Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome - TRACER

Nov 13, 2011
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Merck
Date Presented:
01/01/2011
Date Published:
01/01/2011
Date Updated:
11/13/2011
Original Posted Date:
11/13/2011
References

Description:

Protease-activated receptor 1 (PAR-1) activation by thrombin is one of the most potent stimulators of platelet activation. The current trial sought to study the safety and efficacy of vorapaxar, a novel PAR-1 antagonist, in patients with recent acute coronary syndrome (ACS).

Hypothesis:

Vorapaxar would be superior as compared with placebo for secondary prevention in patients with recent ACS.

Study Design

  • Placebo Controlled
  • Randomized
  • Parallel
  • Stratified
  • Blinded

Patient Populations:

  • Within 24 hours of symptoms
  • Elevated biomarkers or electrocardiogram changes
  • One other high-risk feature (age ≥55 years, prior MI/PCI/CABG, DM, peripheral arterial disease)

    Number of enrollees: 12,944
    Duration of follow-up: 31 months
    Mean patient age: 64 years
    Percentage female: 28%

Exclusions:

  • Concurrent or anticipated treatment with warfarin (or derivatives), oral factor Xa inhibitor, or oral direct thrombin inhibitor after enrollment
  • Concurrent or anticipated treatment with a potent inducer (e.g., rifampin) or potent inhibitor (e.g., ketoconazole, erythromycin) of CYP3A4 isoenzymes
  • History of a bleeding diathesis or evidence of active abnormal bleeding within 30 days before enrollment
  • History at any time of intracranial hemorrhage, intracranial or spinal cord surgery, or a central nervous system tumor or aneurysm
  • Documented sustained severe hypertension (systolic blood pressure >200 mm Hg or diastolic blood pressure >110 mm Hg) at enrollment or within the previous 10 days
  • Severe valvular heart disease, as defined by the American College of Cardiology/American Heart Association
  • History within 2 weeks before enrollment of major surgery other than mentioned above, or of ischemic stroke
  • Known platelet count <100,000/mm3 at time of enrollment or within 24 hours before enrollment
  • Known active hepatobiliary disease, or known unexplained persistent increase in serum alanine aminotransferase or aspartate aminotransferase activity to ≥2 times the upper limit of the reference range within 30 days before enrollment
  • Any serious illness or any condition that the investigator feels would pose a significant hazard to the subject if investigational therapy were initiated or would limit the prognosis of the subject, regardless of investigational therapy
  • Any serious medical comorbidity (e.g., active malignancy) such that the subject’s life expectancy is <24 months

Primary Endpoints:

  • Efficacy: Composite of CV death/MI/stroke/recurrent ischemia with hospitalization/urgent coronary revascularization
  • Safety: Moderate or severe GUSTO bleeding
  • Clinically significant TIMI bleeding

Secondary Endpoints:

  • CV death/MI/stroke

Drug/Procedures Used:

Patients with recent ACS were randomized in a 1:1 fashion to either vorapaxar 2.5 mg daily or placebo. A loading dose of 40 mg of vorapaxar was also given. Stratification was by glycoprotein (GP) IIb/IIIa inhibitor and parenteral direct thrombin inhibitor (DTI) use. The loading dose was given at least 1 hour prior to revascularization. The maintenance dose was for a minimum of 1 year.

Concomitant Medications:

GP IIb/IIIa inhibitor use (21%), DTI (17%), aspirin (96.7%), and thienopyridine (91.8%)

Principal Findings:

The trial was terminated early after a safety review. At that time, a total of 12,944 patients were enrolled at 818 centers in 37 countries (26.3% in North America), 6,471 to vorapaxar and 6,473 to placebo. The mean duration of treatment with a study drug was 386 days.

Baseline characteristics were similar between the two arms. About 17% of the patients were ≥75 years, 86% were White, 31% had diabetes mellitus (DM), and 29% had a prior history of myocardial infarction (MI). The median body weight was 80 kg. The vast majority of patients were troponin/creatine kinase-myocardial band positive (94%), with a high TIMI (Thrombolysis in Myocardial Infarction) risk score (5-7) in about 48% of the patients. About 88% of all patients underwent diagnostic angiography during index hospitalization, 57.8% underwent percutaneous coronary intervention (PCI), and 10.1% coronary artery bypass grafting (CABG).

Over a median duration of follow-up of about 2 years, the primary efficacy endpoint (cardiovascular [CV] death/MI/stroke/recurrent ischemia with hospitalization/urgent coronary revascularization) was similar between the vorapaxar and placebo arms (event rates 18.5% vs. 19.9%, hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.85-1.01, p = 0.07). The key secondary endpoint of CV death/MI/stroke was significantly lowered in the vorapaxar arm (event rates 14.7% vs. 16.4%, p = 0.02). Rates of MI were also lower (event rates 11.1% vs. 12.5%, p = 0.02). Other endpoints, including all-cause mortality (event rates 6.5% vs. 6.1%), stroke (event rates 1.9% vs. 2.1%), and stent thrombosis (1.7% vs. 1.5%) were similar (p > 0.05 for all).

The primary endpoint of moderate to severe GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) bleeding was significantly increased in the vorapaxar arm (7.2% vs. 5.2%, HR 1.35, 95% CI 1.16-1.58, p < 0.001). Similarly, clinically significant TIMI bleeding was increased (20.2% vs. 14.6%, p < 0.001). Rates of TIMI major bleeding (4.0% vs. 2.5%, p < 0.001) and intracranial hemorrhage (1.1% vs. 0.2%, p < 0.001) were elevated. The highest risk was in patients with a low body weight and those who were already on a thienopyridine.

Premature drug discontinuation was noted in 28.2% in the vorapaxar arm and 26.8% in the placebo arm.

Interpretation:

The results of this trial indicate that the addition of vorapaxar to dual antiplatelet therapy in patients hospitalized with a recent ACS (median duration of use 13.0 months) was not associated with a significant reduction in ischemic events, but an increase in bleeding events, as compared with placebo.

Vorapaxar is a novel antiplatelet agent, which inhibits thombin-induced platelet activation and aggregation via inhibition of the PAR-1 receptor. This is an attractive target, since thrombin is one of the most potent platelet activators. Another PAR-1 antagonist, atopaxar, demonstrated similar lack of efficacy and increased bleeding in the phase II LANCELOT-CAD trial. A separate phase II trial, the LANCELOT-ACS trial, which was powered for platelet function studies, demonstrated superior platelet inhibition with atopaxar, with no increase in bleeding events.

References:

Tricoci P, Huang Z, Held C, et al., on behalf of the TRACER Investigators. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med 2011;Nov 13:[Epub ahead of print].

Presented by Dr. Kenneth Mahaffey at the American Heart Association Scientific Sessions, Orlando, FL, November 13, 2011.

Keywords: Follow-Up Studies, Platelet Aggregation Inhibitors, Creatine Kinase, MB Form, Peripheral Arterial Disease, Blood Platelets, Electrocardiography, Thienopyridines, Biomarkers, Thrombosis, Imines, Confidence Intervals, Platelet Glycoprotein GPIIb-IIIa Complex, Stroke, Myocardial Infarction, Acute Coronary Syndrome, Body Weight, Pyridines, Stents, Percutaneous Coronary Intervention, Receptor, PAR-1, Intracranial Hemorrhages, Lactones, Platelet Activation, Coronary Artery Bypass, Diabetes Mellitus, Troponin


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