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


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).


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%


  • 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.


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.


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.

Clinical Topics: Acute Coronary Syndromes, Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), ACS and Cardiac Biomarkers, Aortic Surgery, Interventions and ACS, Interventions and Vascular Medicine

Keywords: Follow-Up Studies, Platelet Aggregation Inhibitors, Creatine Kinase, MB Form, Peripheral Arterial Disease, Blood Platelets, Electrocardiography, Thienopyridines, Biological Markers, 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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