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Apixaban versus Warfarin in Patients with Atrial Fibrillation

Apixaban versus Warfarin in Patients with Atrial Fibrillation. Study by: Granger et al. NEJM, September 2011,Vol. 365. No. 11 Presented by: Amelia Crawford PA-S2. Background. Vitamin K Antagonists (Warfarin) are routinely used in stroke prevention in patients with A.fib

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Apixaban versus Warfarin in Patients with Atrial Fibrillation

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  1. Apixaban versus Warfarin in Patients with Atrial Fibrillation Study by: Granger et al. NEJM, September 2011,Vol. 365. No. 11 Presented by: Amelia Crawford PA-S2

  2. Background • Vitamin K Antagonists (Warfarin) are routinely used in stroke prevention in patients with A.fib • Downfalls of Warfarin: • 1. variable response • 2. requires regular monitoring (INR) • 3. bleeding risks • 4. food & drug interactions • Apixaban is a direct factor Xa inhibitor that has demonstrated stroke risk reduction in patients compared with Aspirin and does not require INR monitoring

  3. Objectives • Primary: To determine whether Apixaban was non-inferior to Warfarin in decreasing the rate of stroke/systemic embolism in patients with A.fib and at least one additional risk factor for stroke. • Non-Inferiority Hypothesis: Apixaban preserves at least 50% of relative risk reduction in the risk of stroke or systemic embolism associated with Warfarin • Secondary: Determine if Apixaban was superior to Warfarin with respect to primary outcome and rates of major bleeding and death.

  4. Design • Randomized, Double Blind Trial • ARISTOTLE Trial- December 2006 to April 2010 funded by Bristol-Myers, Squibb and Pfizer

  5. Study Population 18,201 patients from 1034 clinical sites in 39 countries w/ 2 year follow up Patients with a.fib or flutter + one additional risk factor for stroke: • 75 YOA or older, • prior history of stroke, TIA, or systemic embolism • symptomatic HF within 3 months or LVEJ<40% • DM • HTN requiring pharmacologic therapy 9120 patients assigned to Apixaban and 9081 assigned to Warfarin Patients were similar in baseline characteristics: age, CHAD score, previous anticoagulation treatment, hx of stroke, etc)

  6. Exclusion Criteria • reversible a.fib • severe mitral stenosis • other conditions requiring anti-coagulation (prosthetic heart valve) • stroke within previous 7 days • need for >165mg ASA daily or both ASA & clopidiogrel • renal insufficiency (SCr >2.5mg/dl or CrCl <25ml/min)

  7. Interventions • Patients were randomized to receive either: • 2mg doses of Warfarin in order to achieve INR between 2-3. • Apixaban 5mg BID • Apixaban 2.5mg BID if patient had 2 of the following: • > 80YOA • Body weight of 60kg or < • Serum Creatinine of 1.5mg/dl or > • Patients received monthly study visits to monitor INR • INR’s were monitored using blinded, encrypted point of care INR device, and an algorithm was used to guide warfarin dose • Patients were visited every 3 months to assess clinical outcomes & adverse events.

  8. Outcomes • Primary Efficacy Outcome= Stroke or Systemic Embolism • Secondary Efficacy Outcome= Death from any cause • Primary Safety Outcome= Major bleeding (required transfusion or resulted in death) • Secondary Safety Outcome= Non-major bleeding that required medical care

  9. Statistical Analysis • Primary & Secondary analyses performed using the Cox proportional hazards model

  10. Results • Primary Efficacy Outcomes: • Primary outcome of stroke or systemic embolism was lower for Apixaban group than Warfarin group: • 212 pts in apixaban, 265 pts in warfarin, • HR = 0.79; CI 0.66-0.95; P<0.001 for noninferiority & P = 0.01 for superiority • Reduction in primary outcome with Apixaban was consistent across all major subgroups (age, sex, weight, type of a.fib, dm, hf, prior stroke/tia, renal impairment)

  11. Results • Secondary Efficacy Outcomes: • Death rate lower in Apixaban group than in Warfarin group: • 3.52% vs 3.94% per year: HR 0.89; 95% CI, 0.80-0.99; P= 0.047

  12. Results • Primary Safety Outcomes: • Major Bleeding was lower in Apixaban group (2.13%) compared with Warfarin group (3.09%) • HR= 0.69; 95% CI, 0.60-0.80; P<0.001 • Rate of any bleeding was 18.1% with Apixaban and 25.8% with Warfarin, with an absolute risk reduction of 7.7 percentage points (P<0.001)

  13. Calculations for Primary Outcome Relative Risk = 0.79 Apixaban= 212/9120 = 0.023 Warfarin = 265/9081 = 0.029 Relative Risk Reduction= 0.21 1- 0.79 Absolute Risk Reduction = 0.006 0.029-0.023 NNT= 167 patients 1/0.006 NNH (Major Bleeding) = 67 NNH (Death) = 125

  14. Summary of Results • In patients with A.fib + one or more risk factors for stroke, the use of Apixaban compared with Warfarin, significantly reduced the risk of: • 1. Stroke/Systemic Embolism (21% decrease) • 2. Major Bleeding (31% decrease) • 3. Death (11% decrease) Results were consistent across subgroups Predominant effect is hemorrhagic stroke prevention (49% lower rate than warfarin)

  15. Conclusions • In patients with A.fib, Apixaban is as effective as Warfarin at preventing stroke & systemic embolism, causes less bleeding, and results in lower mortality.

  16. Advantages of Apixaban: rapid absorption, 12hr half-life, 25% renal excretion, no need for INR monitoring • Other options on the horizon: • 1. Dabigatran- Direct Thrombin Inhibitor • 2. Rivaroxaban- Factor Xa Inhibitor All 3 have been shown to be non-inferior to Warfarin in stroke prevention

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