Fast track — ArticlesIntensive 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
Introduction
Intracoronary stents are an important advance in the care of patients with coronary artery disease who undergo percutaneous coronary intervention. Stent use has resulted in greater procedural success and lower rates of post-procedure restenosis than has balloon angioplasty,1, 2 although coronary stents are associated with higher rates of thrombosis. The introduction of dual antiplatelet therapy with aspirin and a thienopyridine has resulted in substantial improvements in reducing stent thrombosis compared with aspirin and an oral anticoagulant.3, 4, 5 These benefits suggest that stent-related ischaemic events might be largely related to platelet activation and aggregation. As such, dual antiplatelet therapy has become a cornerstone of the medical regimen for prevention of ischaemic events in patients undergoing percutaneous coronary intervention with stent placement.6, 7 The subsequent introduction of drug-eluting stents greatly reduced the need for repeated procedures for in-stent restenosis compared with bare-metal stents,8, 9 but also extended the period during which patients are at risk for stent thrombosis.10 Additionally, dual antiplatelet therapy with aspirin and clopidogrel was better than aspirin alone for the reduction of ischaemic events in patients with acute coronary syndromes irrespective of coronary intervention, but seemed particularly beneficial for those with acute coronary syndromes undergoing percutaneous coronary intervention.11, 12
Despite advances in both devices and pharmacological support for patients with acute coronary syndromes undergoing percutaneous coronary intervention, there remains a persistent risk of ischaemic events. Concerns have arisen about the continued thrombotic risk related to intracoronary stenting, particularly in patients with acute coronary syndromes or those treated outside the indications used in pivotal trials for stent approval.13, 14, 15, 16, 17 Efforts to reduce stent-related thromboses and myocardial infarctions have focused on compliance with dual antiplatelet therapy and on extended durations of therapy.18 In addition to these concerns, a growing body of evidence suggests that patients have variable responses to clopidogrel19, 20 and that a lesser response to the drug could be a risk factor for ischaemic complications, including myocardial infarction and stent thrombosis after angioplasty.21, 22, 23, 24
The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38 study25 showed that treatment with prasugrel—a thienopyridine that achieves greater, more rapid, and more consistent platelet inhibition than clopidogrel26—resulted in a 19% reduction in the composite primary endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke in patients with acute coronary syndromes with planned percutaneous coronary intervention. This reduction in ischaemic events with prasugrel compared with clopidogrel was at a cost of higher rates of TIMI major bleeding not related to coronary artery bypass grafting,25 and though rare, higher rates of life-threatening and fatal bleeding. In view of the benefit of aspirin and thienopyridines in preventing thrombotic complications in patients undergoing percutaneous coronary intervention,27, 28, 29, 30 we postulated that prasugrel would show reductions in stent-related thrombotic complications and new ischaemic complications not related to stents. We therefore examined the rates of ischaemic events and stent thrombosis in TRITON–TIMI 38 and the size and timing of the effects of prasugrel compared with clopidogrel in patients receiving different types of intracoronary stents.
Section snippets
Patients
The TRITON–TIMI 38 trial enrolled participants who had a range of acute coronary syndromes.25, 31 Individuals could be enrolled with moderate-risk to high-risk unstable angina or non-ST-elevation myocardial infarction (UA/NSTEMI), or with ST-segment-elevation myocardial infarction (STEMI) after medical therapy with coronary anatomy known to be suitable for percutaneous coronary intervention. Patients could also be enrolled with STEMI and planned primary angioplasty irrespective of whether
Results
Of 13 608 patients enrolled in the TRITON–TIMI 38 trial, 12 844 (94%) received at least one stent. This subset included 6461 who received bare-metal stents only, 5743 who received drug-eluting stents only, and 640 who received both bare-metal stents and drug-eluting stents at the time of the index procedure. Patients who received drug-eluting stents only were more likely to have been enrolled in North America, to have presented with UA/NSTEMI, and to have had previous coronary artery disease,
Discussion
The TRITON–TIMI 38 trial showed that treatment with prasugrel—a thienopyridine that achieves greater, more rapid, and more consistent platelet inhibition than standard dose clopidogrel—resulted in a significant reduction in ischaemic events compared with clopidogrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention with more bleeding.25 The present analysis compared prasugrel to clopidogrel in patients receiving coronary stents as part of their index
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