Elsevier

The Lancet

Volume 386, Issue 9990, 18–24 July 2015, Pages 292-302
The Lancet

Series
Clinical evidence for oral antiplatelet therapy in acute coronary syndromes

https://doi.org/10.1016/S0140-6736(15)60213-6Get rights and content

Summary

Platelet-mediated thrombosis is a major pathophysiological mechanism that underlies acute coronary syndromes, and therefore, antiplatelet therapy is an important foundation in the treatment and prevention of recurrence of these syndromes. Nearly 30 years ago, aspirin was the first agent to show a benefit for acute coronary syndromes and is still a key therapeutic agent. The landmark CURE trial showed that the addition of a P2Y12 antagonist, clopidogrel, to aspirin was beneficial in the treatment of acute coronary syndromes. Despite substantial benefits with clopidogrel, limitations include the slow speed of onset, variable response, and a modest antiplatelet effect. Next-generation P2Y12 antagonists, prasugrel and ticagrelor, overcome these limitations and have been shown, in large-scale clinical trials for acute coronary syndromes, to reduce ischaemic events more than clopidogrel, at the expense of an increase in bleeding. Additional agents that target platelets by alternate mechanisms, including the protease-activated receptor-1 antagonist vorapaxar, have shown ischaemic benefit. These large-scale trials inform treatment decisions that need to balance ischaemic benefit and bleeding risk in patients with acute coronary syndromes. This Series paper describes major trial results, implications for clinical practice, and summarises continuing controversy.

Introduction

Acute coronary syndromes are a leading cause of mortality, morbidity, and loss of productivity. The major pathophysiological mechanism underlying unstable angina and myocardial infarction is atherosclerotic plaque rupture with resultant coronary thrombosis. Platelets adhere to ruptured plaques, aggregate, and release secondary messengers, which result in further thrombosis and vasoconstriction, and serve as a surface for activation of the clotting cascade. As a result, antiplatelet therapies have led to major advances in the treatment of acute coronary syndromes and the prevention of recurrent events. With key components of the thrombotic process targeted, obligate increases in bleeding exist. The past 25 years has seen the completion of various large-scale clinical trials that have investigated the efficacy and safety of several pharmaceutical agents, including aspirin and P2Y12 antagonists, alone or in combination (table 1). These trials provide evidence to guide patient management in balancing the efficacy and safety of pharmaceutical compounds, the pharmacology of which is described in detail in a companion Series paper.8

Section snippets

Aspirin

Historically, the first antiplatelet agent to show benefit in acute myocardial infarction was aspirin, which blocks the production of thromboxane A2. The first major trial,1 ISIS-2, showed the additive benefits of thrombolysis and low-dose aspirin in patients with ST-segment elevation acute myocardial infarction. The Antithrombotic Trialists' collaboration summarised the evidence for the benefit of aspirin in vascular disease, and showed that low-dose aspirin reduced vascular events (6·7% vs

Combination of clopidogrel with aspirin

The CURE trial2 was the landmark trial that established the benefits of addition of the P2Y12 receptor blocker, clopidogrel, to aspirin in patients with non-ST-segment elevation acute coronary syndromes, showing a 20% reduction in the composite outcome of cardiovascular death, myocardial infarction, and stroke, compared with placebo over 9–12 months of therapy. No increase in TIMI major bleeding was noted with the combination of aspirin and clopidogrel, but a 38% increase in the trial primary

Limitations of clopidogrel

Clopidogrel has substantial limitations in the management of acute coronary syndromes with a modest inhibition of platelet aggregation and a delayed onset and offset of action. Although no accepted test or specific target goal exists for platelet inhibition, variability in response to clopidogrel is substantial,22, 23 with estimations that 4–34% of patients have an inadequate response dependent on the method and cut point used. These patients are at high risk of subsequent clinical events

Prasugrel

Prasugrel is a second-generation thienopyridine that, similarly to clopidogrel, needs conversion from an inactive form to an active metabolite by use of cytochromes.35 Unlike clopidogrel, however, prasugrel is rapidly and more wholly metabolised to its active components. This metabolic difference allows prasugrel to have a more rapid onset, higher levels of platelet inhibition, and less interpatient response variability than clopidogrel.36

