From the Guidelines
Apixaban is the preferred anticoagulant for stroke prevention in patients with atrial fibrillation due to its superior efficacy and safety profile compared to warfarin, as demonstrated in the ARISTOTLE trial 1. The ARISTOTLE trial was a landmark clinical study that compared apixaban (Eliquis) to warfarin for stroke prevention in patients with atrial fibrillation. The trial demonstrated that apixaban at a dose of 5 mg twice daily (or 2.5 mg twice daily for patients meeting at least two of these criteria: age ≥80 years, weight ≤60 kg, or serum creatinine ≥1.5 mg/dL) was superior to warfarin in preventing stroke and systemic embolism. Key findings from the trial include:
- Apixaban reduced the rate of stroke and systemic embolism by 21% compared to warfarin (HR, 0.79; 95% CI, 0.66-0.95; P < 0.001 for noninferiority and < 0.01 for superiority) 1
- Apixaban caused significantly less major bleeding compared to warfarin, with an annual rate of 2.13% versus 3.09% (HR, 0.69; 95% CI, 0.60-0.80; P < 0.001) 1
- Apixaban reduced all-cause mortality by 10% compared to warfarin (3.52% vs 3.94%, P = 0.047) 1 The advantages of apixaban include its fixed dosing without need for routine monitoring, fewer drug interactions compared to warfarin, and better safety profile, particularly regarding intracranial hemorrhage. Based on the ARISTOTLE trial results, apixaban is now widely recommended as a first-line anticoagulant for stroke prevention in atrial fibrillation patients, and its use has fundamentally changed clinical practice by providing strong evidence supporting direct oral anticoagulants over traditional vitamin K antagonists for stroke prevention in atrial fibrillation 1.
From the FDA Drug Label
14 CLINICAL STUDIES 14. 1 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation ARISTOTLE
Evidence for the efficacy and safety of apixaban was derived from ARISTOTLE, a multinational, double-blind study in patients with nonvalvular AF comparing the effects of apixaban and warfarin on the risk of stroke and non-central nervous system (CNS) systemic embolism. In ARISTOTLE, patients were randomized to apixaban 5 mg orally twice daily (or 2. 5 mg twice daily in subjects with at least 2 of the following characteristics: age greater than or equal to 80 years, body weight less than or equal to 60 kg, or serum creatinine greater than or equal to 1.5 mg/dL) or to warfarin (targeted to an INR range of 2.0 to 3. 0) Patients had to have one or more of the following additional risk factors for stroke: prior stroke or transient ischemic attack (TIA) prior systemic embolism age greater than or equal to 75 years arterial hypertension requiring treatment diabetes mellitus heart failure ≥New York Heart Association Class 2 left ventricular ejection fraction ≤40% The primary objective of ARISTOTLE was to determine whether apixaban 5 mg twice daily (or 2. 5 mg twice daily) was effective (noninferior to warfarin) in reducing the risk of stroke (ischemic or hemorrhagic) and systemic embolism. Superiority of apixaban to warfarin was also examined for the primary endpoint (rate of stroke and systemic embolism), major bleeding, and death from any cause. A total of 18,201 patients were randomized and followed on study treatment for a median of 89 weeks Forty-three percent of patients were vitamin K antagonist (VKA) “naive,” defined as having received ≤30 consecutive days of treatment with warfarin or another VKA before entering the study. The mean age was 69 years and the mean CHADS2 score (a scale from 0 to 6 used to estimate risk of stroke, with higher scores predicting greater risk) was 2. 1. The population was 65% male, 83% Caucasian, 14% Asian, and 1% Black. There was a history of stroke, TIA, or non-CNS systemic embolism in 19% of patients. Concomitant diseases of patients in this study included hypertension 88%, diabetes 25%, congestive heart failure (or left ventricular ejection fraction ≤40%) 35%, and prior myocardial infarction 14% Patients treated with warfarin in ARISTOTLE had a mean percentage of time in therapeutic range (INR 2.0 to 3. 0) of 62%. Apixaban was superior to warfarin for the primary endpoint of reducing the risk of stroke and systemic embolism (Table 9 and Figure 4). Superiority to warfarin was primarily attributable to a reduction in hemorrhagic stroke and ischemic strokes with hemorrhagic conversion compared to warfarin. Purely ischemic strokes occurred with similar rates on both drugs. Apixaban also showed significantly fewer major bleeds than warfarin [see Adverse Reactions (6. 1)]. Table 9: Key Efficacy Outcomes in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE (Intent-to-Treat Analysis) Apixaban N=9120 n (%/year) Warfarin N=9081 n (%/year) Hazard Ratio (95% CI)P-value Stroke or systemic embolism 212 (1.27) 265 (1.60) 0.79 (0.66,0.95) 0.01 Stroke 199 (1.19) 250 (1.51) 0.79 (0.65,0.95) Ischemic without hemorrhage 140 (0.83) 136 (0.82) 1.02 (0.81,1. 29) Ischemic with hemorrhagic conversion 12 (0.07) 20 (0.12) 0.60 (0.29,1.23) Hemorrhagic 40 (0.24) 78 (0.47) 0.51 (0.35,0.75) Unknown 14 (0.08) 21 (0.13) 0.65 (0.33,1.29) Systemic embolism 15 (0.09) 17 (0.10) 0.87 (0.44,1.
The ARISTOTLE trial was a multinational, double-blind study that compared the effects of apixaban and warfarin on the risk of stroke and non-central nervous system (CNS) systemic embolism in patients with nonvalvular atrial fibrillation (AF). The study found that apixaban was superior to warfarin in reducing the risk of stroke and systemic embolism, with a hazard ratio of 0.79 (95% CI, 0.66-0.95). The superiority of apixaban was primarily due to a reduction in hemorrhagic stroke and ischemic strokes with hemorrhagic conversion. Additionally, apixaban showed significantly fewer major bleeds than warfarin 2.
From the Research
ARISTOTLE Trial Overview
- The ARISTOTLE trial was a randomized clinical trial that compared the efficacy and safety of apixaban with warfarin in patients with atrial fibrillation 3.
- The trial included 18,201 patients with atrial fibrillation who were randomized to receive either apixaban or warfarin 3.
- The primary outcome of the trial was stroke or systemic embolism, and the safety outcome was major bleeding 3.
Key Findings
- The trial found that apixaban was superior to warfarin in preventing stroke and systemic embolism, and caused significantly less major bleeding 3, 4, 5.
- The beneficial effects of apixaban compared to warfarin were consistent in patients with normal or poor renal function over time, as well as in those with worsening renal function 3.
- Patients with peripheral artery disease (PAD) had a higher crude risk of stroke or systemic embolism compared to those without PAD, but the benefits of apixaban versus warfarin for stroke and systemic embolism were similar in patients with and without PAD 6.
Comparison with Other Anticoagulants
- Apixaban was found to have a lower risk of major bleeding compared to dabigatran and rivaroxaban 7, 5.
- Rivaroxaban was associated with an increased risk of major bleeding and intracranial bleeding compared to dabigatran 7.
- Dabigatran, rivaroxaban, and apixaban appeared to have similar effectiveness in preventing stroke and systemic embolism, although apixaban may be associated with a lower bleeding risk 7.