The clinical evidence for the efficacy of PRADAXA was derived from RE-LY (Randomized eva luation of Long-term Anticoagulant Therapy), a multi-center, multi-national, randomized parallel group trial comparing two blinded doses of PRADAXA (110 mg twice daily and 150 mg twice daily) with open-label warfarin (dosed to target INR of 2 to 3) in patients with non-valvular, persistent, paroxysmal, or permanent atrial fibrillation and one or more of the following additional risk factors:

The primary objective of this study was to determine if PRADAXA was non-inferior to warfarin in reducing the occurrence of the composite endpoint, stroke (ischemic and hemorrhagic) and systemic embolism. The study was designed to ensure that PRADAXA preserved more than 50% of warfarin’s effect as established by previous randomized, placebo-controlled trials of warfarin in atrial fibrillation. Statistical superiority was also analyzed.

A total of 18,113 patients were randomized and followed for a median of 2 years. The patient’s mean age was 71.5 years and the mean CHADS score was 2.1. The patient population was 64% male, 70% Caucasian, 16% Asian, and 1% black. Twenty percent of patients had a history of a stroke or TIA and 50% were Vitamin K antagonist (VKA) naïve, defined as less than 2 months total lifetime exposure to a VKA. Thirty-two percent of the population had never been exposed to a VKA. Concomitant diseases of patients in this trial included hypertension 79%, diabetes 23%, and CAD 28%. At baseline, 40% of patients were on aspirin and 6% were on clopidogrel. For patients randomized to warfarin, the mean percentage of time in therapeutic range (INR 2 to 3) was 64%; the mean percentages of time INR measurements were greater than 4 or less than 1.5 were 2% and 5%, respectively.

Relative to warfarin and to PRADAXA 110 mg twice daily, PRADAXA 150 mg twice daily significantly reduced the primary composite endpoint of stroke and systemic embolism (see Table 4 and Figure 1).

The contributions of the components of the composite endpoint, including stroke by subtype, are shown in Table 5. The treatment effect was primarily a reduction in stroke. PRADAXA 150 mg twice daily significantly reduced both ischemic and hemorrhagic strokes relative to warfarin.

The efficacy of PRADAXA 150 mg twice daily was generally consistent across major subgroups (see Figure 2).

Centers were ranked post hoc by the percentage of time that warfarin-treated patients were in therapeutic range (INR 2 to 3). Findings for stroke/systemic embolism, all-cause mortality, and major bleeds are shown for centers above and below the median level of INR control in Table 6. The benefits of PRADAXA 150 mg relative to warfarin were most apparent in patients enrolled at centers with INR control below the median.

The risk of myocardial infarction was numerically greater in patients who received PRADAXA (1.5% for 150 mg dose) than in those who received warfarin (1.1%).

Table 4 First Occurrence of Stroke or Systemic Embolism in the RE-LY Study   PRADAXA
150 mg twice daily  PRADAXA
110 mg twice daily  Warfarin 
Patients randomized 6076 6015 6022
Patients (%) with events  134 (2.2%) 183 (3%) 202 (3.4%)
Hazard ratio vs. warfarin (95% CI) 0.65 (0.52, 0.81) 0.90 (0.74, 1.10)  
   P-value