Authors
Oldgren J, Budaj A, Granger CB, et al.
Title
Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial
References
Eur Heart J 2011;32:2781-9
Background
After an acute coronary syndrome, patients remain at risk of recurrent ischaemic events, despite contemporary treatment, including aspirin and clopidogrel.
Purpose
We evaluated the safety and indicators of efficacy of the novel oral direct thrombin inhibitor dabigatran.
Design
  • Double-blind, placebo-controlled, prospective, multi centre dose-escalation trial
  • 1861 patients (99.2% on dual antiplatelet treatment) were enrolled at mean 7.5 days (SD 3.8) after an ST-elevation (60%) or non-ST-elevation (40%) myocardial infarction
  • Randomization to twice daily treatment with dabigatran 50 mg (n= 369), 75 mg (n= 368), 110 mg (n= 406), 150 mg (n= 347), or placebo (n= 371).
  • Primary outcome was the composite of major or clinically relevant minor bleeding during the 6-month treatment period.
Exclusion Criteria
  • Ongoing or planned treatment with vitamin K antagonists
  • Severe disabling stroke within the previous 6 months or any stroke within the previous 14 days
  • Conditions associated with an increased risk of bleeding such as major surgery (including bypass surgery) in the previous month, history of severe bleeding, gastrointestinal haemorrhage within the past year, gastroduodenal ulcer in the previous 30 days, fibrinolytic agents within 48 h of study entry uncontrolled hypertension, haemoglobin <10 g/dL or platelet count< 100 × 109/L
  • Normal coronary arteries at angiogram for index event
  • Congestive heart failure - New York Heart Association (NHYA) Class IV
  • Severe renal impairment (CrCl<30 mL/min)
Follow-Up
6 months
Treatment Regimen
Twice daily treatment with dabigatran 50 mg, 75 mg, 110 mg, 150 mg, or placebo
Results
Primary Endpoints:
  • There were 96 primary outcome events and, compared with placebo, a dose-dependent increase with dabigatran, hazard ratio (HR) 1.77 (95% confidence intervals 0.70, 4.50) for 50 mg; HR 2.17 (0.88, 5.31) for 75 mg; HR 3.92 (1.72, 8.95) for 110 mg; and HR 4.27 (1.86, 9.81) for 150 mg.

Secondary Endpoints:

  • Compared with placebo, D-dimer concentrations were reduced in all dabigatran dose groups by an average of 37 and 45% at weeks 1 and 4, respectively (P , 0.001). Fourteen (3.8%) patients died, had a myocardial infarction or stroke in the placebo group compared with 17 (4.6%) in 50 mg, 18 (4.9%) in 75 mg, 12 (3.0%) in 110 mg, and 12 (3.5%) in the 150 mg dabigatran groups.
Summary
Dabigatran, in addition to dual antiplatelet therapy (DAPT), was associated with a dose-dependent increase in bleeding events and significantly reduced coagulation activity in patients with a recent myocardial infarction.
Implications
The study contributed to the growing evidence that addition of Dabigatran to DAPT leads to increased major advervese events and an increase in bleeding events. The combination of Dabigatran and DAPT is therefore not recommended.
Related Figures
None.