The major clinical outcomes trial of prasugrel,

Ticagrelor

Ticagrelor is a direct-acting P2Y12 antagonist that does not need metabolic activation and is therefore not dependent on cytochrome P450 enzymes. The drug acts rapidly and has more potent and consistent antiplatelet effects than clopidogrel. Ticagrelor was compared with clopidogrel in patients with acute coronary syndromes in the PLATO trial,45 which enrolled 18 624 patients with moderate to high risk of unstable angina, or non-ST-segment elevation myocardial infarction, or patients with

Vorapaxar

Vorapaxar is a competitive antagonist of the protease-activated receptor, which is a major thrombin receptor on human platelets. Vorapaxar has been studied in two major trials of patients with acute coronary syndromes: TRACER11 and TRA 2P–TIMI 50.12 TRACER enrolled 12 944 patients with non-ST-segment elevation acute coronary syndromes and compared vorapaxar with placebo, in addition to standard therapy, which included aspirin plus clopidogrel in 92% of patients. The combination primary endpoint

Cilostazol

Cilostazol is an orally available cyclic adenosine monophosphate phosphodiesterase III inhibitor that has vasodilatory and antiplatelet effects. This agent is predominantly used for the management of intermittent claudication associated with peripheral arterial disease. Cilostazol has been studied in small studies (predominantly in Asia) as a component of triple antiplatelet therapy with aspirin and clopidogrel. One meta-analysis58 suggests that a strategy of cilostazol, in addition to standard

Combined therapy with aspirin and either prasugrel or ticagrelor

Since both prasugrel and ticagrelor have shown superior outcomes to clopidogrel in pivotal trials, these novel agents are now preferred to clopidogrel as a first-line therapy in conjunction with aspirin, for most patients with acute coronary syndromes, as endorsed by both European and US guidelines.39, 40, 41 Prasugrel is a preferred option for patients undergoing percutaneous coronary intervention (except for patients with a previous history of stroke or transient ischaemic attack, with a

Personalised antiplatelet therapy

In view of the high cost and bleeding risk of the novel agents, and the availability of clopidogrel as a generic drug, it might seem important to identify patients with a poor clopidogrel response (based on platelet-function testing or genotyping) and give them either a high dose of clopidogrel or the novel agents, and use the standard dose of clopidogrel in good responders. However, this approach is currently not recommended in routine practice, by guidelines;39, 40 first, a large genotypic

When to start therapy with oral-antiplatelet agents

Substantial diagnostic uncertainty often exists in patients with suspected acute coronary syndromes in the early phases of management, and some patients might either eventually have other final diagnoses (including some contraindications to antiplatelet therapy, such as aortic dissection) or need urgent surgery (in which case, after the patients have received a potent oral antiplatelet agent, the risk of bleeding would be increased). The diagnostic uncertainty is greatest in patients with

Optimum duration of therapy

Patients with acute coronary syndromes are at high risk of recurrence66 and therefore should receive combined antiplatelet therapy for the initial post-acute coronary syndrome period and subsequently remain indefinitely on single antiplatelet therapy. In addition to the prevention of recurrences, combined antiplatelet therapy also contributes to the prevention of stent thrombosis in the large proportion of patients with acute coronary syndromes who have stents. There is, however, some

Patients needing oral anticoagulation

A subset of patients with acute coronary syndromes need permanent oral anticoagulation (eg, because of a prosthetic heart valve or atrial fibrillation). In these patients, the treatment of combined antiplatelet therapy and oral anticoagulation is complex. Typically, management of acute coronary syndromes will entail an initial period of triple therapy, combining aspirin, clopidogrel, and oral anticoagulation, which increases the risk of bleeding.71, 72 To minimise bleeding, it seems reasonable

Management of patients undergoing CABG

In patients with acute coronary syndromes, a few will need CABG surgery. Although it is recommended to continue aspirin throughout the perioperative period, it is desirable, in most patients, to withhold P2Y12 receptor blockers before and during surgery to minimise bleeding (unless patients are highly unstable). In very unstable patients or those with new stents, injectable reversible antiplatelet agents, such as glycoprotein IIb/IIIa receptor blockers or, in the future, cangrelor, might allow

Conclusions

Antiplatelet therapy improves cardiovascular outcomes after acute coronary syndromes. A broad and comprehensive dataset from large-scale trials allows for evidence-based decisions regarding these therapies (figure 3). The combination of aspirin with a potent inhibitor of the P2Y12 receptor (prasugrel or ticagrelor) is recommended in most patients with acute coronary syndromes, but patient factors and bleeding risk should be considered in the choice of agents. Additional data from trials of

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