Paris, France - In patients with ST-segment-elevation MI (STEMI) undergoing PCI, treatment with the new antiplatelet agent prasugrel (Lilly/Daiichi Sankyo) significantly reduced ischemic events compared with clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis), without a significant increase in bleeding risks [1].

The results, from a prespecified analysis of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON-TIMI 38), showed that treatment with prasugrel resulted in significant reductions in 30-day rates of cardiovascular death, nonfatal MI, or nonfatal stroke, a benefit that persisted out to 15 months. In addition, there were reductions in secondary end points, including a significant reduction in stent thrombosis rates, with prasugrel.

"Our findings were consistent with those of TRITON-TIMI 38 in the cohort presenting with unstable angina or non-STEMI," write lead investigator Dr Gilles Montalescot (Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France) and colleagues in the February 28, 2009 issue of the Lancet. "The significant reductions we noted in cardiovascular death, myocardial infarction, and urgent target vessel revascularization [TVR] at 30 days and 15 months underscore the benefits of prasugrel when viewed in the context of an end point typically used in other trials of PCI for STEMI."

Commenting on the study for heartwire, Dr Deepak Bhatt (Brigham and Women's Hospital, Boston, MA) said prasugrel is a winner over clopidogrel in STEMI patients who undergo primary PCI, especially since these patients are not likely going on to CABG surgery.

"For a patient undergoing primary PCI, I think that giving prasugrel in the emergency department seems like a really useful step and an advance in the care of STEMI patients," said Bhatt. "A lot of the other issues involved in the debate over which is drug is better to use in which patient don't really apply as much. The decision in the emergency department, where you know you're going to do PCI on a patient with clear-cut STEMI, is that the prasugrel 60-mg load is probably the way to go."

Dr Duane Pinto (Beth Israel Deaconess Medical Center, Boston, MA), who also commented on the analysis for heartwire, said that while prasugrel showed benefit without an increased risk of bleeding, he is not an advocate of a one-size-fits-all approach when it comes to selecting treatment in STEMI patients.

"There are an incredible amount of factors that the physician has to consider, such infarct location, comorbidities, risk of bleeding, timing of loading, and timing of the PCI," said Pinto. "This can't exactly be captured in one summative statement. This paper is very compelling in many regards by informing us that there is probably better antiplatelet effect, as measured by the reduction in ischemic complications, but whether that effect is the same across all subgroups, across all flavors of patients, there should be hesitation before drawing that conclusion."

The TRITON trial included 13 608 moderate- to high-risk ACS patients scheduled for PCI and randomized to receive prasugrel (60-mg loading dose and then 10-mg daily maintenance dose) or clopidogrel (300-mg/75-mg) for six to 15 months. The results, which were presented at the American Heart Association 2007 Scientific Sessions and reported extensively by heartwire at that time, showed a significant reduction in the primary efficacy end point (cardiovascular death/MI/stroke), as well as in MI, urgent TVR, and stent thrombosis. But this was at the expense of a significant increase in major bleeding, life-threatening bleeding, and fatal bleeding.

In this predefined analysis, Montalescot and colleagues report the results of the 3534 patients presenting with STEMI. At 30 days, treatment with prasugrel reduced the primary end point as well as reduced the risk of cardiovascular death, all-cause death, and stent thrombosis compared with clopidogrel. A secondary end point, a composite of cardiovascular death, MI, or TVR, was also reduced at 30 days.

Reductions in the primary end point, a composite of cardiovascular death, nonfatal MI, and nonfatal stroke, were maintained at 15 months, as were reductions in the secondary end point and other individual end points, including MI. Stent-thrombosis rates were also maintained with prasugrel at 15 months. All-cause and cardiovascular mortality rates, however, were similar between the two treatments at 15 months, despite statistically significant early benefits at 30 days.

In contrast with the overall study, there was no increased bleeding in the STEMI patients treated with prasugrel compared with those randomized to clopidogrel.

