Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes - TRILOGY ACS

Description:

The goal of the trial was to evaluate treatment with prasugrel compared with clopidogrel among patients with non-ST-elevation acute coronary syndromes (NSTE-ACS) selected for medical management without revascularization.

Hypothesis:

Prasugrel will reduce cardiovascular events compared with clopidogrel.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Patients with a NSTE-ACS selected for a strategy of medical management without planned routine invasive therapy with at least one of these four high-risk criteria:
    1) Age ≥60 years
    2) Diabetes
    3) Prior MI
    4) Prior revascularization (percutaneous coronary intervention [PCI] or CABG)

    Number of enrollees: 9,326
    Duration of follow-up: 17 months
    Mean patient age: 66 years
    Percentage female: 39%

Exclusions:

  • Stroke or transient ischemic attack
  • PCI or CABG within the last 30 days
  • Dialysis
  • Use of oral anticoagulant

Primary Endpoints:

  • Cardiovascular death, MI, or stroke among patients <75 years of age

Secondary Endpoints:

  • If superiority for the primary endpoint, then analysis of cardiovascular death, MI, or stroke among the entire cohort of patients including those >75 years of age
  • All-cause mortality
  • Cardiovascular death
  • MI
  • Stroke
  • GUSTO severe or life-threatening bleeding not related to CABG
  • TIMI major bleeding not related to CABG

Drug/Procedures Used:

Patients with NSTE-ACS (<75 years of age) selected for medical management without revascularization (n = 7,243) were randomized within 10 days of the index event to prasugrel 10 mg daily versus clopidogrel 75 mg daily (patients <60 kg received prasugrel 5 mg daily.) In addition, NSTE-ACS patients ≥75 years of age (n = 2,083) were randomized to prasugrel 5 mg daily versus clopidogrel 75 mg daily.

Patients who were randomized within 72 hours of first medical contact were loaded with prasugrel 30 mg versus clopidogrel 300 mg, followed by maintenance therapy. Patients randomized after 72 hours of first medical contact were started on study drug maintenance therapy. Study drugs were administered for 6-30 months.

Concomitant Medications:

All patients received aspirin and best medical therapy.

Principal Findings:

Overall, 9,326 patients were randomized. The median duration of study drug was 15 months, median age was 66 years, 39% were women, NSTE myocardial infarction (MI) was present in 70% and unstable angina in 30%, 38% had diabetes, 43% had prior MI, median GRACE risk score was 122, 41% had coronary angiography performed before randomization, and 7.9% underwent revascularization.

At 30 months, among patients <75 years of age, the primary outcome of cardiovascular death, MI, or stroke occurred in 13.9% of the prasugrel group versus 16.0% of the clopidogrel group (hazard ratio [HR] = 0.91, p = 0.21). Similar results were seen in the overall population and among those ≥75 years of age. When analyzing, multiple recurrent events (all components of the primary outcome including first and additional events) occurred less frequently with prasugrel (HR = 0.85, p = 0.04). Rates of severe bleeding were similar between the two groups and among those ≥75 years of age.

Individual endpoints in the primary cohort of patients <75 years of age:

- All-cause mortality: 7.8% vs. 8.1%, HR = 0.96, p = 0.63
- Cardiovascular death: 6.6% vs. 6.8%, HR = 0.93, p = 0.48
- MI: 8.3% vs. 10.5%, HR = 0.89, p = 0.21
- Stroke: 1.5% vs. 2.2%, HR = 0.67, p = 0.08
- Noncoronary artery bypass grafting (CABG) GUSTO severe or life-threatening bleeding: 0.9% vs. 0.6%, HR = 0.94, p = 0.87
- Non-CABG Thrombolysis in MI (TIMI) major bleeding: 2.1% vs. 1.5%, HR = 1.31, p = 0.27

At 30 months, among all patients (including those ≥75 years of age), cardiovascular death, MI, or stroke occurred in 18.7% of the prasugrel group versus 20.3% of the clopidogrel group (HR = 0.96, p = 0.45).

- All-cause mortality: 11.6% vs. 12.2%, HR = 0.94, p = 0.40
- Cardiovascular death: 9.9% vs. 10.2%, HR = 0.93, p = 0.38
- MI: 10.7% vs. 12.3%, HR = 0.96, p = 0.58
- Stroke: 2.2% vs. 2.6%, HR = 0.89, p = 0.52
- Non-CABG GUSTO severe or life-threatening bleeding: 1.1% vs. 1.0%, HR = 0.83, p = 0.53
- Non-CABG TIMI major bleeding: 2.5% vs. 1.8%, HR = 1.23, p = 0.29

Secondary analysis: Angiography (n = 3,085) versus no angiography (n = 4,158): Patients undergoing angiography were younger, male, enrolled in Western countries, and more likely to present with NSTEMI versus unstable angina. Baseline GRACE risk score was lower (112 vs. 117). The primary endpoint (cardiovascular death, MI, stroke) was significantly lower in the angiographic cohort as compared with the no angiography cohort (12.8% vs. 16.5%, HR = 0.63, 95% CI 0.53-0.75; p < 0.0001). Individual endpoints including cardiovascular death (4.7% vs. 8.2%, p = 0.0007), MI (8.7% vs. 9.9%, p < 0.0001), and TIMI major (2.0% vs. 1.6%, p = 0.66) and major/minor bleeding (3.2% vs. 2.3%, p = 0.44) were similar.

