Randomised Dabigatran Etexilate Dose Finding Study in Patients With Acute Coronary Syndromes Post Index Event - RE-DEEM

Description:

Evidence regarding the efficacy and safety of the combination of dual antiplatelet therapy and oral anticoagulants in patients with acute coronary syndromes (ACS) is limited. The current trial was a phase II study intended to study the safety and efficacy of four different doses of dabigatran, an oral direct thrombin inhibitor, when given in addition to dual antiplatelet therapy in patients with a recent ST-elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI) at high risk of new ischemic cardiovascular events.

Hypothesis:

Dabigatran would not result in an excess of clinically significant bleeding.

Study Design

  • Randomized
  • Blinded
  • Placebo Controlled

Patients Screened: 2,024
Patients Enrolled: 1,878
Mean Follow Up: 6 months
Mean Patient Age: 62 years
Female: 24%

Patient Populations:

  • Stable patients after a STEMI or NSTEMI

Primary Endpoints:

Major and minor bleeding defined by the International Society of Thrombosis and Hemostasis:
  • Fatal bleed and/or
  • Symptomatic bleeding in a critical location and/or
  • Drop in hemoglobin ≥2 g/dl, or need for blood transfusion of at least 2 U, or
  • Overt bleeding, but does not meet one of the above definitions

Secondary Endpoints:

  • Levels of coagulation activity
  • Composite of cardiovascular death, MI, or stroke

Drug/Procedures Used:

Patients were randomized initially only to placebo or one of the two lower doses (50 and 75 mg twice daily) in a 1:1:1 ratio. An independent Data Safety and Monitoring Board reviewed unblinded data and advised the release of the 110 mg dose in a second stage and the 150 mg dose group in a third stage. In the last (fourth) stage of the trial, the randomization was re-programmed to achieve balance between the five groups.

Concomitant Medications:

Aspirin (100%), thienopyridine (100%), angiotensin-converting enzyme inhibitor (73%), and beta-blockers (86%)

Principal Findings:

A total of 1,878 patients were randomized, 369 to the 50 mg dabigatran arm, 368 to the 75 mg arm, 406 to the 110 mg arm, 347 to the 150 mg arm, and 371 to placebo. (Note: 17 of the 1,878 patients did not receive the study drug.) The mean age was 62 years, 24% were women, 31% had diabetes, 29% had a previous MI, the index diagnosis was STEMI in 60% and NSTEMI in 40%, 54% had percutaneous coronary intervention (PCI) during their index event, and the mean time from hospital presentation to randomization was 7.4 days.

The incidence of the primary endpoint, major and clinically significant minor bleeding (by intention-to-treat) at 6 months, occurred in 3.5% of the 50 mg group, 4.3% of the 75 mg group, 7.9% of the 110 mg group, 7.8% of the 150 mg group, and 2.2% with placebo (p < 0.001 for trend). TIMI major bleeding was 0.3%, 0%, 1.2%, 0.3%, and 0.3%, respectively. The most frequently reported bleeding events were gastrointestinal bleeds (2.4% vs. 3.0% vs. 4.9% vs. 3.2% vs. 1.3%) and epistaxis (3.3% vs. 2.2% vs. 4.2% vs. 3.7% vs. 0.8%).

The incidence of major adverse cardiac events (cardiovascular death, nonfatal MI, nonhemorrhagic stroke) was similar (4.6% vs. 4.9% vs. 3.0% vs. 3.5% vs. 3.8, p = NS), as was all cause-mortality (2.2% vs. 2.7% vs. 1.7% vs. 2.0% vs. 3.8%, p = NS).

Interpretation:

Dabigatran is a newer univalent direct thrombin inhibitor, which differs from bivalent direct thrombin inhibitors such as bivalirudin, in binding only to the active site of thrombin. The current phase II trial on the use of dabigatran in ACS patients, indicates that although the addition of dabigatran to dual antiplatelet therapy was well-tolerated, there was a dose-related increase in bleeding at 6 months, as compared with dual antiplatelet alone.

These findings are similar to those noted in phase II trials in ACS patients with other direct thrombin inhibitors such as ximelagatran (ESTEEM) and oral anti-Xa agents such as rivaroxaban (ATLAS-TIMI 46) and apixaban (APPRAISE). Results in AF, comparing dabigatran to warfarin, on the other hand, have been very promising (RE-LY). The role of these agents in ACS patients may thus be relegated to patients in need of triple therapy (dual antiplatelet therapy + Coumadin), although further phase III trials are needed to fully investigate their safety and effectiveness.

References:

Oldgren J, Budaj A, Granger CB, et al.; on behalf of the RE-DEEM Investigators. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J 2011;May 7:[Epub ahead of print].

Presented by Dr. Jonas Oldgren at the American Heart Association Scientific Sessions, Orlando, FL, November 18, 2009.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Anticoagulation Management and ACS, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and ACS

Keywords: Myocardial Infarction, Stroke, Acute Coronary Syndrome, Thrombin, Warfarin, Epistaxis, Percutaneous Coronary Intervention, Catalytic Domain, beta-Alanine, Azetidines, Benzylamines, Benzimidazoles, Intention to Treat Analysis, Diabetes Mellitus


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