The TRILOGY Acute Coronary Syndrome (ACS) trial was a phase 3, randomised, double-blind, double-dummy, active-control study which evaluated whether prasugrel was superior to clopidogrel for long-term therapy in 7243 people with ACS (unstable angina or non-STEMI) treated medically without planned revascularisation. In the main analysis of patients under the age of 75 years, at 30 months there was no statistically significant difference between the prasugrel group and the clopidogrel group in the rate of the primary end point (death from cardiovascular causes, MI, or stroke):prasugrel 13.9%, clopidogrel 16.0% (95% confidence intervals [CIs] 0.79 to 1.05, p = 0.21).
In the current paper, the authors carried out a sub-group analysis (that was pre-specified in the main TRILOGY ACS trial) to assess the clinical characteristics and outcomes of patients treated with or without pre-enrolment angiography. They also aimed to assess the effect of prasugrel compared with clopidogrel within the two angiography cohorts. The following results are reported:
• 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; P-interaction=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.
The authors discuss the results of their analysis and note that the main limitation is that this is a sub-group analysis of a trial with an overall neutral primary outcome measure. They conclude, “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.”
The authors of a related Comment article discuss the results of the analysis suggest that whilst the results are clear, the explanation for these findings may be “less so” and could potentially be down to patient selection for the trial. Although they congratulate the study authors, they write, “Because this study is a subgroup analysis of an overall negative primary outcome and P-interaction for heterogeneity of prasugrel effect based on angiographic status was not significant, the results should be considered as hypothesis-generating rather than definitive. However, the hypothesis is plausible and sound.” The authors also note, “Because the patent for prasugrel expires in 2017, a randomised trial in such patients is unlikely to be done in the near future, leaving doctors with compelling but inconclusive evidence for use of prasugrel in this heterogeneous and often undertreated population.”
NICE published guidance on the use of prasugrel in ACS in 2009 and recommends prasugrel in combination with aspirin as an option for preventing atherothrombotic events in people with ACS having percutaneous coronary intervention, only when:
• immediate primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction is necessary or
• stent thrombosis has occurred during clopidogrel treatment or
• the patient has diabetes mellitus.