Elsevier

The Lancet

Volume 375, Issue 9711, 23–29 January 2010, Pages 283-293
The Lancet

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Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study

https://doi.org/10.1016/S0140-6736(09)62191-7Get rights and content

Summary

Background

Variation in and irreversibility of platelet inhibition with clopidogrel has led to controversy about its optimum dose and timing of administration in patients with acute coronary syndromes. We compared ticagrelor, a more potent reversible P2Y12 inhibitor with clopidogrel in such patients.

Methods

At randomisation, an invasive strategy was planned for 13 408 (72·0%) of 18 624 patients hospitalised for acute coronary syndromes (with or without ST elevation). In a double-blind, double-dummy study, patients were randomly assigned in a one-to-one ratio to ticagrelor and placebo (180 mg loading dose followed by 90 mg twice a day), or to clopidogrel and placebo (300–600 mg loading dose or continuation with maintenance dose followed by 75 mg per day) for 6–12 months. All patients were given aspirin. The primary composite endpoint was cardiovascular death, myocardial infarction, or stroke. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00391872.

Findings

6732 patients were assigned to ticagrelor and 6676 to clopidogrel. The primary composite endpoint occurred in fewer patients in the ticagrelor group than in the clopidogrel group (569 [event rate at 360 days 9·0%] vs 668 [10·7%], hazard ratio 0·84, 95% CI 0·75–0·94; p=0·0025). There was no difference between clopidogrel and ticagrelor groups in the rates of total major bleeding (691 [11·6%] vs 689 [11·5%], 0·99 [0·89–1·10]; p=0·8803) or severe bleeding, as defined according to the Global Use of Strategies To Open occluded coronary arteries, (198 [3·2%] vs 185 [2·9%], 0·91 [0·74–1·12]; p=0·3785).

Interpretation

Ticagrelor seems to be a better option than clopidogrel for patients with acute coronary syndromes for whom an early invasive strategy is planned.

Funding

AstraZeneca.

Introduction

Clopidogrel, a thienopyridine, in addition to aspirin is recommended for prevention of myocardial infarction and stent thrombosis in patients with acute coronary syndromes with or without ST elevation.1, 2, 3, 4 It is a prodrug that undergoes hepatic conversion, therefore leading to delayed onset of action and substantial variability between individuals in levels of platelet inhibition. Up to a third of patients are low responders who have inadequate levels of inhibition.5 Prasugrel, another thienopyridine, is metabolised differently and results in higher levels of inhibition than does clopidogrel, without any low responders;6 the increased inhibition further reduces the risk of myocardial infarction and stent thrombosis when started at the time of percutaneous coronary intervention (PCI) in patients with acute coronary syndromes, albeit with an increased risk of bleeding.7 Because both thienopyridines are irreversible platelet inhibitors, patients need to produce new platelets to regain normal platelet function. To avoid the risk of severe bleeding, treatment has to be stopped for 5–7 days before coronary artery bypass graft (CABG) or other surgery can be undertaken. Because of these properties, the early initiation of thienopyridines in patients with acute coronary syndromes is quite variable and controversial.8

Ticagrelor, a reversible and direct-acting oral P2Y12-receptor antagonist, provides greater and more consistent platelet inhibition than does clopidogrel, with more rapid onset and offset of action.9, 10, 11 In the PLATelet inhibition and patient Outcomes (PLATO) trial, reversible long-term P2Y12 inhibition with ticagrelor was better than that with clopidogrel for the prevention of cardiovascular and total death, myocardial infarction, and stent thrombosis, without an increase in the rates of major bleeding in a broad population of patients with acute coronary syndromes who were started on treatment as soon as possible after hospital admission.12 We therefore compared ticagrelor with clopidogrel in patients with acute coronary syndromes who were planned to undergo an invasive strategy.

Section snippets

Patients

The details of the study design, patient population, and outcome definitions have been reported by James and colleagues.13 PLATO was a prospective, randomised, double-blind, event-driven trial of patients hospitalised for acute coronary syndromes with or without ST-segment elevation, with an onset of symptoms in the previous 24 h. It was done in 862 centres in 43 countries. Inclusion criteria for patients with non-ST-elevation acute coronary syndromes were at least two of the following:

Results

Figure 1 shows the trial profile. 18 624 patients with acute coronary syndromes (with or without ST elevation) were recruited into the PLATO trial between October 11, 2006, and July 18, 2008. 13 408 (72·0%) were specified by the investigator at the time of randomisation as planned to be managed with an invasive strategy. The baseline characteristics of the two groups were well balanced (table 1). 6575 (49·1%) patients for whom invasive strategy was planned had ST-elevation myocardial

Discussion

Patients given ticagrelor had significant and clinically relevant reductions in cardiovascular and total deaths, myocardial infarction, and stent thrombosis, without an increase in risk of major bleeding. The benefits with respect to clinical events and stent thrombosis were consistent whether or not patients were given standard or higher loading doses of clopidogrel, as advocated for patients undergoing invasive strategies.1, 3, 16 Thereby, ticagrelor has important advantages, and improves the

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