Sue Hughes

March 29, 2008

March 29, 2008 (Chicago, IL) – A new analysis from the TRITON-TIMI 38 trial shows a consistent reduction in stent thrombosis with prasugrel vs clopidogrel irrespective of many other factors [1]. The risk of stent thrombosis will therefore be another factor that can be considered when weighing which of these antiplatelet agents to use, TRITON investigators said.

The latest data, presented today at the American College of Cardiology 57th Annual Scientific Session/i2 Summit-SCAI Annual Meeting and published simultaneously online in the Lancet, also show that clinical ischemic events were reduced with prasugrel compared with clopidogrel to a similar extent in patients receiving bare-metal stents and those receiving drug-eluting stents.

Dr Stephen Wiviott (Brigham and Women's Hospital, Boston. MA), who presented the latest data, concluded: "Intensive antiplatelet therapy with prasugrel reduced stent thrombosis compared with clopidogrel regardless of stent type or stent-thrombosis definition used. This reduction was seen both early and late after stent implantation and across a broad range of clinical and procedural characteristics."

He added that for every 1000 patients treated, use of prasugrel instead of clopidogrel would be associated with a reduction of 12 cases of stent thrombosis and an additional 15 ischemic events (CV death, MI, stroke) not associated with stent thrombosis, at the cost of five extra major bleeds.

The TRITON-TIMI 38 trial, the main results of which were reported last November, showed significantly reduced ischemic events with prasugrel compared with clopidogrel, but at the expense of an increase in major bleeding in 13 608 moderate- to high-risk ACS patients scheduled for PCI.

The current analysis focuses on the 12 844 patients who received at least one coronary stent. Of these, 5743 received only drug-eluting stents and 6461 received only bare-metal stents. Results showed that prasugrel compared with clopidogrel reduced the primary end point (CV death/nonfatal MI/nonfatal stroke) in the whole stented cohort, in patients with only drug-eluting stents, and in patients with only bare-metal stents.

Primary end point (CV death/nonfatal MI/nonfatal stroke) for prasugrel vs clopidogrel stratified by stent type
Patient group Prasugrel (%) Clopidogrel (%) HR (95% CI) p
Any stent 9.7 11.9 0.81 (0.72–0.90) 0.0001
Bare-metal stent 10.0 12.2 0.80 (0.69–0.93) 0.003
Drug-eluting stent 9.0 11.1 0.82 (0.69–0.97) 0.019

Stent thrombosis occurred in 210 patients and was associated with death or MI in 186 of these (89%). Stent thrombosis was reduced with prasugrel overall, in patients with drug-eluting stents only, and in those with bare-metal stents only.

TRITON-TIMI 38: Percent of patients with definite stent thrombosis
Patient group Prasugrel (%) Clopidogrel (%) HR (95% CI) p
Any stent 0.88 2.03 0.42 (0.31–0.59) <0.0001
Bare-metal stent 0.96 2.13 0.44 (0.29–0.69) 0.0002
Drug-eluting stent 0.70 1.92 0.35 (0.21–0.61) 0.0001

Discussant of this new analysis at the late-breaking clinical-trial session, Dr George Dangas (Columbia University Medical Center, New York), said: "These data show clearly that a more intensive antiplatelet agent can reduce stent thrombosis. But this warrants careful risk/benefit evaluation, since prasugrel also increases bleeding. The key question is whether it is possible to identify ahead of time those patients who are at increased risk of stent thrombosis and those who are increased risk of bleeding and to treat those patients accordingly."

Wiviott commented to heartwire : "As with all therapies, we have to balance what kinds of events are prevented and what kind of events are increased. We need to think about which patients are best served by which types of therapy." He continued: "More intensive antiplatelet therapy will almost always reduce events but increase bleeding. My take on the main results of TRITON is that prasugrel gives a favorable risk/benefit balance for the majority of patients. But I would still have to think about individual patient characteristics, and the risk of stent thrombosis is one characteristic that needs to be factored in. For patients at high risk of stent thrombosis such as those with complex lesions, this is another reason to use prasugrel. But if a patient had a simple lesion and a history of GI bleeding, I may be more likely to opt for clopidogrel."

Dr Harvey White (Green Lane Hospital, Auckland, New Zealand), who was also a TRITON investigator, commented to heartwire : "There are certain patient groups that do have a known increased risk of stent thrombosis. These include those with ST-elevation MI, those with diabetes or long or complex lesions, and those who smoke. These are among the patients who may get most benefit from a drug like prasugrel. Diabetics, in particular, did very well on prasugrel in the main study, and we know that they have a high rate of stent thrombosis, so they are an obvious group to treat with prasugrel."

In the current paper, the TRITON investigators reach similar conclusions. "Although relative reductions in stent thrombosis were consistent across several subgroups of patients, the absolute benefit in specific groups of patients at higher risk for stent thrombosis was notable. These groups include people with diabetes (1.6% absolute reduction), stents of more than 20 mm in length (1.5% absolute reduction), bifurcation stents (3.2% absolute reduction), and those with myocardial infarction before presentation (2.6% absolute reduction)," they write.

Noting that the trial compared the approved 300-mg loading dose of clopidogrel and 60 mg of prasugrel administered after the coronary anatomy was known to be suitable for PCI, the authors say that these data cannot directly address the effects of prasugrel compared with higher-dose clopidogrel or the effects of substantial pretreatment. But they add that the full effect of 300-mg clopidogrel would be expected to be present by six to eight hours, and since acute (<24 h) stent thrombosis was infrequent and prasugrel showed substantial reductions in stent thrombosis in the subacute period (24 hours to 30 days) and beyond, this suggests that speed of onset of prasugrel alone did not account for these findings.

  1. Wiviott SD, Braunwald E, McCabe CH, et al. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet 2008. DOI:10.1016/S0140-6736(08)60422-5. Available at: http://www.thelancet.com .

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