The TRITON trial: Prasugrel vs clopidogrel in ACS [Classics Series]

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1. Prasugrel was more effective than clopidogrel in reducing the incidence of recurrent myocardial infarction in patients presenting with acute coronary syndrome, though there was no difference in mortality between the two groups

2. Patients treated with prasugrel had a significantly higher incidence of fatal major bleeding compared to clopidogrel

Original Date of Publication: November 4, 2007

Study Rundown: Current acute coronary syndrome (ACS) management guidelines call for treatment with dual antiplatelet therapy, usually consisting of an aspirin and clopidogrel, a thienopyridine. However, it is known that there is much interpatient variability in the metabolism of clopidogrel, which may lead to variable efficacy of the drug in different patients. Prasugrel, a newer thienopyridine, is shown to be more rapid and less variable in its platelet-binding activity. The TRITON trial sought to determine whether treatment with prasugrel and aspirin produced better outcomes than the standard treatment with clopidogrel and aspirin in the management of patients with ACS.

The study demonstrated that prasugrel was significantly more effective than clopidogrel at reducing the incidence of recurrent myocardial infarctions (HR 0.76; 95%CI 0.67-0.85). Notably, the study did not show a significant mortality benefit with using prasugrel. Moreover, the study also revealed that prasugrel use was linked with significantly higher incidence of major bleeding, both related to instrumentation and also spontaneous bleeding. While analysis of net clinical benefit still showed preference for prasugrel, stratification of groups revealed that prasugrel showed no clinical net benefit for patients who had a prior history of CVA/TIA, are above 75 years of age, or are below 60 kg for weight.

In summary, this study showed that prasugrel is more effective than clopidogrel in preventing recurrent myocardial infarctions and subsequent deaths, but also increases the risk of major bleeding. Overall, the net clinical benefit of prasugrel provides evidence for its use in ACS management, but it must be used with caution. Patients should be counseled of the increased risk of bleeding with this drug over clopidogrel, and it should be avoided in certain patient populations altogether as it does not provide any clinical benefit.

Click to read the study in NEJM

In-Depth [randomized, controlled study]: The TRITON trial was a large, multicenter, double-blinded, randomized controlled trial that enrolled 13,608 patients with acute coronary syndrome at 707 sites to receive either prasugrel or clopidogrel along with aspirin as part of the dual antiplatelet regimen for ACS management. Patients who presented with symptoms lasting greater than 10 minutes within 72 hours of enrollment, had a TIMI score greater than 3, had >1 mm ST segment change, or had an increased blood level of biomarker of cardiac necrosis were eligible. Patients who had received any thienopyridine in the past 5 days, had an increased risk of bleeding, or another contraindication to antiplatelet therapy were excluded. Eligible patients received a loading dose of one of the antiplatelet agents and were continued on daily maintenance dosing along with a low-dose aspirin (75 to 162 mg daily). Patients were followed for 6-15 months, with study visits performed at hospital discharge, 30 days, 90 days, and every 3 months after that. The primary outcome was a composite of the rate of death related to cardiovascular events, non-fatal myocardial infarction, or non-fatal stroke in the follow-up period.

The study demonstrated that treatment with prasugrel significantly reduced the incidence of the primary outcome when compared to clopidogrel (HR 0.81; 95%CI, 0.73-0.90). A significant reduction in the primary endpoint was seen in the prasugrel group at 3 days and the trend persisted throughout the follow-up period. The difference between the two groups was due to a significant decrease in the rate of recurrent myocardial infarctions (HR 0.76; 95%CI 0.67-0.85) in the prasugrel group compared to the clopidogrel group. There was no significant difference between the two groups in terms of mortality, though prasugrel use was linked with significantly lower rates of urgent target-vessel revascularization (HR 0.66; 95%CI 0.54-0.81) and stent thrombosis (HR 0.48; 95%CI 0.36-0.64). The study also demonstrated, however, that the prasugrel group had a significantly higher incidence of fatal major bleeding compared to clopidogrel group (0.4% vs. 0.1%, p=0.002).

By Milana Bogorodskaya and Andrew Cheung, M.D.

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