Elsevier

American Heart Journal

Volume 167, Issue 4, April 2014, Pages 437-444.e5
American Heart Journal

Trial Design
Design and rationale for the Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial

https://doi.org/10.1016/j.ahj.2013.12.020Get rights and content

Background

P2Y12 receptor antagonist therapy is recommended in addition to ASA for up to 1 year after acute coronary syndrome to reduce ischemic events. In contrast, the benefit of long-term dual antiplatelet therapy beyond 1 year remains unclear. Ticagrelor is a potent, reversibly binding P2Y12 receptor-antagonist that has been shown to be superior to clopidogrel in patients with acute coronary syndromes for up to 1 year.

Study Design

PEGASUS-TIMI 54 is a randomized, double-blind, placebo-controlled, multinational clinical trial designed to evaluate the efficacy and safety of ticagrelor in addition to aspirin (75-150 mg) for the prevention of major adverse cardiovascular events in patients with a history of myocardial infarction and risk factors. Patients with a history of spontaneous myocardial infarction within 1 to 3 years are randomized in a 1:1:1 fashion to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or matching placebo, all with low dose ASA, until the end of the study. The primary endpoint is a composite of cardiovascular death, myocardial infarction, or stroke. Recruitment began in October 2010 and completed in April 2013 with a sample size of over 21,000 patients. The trial is planned to continue until the latest of either 1,360 adjudicated primary end points are accrued or the last patient randomized has been followed for at least 12 months.

Conclusions

PEGASUS-TIMI 54 is investigating whether the addition of intensive antiplatelet therapy with ticagrelor to low-dose aspirin reduces major adverse cardiovascular events in high-risk patients with a history of myocardial infarction.

Section snippets

Study design and population

PEGASUS-TIMI 54 is a randomized, double-blind, placebo-controlled multinational clinical trial designed to evaluate the efficacy and safety of ticagrelor in addition to low dose aspirin for long-term treatment of stable patients with a history of spontaneous MI. The primary hypothesis is that the addition of ticagrelor to standard therapy will reduce the incidence of major adverse cardiovascular events during long-term follow-up (Figure).

Study patients must have a history of a spontaneous MI

Treatment dose selection

Based on the results of the PLATO trial 90 mg twice daily was a logical dose to be tested in PEGASUS-TIMI 54. However, recognizing that in the chronic setting the optimal intensity of platelet inhibition for long-term therapy is unknown and might be less than what is needed in the acute setting, a second dose arm using ticagrelor 60 mg twice daily was added, which, based on pharmacokinetic and pharmacodynamic modeling, is expected to provide less platelet inhibition than 90 mg twice daily, but

Study end points

The primary end point of the trial is a composite of cardiovascular death, MI, or stroke. Secondary endpoints include cardiovascular death and all-cause mortality. Other efficacy endpoints include: the composite of cardiovascular death or coronary or cerebrovascular arterial thrombosis hospitalization (defined as myocardial infarction, stroke, or hospitalization for urgent coronary revascularization, unstable angina, or transient ischemic attack); the composite of coronary heart disease death,

Statistical considerations

The primary efficacy analysis of PEGASUS-TIMI 54 will be based on the time from randomized treatment assignment to the first occurrence of any element of the primary composite endpoint including cardiovascular death, MI, or stroke. Each treatment dose (ie, 90 mg twice daily or 60 mg twice daily) will be tested independently against placebo. To control the overall type I error at 5%, alpha will be apportioned equally to each ticagrelor dose versus placebo comparison.

Secondary endpoints

Substudies

A series of scientific substudies are planned in patients randomized in selected countries, including measurement of plasma and serum biomarkers at baseline and 4 months, pharmacogenetics, pharmacodynamics as measured through platelet function testing, pharmacokinetics, health economics and quality of life.

Study organization

The PEGASUS-TIMI 54 trial is being conducted in 31 countries and more than 1,145 sites. Recruitment began in the USA in October 2010 and was completed in April 2013. Initial baseline characteristics of the trial cohort are presented in Table 2.

The trial operations group is a partnership composed of members of the TIMI Study Group and Astra Zeneca, the trial sponsor (online Appendix C). An Executive Committee monitors ongoing conduct in the trial. A Steering committee composed of academic

Discussion

The PEGASUS-TIMI 54 trial will define the role of dual-antiplatelet therapy with aspirin and ticagrelor in stable patients with a history of MI between 1 and 3 years previously and at least one additional atherothrombotic risk factor. Although background therapies have improved, patients with prior MI remain at heightened risk of recurrent events.31 New long-term therapies are needed for this high-risk population.31, 32

The addition of a P2Y12 receptor antagonist is uniformly recommended by

Summary

PEGASUS-TIMI 54 is investigating whether addition of ticagrelor to a background of aspirin reduces major adverse cardiovascular events in stable patients with a history of myocardial infarction.

Disclosures

Disclosures of relationships with industry disclosures:

The PEGASUS-TIMI 54 Study was funded through a grant from AstraZeneca.

The TIMI Study Group has received research grant support through Brigham and Women's Hospital from Abbott, Amgen, AstraZeneca, Beckman Coulter, BG Medicine, BRAHMS, Bristol-Myers Squibb, Buhlmann, Critical Diagnostics, CV Therapeutics, Daiichi Sankyo Co Ltd, Eli Lilly and Co, GlaxoSmithKline, Genzyme, Merck and Co, Intarcia, Merck, Nanosphere, Novartis Pharmaceuticals,

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    Clinical Trial Registration Information: URL: http://www.clinicaltrials.gov Registration Number: NCT01225562.

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