Interestingly, a post hoc analysis revealed that ischemic event rates at 15 months were significantly lower with prasugrel only in STEMI patients with an anterior MI. In STEMI patients with nonanterior MI, treatment effects did not differ for the primary endpoint. The test for heterogeneity of the effect of prasugrel was significant (p=0.0053).

"As is the case with many adjunctive therapies in infarct treatment, the highest-risk individuals tend to gain the most," said Pinto. "In this case, the anterior MI patients and diabetics gain the most. Those are the higher-risk individuals. People where you might not be getting as much bang for your buck but might still have the penalty of bleeding, include nonanterior MI patients, where there is not a clear signal of benefit."

Pinto told heartwire that TRITON is reflective of the general population, where 40% of infarctions are anterior MIs. This absence of benefit in the nonanterior group "should give a clinician pause," he said.

Also commenting on the TRITON analysis for heartwire, Dr Paul Gurbel (Sinai Hospital, Baltimore, MD) said the findings go along with the main TRITON results but added, as did investigators, that the study was not prospectively designed or powered to test the superiority of prasugrel over clopidogrel in STEMI patients. Commenting on the infarct location issue, Gurbel said that it's possible that nonanterior MIs might have been clinically silent, whereas a recurrent event in the left anterior descending artery, for example, is likely to be captured.

Regarding the lack of bleeding risk observed in STEMI patients, he said the results "are not what you'd expect" considering the amount of GP IIb/IIIa inhibitor use. Also, he noted that the rate of non-CABG TIMI major bleeding was greater in STEMI patients than in the overall cohort—up from 1.8% to 2.1% in the STEMI cohort—but was unchanged with prasugrel, another finding that is unexpected, given that prasugrel is a more potent antiplatelet agent.

"I don't think you can say that you don't have a bleeding hazard with prasugrel in STEMI patients," said Gurbel. "I think that's the wrong conclusion. I don't think the investigators are trying to say that either. I think we need to be cautious about any interpretation of these data."

In an editorial accompanying the published study [2], Dr Gregg Stone (Columbia University, New York) writes that the TRITON study shows that additional freedom from ischemic events is possible with more powerful platelet inhibition in acute coronary syndrome (ACS) patients undergoing PCI. Also, the study "provides a tantalizing glimpse that balancing ischemic and hemorrhagic risk through careful selection of patients and personalized pharmacotherapy should result in improved outcomes for patients with cardiovascular disease."

Stone notes several limitations of the TRITON study, the first being the dose of the comparator drug. In the study, prasugrel was compared with a 300-mg loading dose of clopidogrel rather than the more potent 600-mg dose, the current standard of care for primary PCI. He also notes that STEMI patients enrolled in the study between 12 hours and 14 days after symptom onset, designated secondary PCI, likely did not receive the full benefit of clopidogrel because of inadequate preloading. Overall, 72% of patients in the clopidogrel arm received the study drug during PCI, whereas just 27% were preloaded within the allocated 24 hours prior to the procedure.

"These limitations are not idle academic musings," writes Stone. "The size of the 30-day reduction in major adverse cardiovascular events in TRITON with prasugrel was similar to that seen with adequate clopidogrel loading compared with placebo in the PCI-CURE and PCI-CLARITY studies."

Speaking with heartwire, Bhatt said the issues raised by Stone have validity.

"What if we used the 600-mg loading dose, or what if we pretreated? Would the relative benefits be the same?" asked Bhatt. "There'd probably be less benefit, but we know there are people who would benefit from prasugrel, because even with the higher doses of clopidogrel there are different SNPS that predispose to a lower clopidogrel effect. So even if the trials had been done with different doses or preloading, there'd probably be some differential in favor of prasugrel, but I do think the differential would be attenuated."

Whether the benefit would be worth the cost in bleeding is unknown, said Bhatt. "You have to do those trials, which are probably never going to be done on a large scale," he said. "We won't have a precise answer, and we'll be left trying to practice the fine art of medicine and interpret the data we have."

Earlier this week, the European Commission granted marketing approval of prasugrel for the prevention of atherothrombotic events in patients with ACS undergoing PCI. The Food and Drug Administration has yet to make a decision, but an advisory panel voted unanimously to approve the drug.