Dabigatran clinical studies

Dabigatran clinical studies
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]

Clinical Studies

The clinical evidence for the efficacy of PRADAXA was derived from RE-LY (Randomized Evaluation 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:

• Previous stroke, transient ischemic attack (TIA), or systemic embolism
• Left ventricular ejection fraction <40%
• Symptomatic heart failure, ≥ New York Heart Association Class 2
• Age ≥75 years
• Age ≥65 years and one of the following: diabetes mellitus, coronary artery disease (CAD), or hypertension

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 CHADS2 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%.

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 2).

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 was superior in reducing ischemic and hemorrhagic strokes relative to warfarin.

In the RE-LY trial, the rate of all-cause mortality was lower on dabigatran 150 mg than on warfarin (3.6% per year versus 4.1% per year). The rate of vascular death was lower on dabigatran 150 mg compared to warfarin (2.3% per year versus 2.7% per year). Non-vascular death rates were similar in the treatment arms.

The efficacy of PRADAXA 150 mg twice daily was generally consistent across major subgroups (see Figure 3).

In RE-LY, a higher rate of clinical myocardial infarction was reported in patients who received PRADAXA (0.7 per 100 patient-years for 150 mg dose) than in those who received warfarin (0.6).