Prasugrel resulted in a significant reduction in the primary efficacy endpoint (cardiovascular death/MI/stroke) when compared with clopidogrel in the angiographic subset (10.7% vs. 14.9%, p = 0.032), but not in the nonangiographic subset (16.3% vs. 16.7%, p = 0.95) (p for interaction by angiography = 0.08). Similarly, there was a significant reduction in MI with prasugrel in the angiographic subset (7.2% vs. 10.3%, p = 0.047), but not in the nonangiographic subset (9.2% vs. 10.6%, p = 0.99) (p for interaction = 0.12). TIMI major bleeding trended higher in the prasugrel arm of the angiographic subset (2.7% vs. 1.4%, p = 0.07).

Platelet function substudy: A proportion of patients were enrolled in a platelet function substudy (27.5%) and underwent platelet function testing with the VerifyNow assay at baseline; 2 hours; and 1, 3, 6, 12, 18, 24, and 30 months. Among patients <75 years of age and >60 kg, the median platelet reactivity unit at 30 days was 64 in the prasugrel group versus 200 in the clopidogrel group (p < 0.001), which persisted during follow-up. A similar finding was observed among patients <75 years of age and <60 kg; however, the difference was less pronounced.

The continuous distribution of platelet reactivity units at 30 days did not differ for those who had a subsequent primary ischemic event compared with those who did not have a subsequent primary event (p = 0.07).

Interpretation:

Among patients with NSTE-ACS selected for medical management without revascularization, the long-term use of prasugrel did not reduce adverse outcomes compared with clopidogrel. Major bleeding was similar between groups; however, major or minor bleeding appeared increased with prasugrel. These results differ from a clear benefit of prasugrel over clopidogrel in reducing cardiovascular events in patients with planned PCI seen in the TRITON-TIMI 38 trial.

On subgroup analysis, patients undergoing angiography prior to randomization to medical therapy (and therefore confirmed coronary artery disease) seemed to benefit from prasugrel compared with clopidogrel. However, these results are hypothesis generating and need further validation. They also have to be viewed in the setting of an overall negative trial, a marginal p-value for interaction and significant differences between patients who underwent angiography versus those who did not. High platelet reactivity was not associated with ischemic events among NSTE-ACS patients initially managed without revascularization. This may help to explain the overall trial’s negative finding.

While most patients with NSTE-ACS will undergo invasive therapy and revascularization, some patients are either deemed not to be candidates for catheterization, or coronary anatomy is not optimal for revascularization (e.g., small vessel disease, chronic total occlusion, etc.). In this more heterogeneous population, a benefit of prasugrel could not be seen. The reduction in prasugrel dose among older and low body weight patients, which was based on pharmacokinetics, appears to have given similar results as the standard dose in those <75 years of age, but further analyses will be helpful to determine its effects. Since outcomes were not different, prasugrel could potentially be an alternative to clopidogrel, although further analyses refining the patient population may be helpful in determining if certain groups had a benefit of prasugrel.

References:

Wiviott SD, White HD, Ohman EM, et al. Prasugrel versus clopidogrel for patients with unstable angina or non-ST-segment elevation myocardial infarction with or without angiography: a secondary, prespecified analysis of the TRILOGY ACS trial. Lancet 2013;382:605-613.

Roe MT, Goodman SG, Ohman EM, et al. Elderly Patients With Acute Coronary Syndromes Managed Without Revascularization: Insights Into the Safety of Long-Term Dual Antiplatelet Therapy With Reduced-Dose Prasugrel vs. Standard-Dose Clopidogrel. Circulation 2013;Jul 12:[Epub ahead of print]

Roe MT, Armstrong PW, Fox KA, et al., on behalf of the TRILOGY ACS Investigators. Prasugrel Versus Clopidogrel for Acute Coronary Syndromes Without Revascularization. N Engl J Med 2012;367:1297-1309.

Gurbel PA, Erlinge D, Ohman EM, et al., on behalf of the TRILOGY ACS Platelet Function Substudy Investigators. Platelet function during extended prasugrel and clopidogrel therapy for patients with ACS treated without revascularization: The TRILOGY ACS platelet function substudy. JAMA 2012;308:1785-94.

Presented by Dr. M.T. Roe at the European Society of Cardiology Congress, Munich, August 27, 2012.

Presented by Dr. Stephen Wiviott at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2012), Miami, FL, October 24, 2012.

Presented by Dr. Paul Gurbel at the American Heart Association Scientific Sessions, Los Angeles, CA, November 4, 2012.

 

Clinical Topics: Acute Coronary Syndromes, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Interventions and ACS, Interventions and Imaging, Angiography, Nuclear Imaging

Keywords: Myocardial Infarction, Stroke, Acute Coronary Syndrome, Follow-Up Studies, Thiophenes, Ticlopidine, Blood Platelets, Piperazines, Polyethylene Glycols, Percutaneous Coronary Intervention, Coronary Angiography, Catheterization, Diabetes Mellitus


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