Prasugrel Efficacy in STEMI Largely Unaffected by PCI Timing

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Compared with clopidogrel, prasugrel yields better efficacy irrespective of the timing of percutaneous coronary intervention (PCI) after ST-segment elevation myocardial infarction (STEMI), especially in the prevention of nonprocedural MI events. The findings, from a substudy of TRITON-TIMI 38, were published in the June 2014 issue of JACC: Cardiovascular Interventions.

Compared with clopidogrel, prasugrel treatment reduced the primary efficacy endpoint of CV death, nonfatal MI, or nonfatal stroke at 15 months (HR 0.79; 95% CI 0.65-0.97; P = .022). This reduction was consistent for both primary (HR 0.89; 95% CI 0.69-1.13) and secondary PCI (HR 0.65; 95% CI 0.46-0.93; P for interaction = .15).

However, at 30 days, there was a trend toward greater treatment effect with prasugrel in patients receiving secondary compared with primary PCI for the primary endpoint and a significant advantage for the composite of CV death, nonfatal MI, or urgent TVR (table 1). These differences were primarily driven by lower MI risk seen in secondary vs primary PCI patients (P = .01 for interaction).

Table 1. Risk of Adverse Events at 30 Days: Prasugrel vs Clopidogrel

For MI, an interaction according to PCI timing between the effect of prasugrel compared with clopidogrel was apparent only for procedural events at 30 days (P = .02 for interaction) and 15 months (P = .03 for interaction). Prasugrel’s protection against nonprocedural MI events, on the other hand, was consistent in both primary and secondary PCI.

At 30 days there were no differences by PCI timing in stent thrombosis or major bleeding unrelated to CABG surgery. So few non-CABG-related TIMI major bleeding events developed by 15 months that clopidogrel and prasugrel resulted in similar risk overall; however, prasugrel offered protection against bleeding within the secondary PCI group but not in the primary PCI group  (P = .02 for interaction).

Paying Attention to Timing

“Patients with STEMI who were managed with PCI late after presentation appeared to be a highly selected group who derived long-term efficacy from more potent antithrombotic therapy with a more favorable risk balance for spontaneous bleeding,” Dr. Wiviott and colleagues write.

The substudy is “informative,” they add, “because perception of a difference in treatment effect by PCI timing involving endpoints that included nonfatal MI may have appeared as a result of the inherent difficulty in distinguishing a recurrent primary procedural MI from one that develops later in the course of therapy when the increase and decrease in cardiac ischemia biomarkers is well established after initial STEMI presentation.”

Clarification Still Needed

In an accompanying editorial, Matthew T. Roe, MD, MHS, and Matthew W. Sherwood, MD, both of Duke Clinical Research Institute (Durham, NC), write that the “results provide important clarifications for the relative benefits of prasugrel observed in the STEMI population but also uncover a number of interesting findings from the trial.”

First, they say, the 29% of secondary PCI patients who received fibrinolytic therapy before randomization should not have included patients with failed therapy who underwent rescue PCI because this would have disqualified them from enrollment in the TRITON trial. However, these data were not collected. Next, reasons for nonuse of reperfusion therapy for the 71% of patients not treated with fibrinolysis also were not collected, “so the secondary PCI patients are likely a heterogeneous group who may not relate to the typical STEMI patients treated in US practice,” they note.

The editorial also points out that the divergent bleeding results “are perplexing and do not appear to be explained by differences in key bleeding risk factors… between the groups, yet these findings are not emphasized in the paper.”

Lastly, they write, “this analysis carefully delineates a major impediment for the conduct and interpretation of a trial for a novel antithrombotic agent administered for STEMI patients undergoing PCI: that is, confounding by the ascertainment of periprocedural MI events in the primary versus secondary PCI setting.”

For patients undergoing secondary PCI, they explain, “initial marker elevations likely down trended by the time PCI was performed, so the detection of periprocedural MI events was inadvertently facilitated by the inherent delays to the PCI procedure in this group.”

Even with these problems, Drs. Roe and Sherwood say the findings should inform practice guideline recommendations and future trials.

“The current Class IIA-B recommendation for the use of prasugrel for STEMI patients undergoing nonrescue PCI after fibrinolytic therapy (after the specified time delays to allow for resolution of the lytic effect to minimize bleeding risk) should be reconsidered for upgrade in light of these results,” they conclude.

Sources:
1. Udell JA, Braunwald E, Antman EM, et al. Prasugrel versus clopidogrel in patients with ST-segment elevation myocardial infarction according to timing of percutaneous coronary intervention: a TRITON-TIMI 38 subgroup analysis (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38). J Am Coll Cardiol Intv. 2014;7:604-612.

2. Roe MT, Sherwood MW. Uncovering the shroud on antiplatelet therapy for patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention. J Am Coll Cardiol Intv. 2014;7:613-614.

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