Elsevier

The Lancet

Volume 382, Issue 9892, 17–23 August 2013, Pages 605-613
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(13)61451-8Get rights and content

Summary

Background

Treatment with prasugrel and aspirin improves outcomes compared with clopidogrel and aspirin for patients with acute coronary syndrome who have had angiography and percutaneous coronary intervention; however, no clear benefit has been shown for patients managed first with drugs only. We assessed outcomes from the TRILOGY ACS trial based on whether or not patients had coronary angiography before treatment was chosen.

Methods

TRILOGY ACS (ClinicalTrials.gov number NCT00699998) was a randomised controlled trial, done at more than 800 sites worldwide. Patients with non-ST-elevation acute coronary syndrome who were selected for management without revascularisation were randomly assigned to clopidogrel or prasugrel. The primary endpoint was cardiovascular death, myocardial infarction, or stroke at 30 months. In the present analysis we assessed differences in the primary endpoint by angiography status and whether the effects of treatment on the primary endpoint differed between patients who had angiography before enrolment and those who had not.

Findings

7243 patients younger than 75 years were included in the TRILOGY ACS primary analysis. 3085 (43%) had angiography at baseline, 4158 (57%) had not. Fewer patients who had angiography reached the primary endpoint at 30 months compared with those who did not have angiography, according to Kaplan-Meier analysis (281/3085 [12·8%] vs 480/4158 [16·5%], adjusted hazard ratio [HR] 0·63, 95% CI 0·53–0·75; p<0·0001). The proportion of patients who reached the primary endpoint was lower in the prasugrel group than in the clopidogrel group for those who had angiography (122/1524 [10·7%] vs 159/1561 [14·9%], HR 0·77, 95% CI 0·61–0·98; p=0·032) but did not differ between groups in patients who did not have angiography (242/2096 [16·3%] vs 238/2062 [16·7%], HR 1·01, 0·84–1·20; p=0·94; pinteraction=0·08). Overall, TIMI major bleeding and GUSTO severe bleeding were rare. Bleeding outcomes tended to be higher with prasugrel but did not differ significantly between treatment groups in either angiography cohort.

Interpretation

Among patients who had angiography who took prasugrel there were fewer cardiovascular deaths, myocardial infarctions, or strokes than in those who took clopidogrel. This result needs to be corroborated, but it is consistent with previous trials of more versus less intensive antiplatelet treatment. When angiography is done for acute coronary syndrome and anatomic coronary disease confirmed, the benefits and risks of intensive antiplatelet treatment exist whether the patient is treated with drugs or percutaneous coronary intervention.

Funding

Daiichi Sankyo, Eli Lilly.

Introduction

Coronary revascularisation with percutaneous coronary intervention or coronary artery bypass grafting is recommended for patients with unstable angina or non-ST-segment elevation myocardial infarction (UA/NSTEMI).1, 2 However, many such patients are managed without revascularisation.3, 4 Patients who are not revascularised can be treated with drugs either with or without invasive assessment of coronary anatomy.

Treatment with two antiplatelet drugs is also a cornerstone of management of UA/NSTEMI. Based on the CURE trial,5 guidelines recommend dual antiplatelet treatment with aspirin and a P2Y12 antagonist as adjunctive treatment, irrespective of whether the treatment strategy includes coronary revascularisation. Subsequent trials, including TRITON–TIMI 386 and PLATO,7 have shown that more intensive P2Y12 antagonist treatment has greater efficacy for patients with UA/NSTEMI compared with a standard regimen of clopidogrel: most patients had coronary angiography and were treated with coronary revascularisation. In TRITON–TIMI 38, all patients with UA/NSTEMI were enrolled only after percutaneous coronary intervention was planned. In this population, prasugrel reduced cardiovascular death, myocardial infarction, and stroke more than clopidogrel, but with a higher risk of bleeding. However, in the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial—in which patients were treated without planned revascularisation with or without pre-enrolment angiography at the discretion of the treating doctor—neither a significant reduction in cardiovascular events nor an increase in severe bleeding was reported.8, 9

We present results of a subgroup analysis of TRILOGY ACS, in which we assessed differences in patient characteristics, outcomes, and effects of prasugrel compared with clopidogrel based on whether or not patients underwent coronary angiography before enrolment.

Section snippets

Study design and procedures

TRILOGY ACS was a phase 3, randomised, double-blind, double-dummy, active-control study done at more than 800 sites worldwide (ClinicalTrials.gov number NCT00699998).9 The study was done in accordance with the Declaration of Helsinki, and national and local regulatory authorities approved the trial protocol in all participating countries and at all sites.

At enrolment, all participants were scheduled to be treated with drugs only without revascularisation. Patients were excluded if percutaneous

Results

The 7243 patients included in the primary study population were younger than 75 years (figure 1); of whom, 3085 (43%) were treated after angiography and 4158 (57%) were treated without angiography. The most common reasons for not having angiography were patient refusal (n=1322; 32%), unavailability of on-site angiography (n=1185; 29%), and either an unsuitable coronary anatomy or other contraindication (n=506, 12%); 1145 patients (28%) gave other or no reason.

In both groups (with or without

Discussion

Patients in the TRILOGY ACS trial who were treated after coronary angiography differed from those who did not have angiography with respect to baseline characteristics and clinical outcomes, as well as the benefit and risk of prasugrel.

The differences in baseline characteristics between groups probably contributed to the differences in clinical outcomes—higher rates of post-acute coronary syndrome events, but not events modifiable by antiplatelet drugs. The differences in event rates are

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