Trial DesignDesign 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
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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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2018, Journal of Vascular SurgeryCitation Excerpt :GUSTO severe (1.7% vs 1.7%; P = .901) and moderate (2.5% vs 1.9%; P = .259) bleeding occurred at similar rates in each group, but minor GUSTO bleeding occurred at higher rates in the DAPT group (34.4% vs 20.8%; P < .001). A subgroup analysis35 of 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) trial48,49 studied the use of ticagrelor (90 mg or 60 mg BID) and aspirin DAPT in patients with PAD who had a prior MI and at least one atherothrombotic risk factor. At 36 months, the use of DAPT was found to reduce the rates of MACEs (90 mg BID: 16.3% vs 19.3% [P = .24]; 60 mg BID: 14.1% vs 19.3% [P = .045]), cardiovascular death (90 mg BID: 7.9% vs 9.6% [P = .46]; 60 mg BID: 4.2% vs 9.6% [P = .014]), and MALEs (acute limb ischemia or peripheral revascularization for ischemia; 90 mg BID: 4.5% vs 7.3% [P = .28]; 60 mg BID: 7.0% vs 7.3% [P = .73]) while increasing rates of TIMI major or minor bleeding (90 mg BID: 3.1% vs 2.2% [P = .40]; 60 mg BID: 3.2% vs 2.2% [P = .58]) compared with the use of MAPT.
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Clinical Trial Registration Information: URL: http://www.clinicaltrials.gov Registration Number: NCT01225562.