Reduction in recurrent cardiovascular events with prasugrel compared with clopidogrel in patients with acute coronary syndromes from the TRITON-TIMI 38 trial

Abstract

Aims: In the TRITON-TIMI 38 trial, greater platelet inhibition with prasugrel reduced the first occurrence of the primary endpoint (cardiovascular death, MI, or stroke) compared with clopidogrel in patients with an acute coronary syndrome (ACS) undergoing planned percutaneous coronary intervention. We hypothesized that prasugrel would reduce not only first events but also recurrent primary endpoint events and therefore total events compared with clopidogrel.

Methods and results: Poisson regression analysis was performed to compare the number of occurrences of the primary endpoint between prasugrel and clopidogrel in TRITON-TIMI 38. Landmark analytic methods were used to evaluate the risk of a recurrent primary endpoint event following an initial non-fatal endpoint event. Among patients with an initial non-fatal event, second events were significantly reduced with prasugrel compared to clopidogrel (10.8 vs. 15.4%, HR 0.65, 95% CI 0.46-0.92; P = 0.016), as was CV death following the non-fatal event (3.7 vs. 7.1%, HR 0.46, 95% CI 0.25-0.82; P = 0.008). Overall there was a reduction of 195 total primary efficacy events with prasugrel vs. clopidogrel (rate ratio 0.79, 95% CI 0.71-0.87; P < 0.001). Recurrent bleeding events occurred infrequently (TIMI major non-CABG bleeds: four with prasugrel and two with clopidogrel). Study drug discontinuation was frequent following the initial major bleeding event (42% of patients discontinued study drug).

Conclusion: While standard statistical analytic techniques for clinical trials censor patients who experience a component of the primary composite endpoint, total cardiovascular events remain important to both patients and clinicians. Prasugrel, a more potent anti-platelet agent, reduced both first and subsequent cardiovascular events compared with clopidogrel in patients with ACS.

Figure 1

Additional primary endpoint events by randomized therapy. The prasugrel group had a lower number of both first events (P < 0.001), additional events (P < 0.001), and total events (P < 0.001).

Figure 2

(A) Landmark analysis of time from first event to second event by randomized therapy. The occurrence of a subsequent ischaemic event was significantly reduced in the prasugrel group (HR 0.65, 95% CI 0.46–0.92; P = 0.016). (B) Landmark analysis of time from first event to cardiovascular death by randomized therapy. Cardiovascular mortality following a non-fatal ischaemic event occurred significantly less frequently among patients treated with prasugrel (HR 0.46, 95% CI 0.25–0.82).

Figure 3

Subsequent primary events during follow-up by randomized therapy among subgroups. Among patients with a first, non-fatal ischaemic event, second events were directionally lower with prasugrel in all subgroups (i.e. point estimate falls to the left of the line of unity). With the exception of history of diabetes (interaction P = 0.036), there were no other significant interactions by subgroup. Rates are Kaplan–Meier failure rates at 15 months.