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

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. OutcomePatients w/ Event (A) Event Rate (A) Patients w/Event (W) Event Rate (W) Hazard RatioP Value Stroke or SE: Ischemic Hemorrhagic Systemic Embolism 212 162 40 15 1.27 %/yr 0.97 0.24 0.09 265 175 78 17 1.60 %/yr 1.05 0.47 0.10 0.79 (0.66–0.95) 0.92 (0.74–1.13) 0.51 (0.35–0.75) 0.87 (0.44–1.75) 0.01 0.4 <0.001 0.047 Death from any Cause 6033.52 %/yr6993.94%/yr0.89 (0.80–0.998)0.047

14. 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

15. 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)

16. 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.

17. 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