup 24 months 1º EP = Stroke or SEE (Noninferiority Boundary HR 1.38) 2º EP = Stroke or SEE or All-Cause Mortality Safety EP’s = Major Bleeding, Hepatic Function Chritian TR et al.Am Heart J 2010:160:635-641.e2.

  41. European Heart Journal doi:10.1093/eht039

  42. Characteristics of Betrixaban • Orally-active and selective fXa inhibitor • Oral bioavailability 34%, • Peak to trough concentration profile 2.5 : 1 • ~20 hour effective half-life • No dose adjustment expected for renal impairment • Excreted mostly unchanged through bile with minimal renal excretion (<5%) • Antidote in development • No major drug interactions expected • Not substrate for CYP450 system • Substrate for efflux proteins including P-glycoprotein Stuart JC et al. European Heart Journal. doi:10.1093

  43. EXPLORE-Xa : Study Objectives • Primary Objective • Safety and tolerability of oral betrixaban at doses of 40, 60 and 80 mg once a day compared with dose-adjusted warfarin in patients with non-valvular atrial fibrillation or atrial flutter • Primary Endpoint • Time to major and clinically relevant non-major bleeding • Secondary Endpoints • Time to any bleeding, death, stroke, MI or systemic embolism • Secondary Objective • Pharmacokinetics (PK) and pharmacodynamics (PD) of betrixaban Stuart JC et al. European Heart Journal. doi:10.1093

  44. EXPLORE-Xa: Main Inclusion Criteria • Male or female, age ≥ 18 years • AF at the time of enrollment or documented within the last year • At least one risk factor for stroke • Need for renal dialysis within one year • AF due to reversible causes, mechanical prosthetic valve • SBP > 160 mmHg on repeated measurements • Active infective endocarditis EXPLORE-Xa: Main Exclusion Criteria Stuart JC et al. European Heart Journal. doi:10.1093

  45. N=561 Patients Screened N=508 Patients Randomized N=53 Patients Not Randomized N=127 Betrixaban 40 mg N=127 Betrixaban 60 mg N=127 Betrixaban 80 mg N=127 Open-Label Warfarin N=116 Completed N=115 Completed N=116 Completed N=119 Completed EXPLORE-Xa: Patient Disposition &Follow-Up • Minimum follow-up 3 months; Maximum 12 months; • Median 4.9 months Stuart JC et al. European Heart Journal. doi:10.1093

  46. All Betrixaban Warfarin Total N=381 N=127 N=508 Median Age (years) 74 74 74 47.2% Age ≥75 years 47.2% 47.2% Male 65.4% 70.1% 66.5% White 97.4% 99.2% 97.8% Weight > 90 kg 45.1% 48.8% 46.1% Country US 72.4% 73.2% 72.6% Canada 24.9% 25.2% 25.0% Germany 2.6% 1.6% 2.3% Baseline CHADS2 score 0-1 28.1% 29.1% 28.3% 2 39.9% 33.1% 38.2% 3-6 32.0% 37.8% 33.5% - - 2.2 Mean CHADS2 score Baseline GFR (Cockcroft-Gault) < 40 mL/min 9.2% 4.7% 8.1% 40-70 mL/min 38.6% 37.8% 38.4% > 70 mL/min 52.2% 57.5% 53.5% Concurrent Aspirin Use < 162 mg 38.6% 38.6% 38.6% No Vitamin K Antagonist Experience 12.6% 14.2% 13.0% EXPLORE-Xa: Baseline Characteristics Stuart JC et al. European Heart Journal. doi:10.1093

  47. EXPLORE-Xa: Major Bleeding or Clinically Relevant Non-Major Bleeding Stuart JC et al. European Heart Journal. doi:10.1093

  48. EXPLORE-Xa: Bleeds, strokes & deaths Stuart JC et al. European Heart Journal. doi:10.1093

  49. EXPLORE-Xa: ALT Elevations (in % of Patients) Stuart JC et al. European Heart Journal. doi:10.1093

  50. EXPLORE-Xa: Type of GI Adverse Events by Treatment Stuart JC et al. European Heart Journal. doi:10.1093

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