Trial Design
Comparison of ticagrelor, the first reversible oral P2Y12 receptor antagonist, with clopidogrel in patients with acute coronary syndromes: Rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial

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Background

Antiplatelet therapy is essential treatment for acute coronary syndromes (ACS). Current therapies, however, have important limitations affecting their clinical success. Ticagrelor, the first reversible oral P2Y12 receptor antagonist, provides faster, greater, and more consistent adenosine diphosphate–receptor inhibition than clopidogrel. The phase III PLATelet inhibition and patient Outcomes (PLATO) trial is designed to test the hypothesis that ticagrelor compared with clopidogrel will result in a lower risk of recurrent thrombotic events in a broad patient population with ACS.

Methods

PLATO is an international, randomized, double-blind, event-driven trial involving >18,000 patients hospitalized for ST-elevation ACS with scheduled primary percutaneous coronary intervention or for non–ST-elevation ACS. After loading doses of ticagrelor 180 mg or clopidogrel 300 mg in a double-blind, double-dummy fashion (with provision for additional 300 mg clopidogrel at percutaneous coronary intervention), patients will receive ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for 6 to 12 months on top of acetylsalicylic acid. The primary efficacy end point is time to first occurrence of death from vascular causes, myocardial infarction, or stroke. The primary safety variable is PLATO-defined major bleeding. An extensive substudy program will explore the pathophysiology of ACS, indicators of prognosis and response to treatment, mechanisms of effect and safety of the study medications, health economics, and quality of life.

Conclusion

The PLATO study will provide a pivotal comparison of the efficacy and safety of ticagrelor with those of clopidogrel in ACS patients, together with extensive information on treatment outcomes in different subsets of ACS in a broad patient population.

Section snippets

Background

Dual therapy with aspirin and the thienopyridine clopidogrel is a standard treatment in patients with acute coronary syndromes (ACS) with or without ST-segment elevation and after stent procedures.1, 2, 3 However, approximately 15% to 48% of patients have a poor platelet inhibition response to clopidogrel,4, 5, 6, 7, 8 a factor that contributes to a residual high risk of recurrent events.7

Clopidogrel is a prodrug that requires 2-step metabolism for conversion to its active metabolite, which

Study objectives

The primary objective of PLATO (D5130C05262) is to test the hypothesis that ticagrelor is superior to clopidogrel for the prevention of vascular events (death from vascular causes, MI, or stroke) in patients with non–ST-elevation ACS or ST-elevation ACS.

The primary efficacy variable is time to first occurrence of any event from the composite of death from vascular causes, MI, or stroke. The rationale for choosing this composite end point was to use the most unbiased estimate of the effect

Study design and organization

The PLATO trial is a phase III multicenter randomized, double-blind, double-dummy, parallel-group, event-driven, international trial of approximately 18,000 patients hospitalized because of ACS. Patients are randomized to receive ticagrelor or clopidogrel in a 1:1 ratio using a randomization schedule blocked by site. Randomization must take place within 24 hours of onset of the most recent cardiac ischemic symptoms and before any planned or urgent PCI. Initial background assessments include

Patient population

The PLATO study involves >18,000 patients recruited from approximately 800 sites in 43 countries. The primary enrollment criteria state that a patient must be ≥18 years and hospitalized with documented evidence of non–ST-elevation or ST-elevation ACS in the 24 hours before randomization. Inclusion and exclusion criteria details are shown in Table I, Table II. Patients with ST-elevation ACS treated with fibrinolysis will be excluded because of lack of safety data with this combination of

Treatment regimens and concomitant medications

Patients are randomly assigned to oral maintenance treatment with ticagrelor 90 mg twice daily plus placebo (matched to clopidogrel) or clopidogrel 75 mg once daily plus placebo (matched to ticagrelor) as early as possible after the index event and not >24 hours postevent. The ticagrelor 90 mg dose was chosen because it is well tolerated and produces significantly greater IPA than clopidogrel 75 mg.15, 16 Patients randomized to ticagrelor receive a loading dose of 180 mg (two 90 mg tablets) of

Efficacy

Sample size is based on an expected primary composite efficacy end point (death from vascular causes, MI, or stroke) event rate of 11% in the clopidogrel group over 12 months. This expected rate was based on the rate of 9.3% over an average of 9 months in the CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) study4 and by an event rate of 12% in ST-elevation ACS with primary PCI over a 6- to 18-month treatment period.2 It is assumed that the hazard rate of an event in the

Present status

The first patient was enrolled in October 2006. By July 1, 2008, >18,000 patients had been enrolled; and enrollment ceased in mid-July 2008. The Holter program was ended according to the protocol in November 2007. The DSMB reviewed the emerging data on patient safety after enrollment of 12,889 patients in March 2008 and recommended continuation of enrollment without protocol alterations and that further follow-up on safety laboratory testing was not necessary. The statement to continue the

Conclusion

The PLATO trial includes a broad ACS patient population recruited as early as possible after admission to the hospital, including patients with and without ST-segment elevation and those managed early invasively and conservatively. The trial includes currently recommended doses of clopidogrel, including the 600-mg loading dose, and initiation of therapy before PCI.20 The protocol also allows clopidogrel-exposed patients, both as maintenance treatment and loading dose. Therefore, the trial will

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Randomized Clinical Trial #: NCT00391872.

Dr. Raymond J. Gibbons served as guest editor for this manuscript.

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