Introduction

The increased risk of stroke in atrial fibrillation (AF) patients is effectively reduced with vitamin K antagonists (VKA) such as warfarin. Nevertheless, a narrow therapeutic range, drug and food interactions, regular monitoring, and risk of bleeding have hindered their use. Apixaban, a novel oral direct factor Xa inhibitor has also shown promising results in terms of reducing the risk of stroke in a similar population, when compared with aspirin.

Aim

Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial compared apixaban vs. warfarin for the prevention of stroke or systemic embolism (SE) in AF patients having at least one additional risk factor for stroke.

Patient Profile

• Patients with AF/atrial flutter, having at least one additional risk factor for stroke [age ≥75 years; previous stroke, transient ischemic attack (TIA), or SE; symptomatic heart failure within the previous 3 months or left ventricular ejection fraction <40%; diabetes mellitus; or hypertension requiring pharmacologic treatment] (n=18,201)

  Methods

  Study Design

• A randomized, double-blind trial

  Treatment Strategy

• Patients were randomized to:
  • Apixaban (5 mg twice daily); patients aged ≥80 years, those having body weight <60 kg, or a serum creatinine ≥1.5 mg/dL were treated with apixaban 2.5 mg twice daily (n=9120).
  • Dose-adjusted warfarin (target international normalized ratio, 2.0 to 3.0) (n=9081)

  Outcomes

  Primary Outcome

• Incidence of ischemic or hemorrhagic stroke or SE
• Incidence of major bleeding

  Secondary Outcome

• Death from any cause
• A composite of major bleeding and clinically relevant non-major bleeding
• To determine the superiority of apixaban vs. warfarin with respect to the primary outcome and in terms of major bleeding and death from any cause.

Follow-up

• Median duration 1.8 years

  Results

• The median age of the study population was 70 years; 35.3% of the patients were women, the mean CHADS₂ score was 2.1; 57% patients were previously treated with VKA, 19% had a history of stroke, TIA, or SE.
• Patients treated with apixaban vs. warfarin had a significant 21% reduction in the risk of stroke [1.27% per year vs. 1.60% per year; hazard ratio (HR): 0.79; 95% confidence interval (CI): 0.66 to 0.95; P<0.001 for noninferiority; P=0.01 for superiority] (Fig. 1).
• Patients treated with apixaban vs. warfarin had a 31% lower incidence of major bleeding (2.13% per year vs. 3.09% per year; HR: 0.69; 95% CI: 0.60 to 0.80; P<0.001), and an 11% lower risk of death from any cause (3.52% vs. 3.94%; HR: 0.89; 95% CI; 0.80 to 0.99; P=0.047) (Fig. 1).

Fig. 1: The incidence of key primary & secondary outcomes of the study

• Patients treated with apixaban vs. warfarin had 11% reduction in the risk of death from cardiovascular (CV) causes (including death from hemorrhagic stroke; 1.80% per year vs. 2.02% per year; HR: 0.89; 95% CI: 0.76 to 1.04), and an insignificant 7% reduction in the risk of death from non-CV causes (including fatal bleeding other than that from hemorrhagic stroke; 1.14% per year vs. 1.22% per year; HR: 0.93; 95% CI, 0.77 to 1.13).
• Patients treated with apixaban vs. warfarin had a 49% reduction in the risk of hemorrhagic stroke (0.24% per year vs. 0.47% per year; HR: 0.51; 95% CI: 0.35 to 0.75; P<0.001), and a non-significant 8% reduction in the risk of ischemic or uncertain type of stroke (0.97% per year vs. 1.05%; HR: 0.92; 95% CI: 0.74 to 1.13; P=0.42).
• The risk of intracranial hemorrhage reduced by 58% in apixaban vs. warfarin-treated patients (0.33% per year vs. 0.80% per year; HR: 0.42; 95% CI: 0.30 to 0.58; P<0.001). The rate of any bleeding was lower in apixaban vs. warfarin-treated patients (18.1% vs. 25.8% per year; P <0.001).
• The reduction in the primary outcome with apixaban vs. warfarin was consistent across all major subgroups of patients. Diabetes status and renal function at baseline influenced the impact of apixaban on the risk of major bleeding; patient without diabetes (P=0.003 for interaction) and with moderate or severe renal impairment (P=0.03 for interaction), had a greater reduction in bleeding when treated with apixaban.
• The incidence of adverse events did not differ significantly in the apixaban- and warfarin-treated patients.

Conclusions

• Apixaban was superior to warfarin in preventing stroke or SE in patients with AF. Apixaban also caused lesser bleeding and resulted in lower mortality, when compared to warfarin.
• The predominant effect of apixaban on stroke prevention was on hemorrhagic stroke, preventing a hemorrhagic stroke in 4 patients per 1000 and preventing of an ischemic or unknown type of stroke in 2 patients per 1000.