Rationale and design of the EXenatide study of cardiovascular event lowering (EXSCEL) trial

Exenatide once-weekly is an extended release formulation of exenatide, a glucagon-like peptide–1 receptor agonist, which canimprove glycemic control, body weight, blood pressure, and lipid levels in patients with type 2 diabetes mellitus (T2DM). TheEXenatide Study of Cardiovascular Event Lowering (EXSCEL) will compare the impact of adding exenatide once-weekly to usualcare with usual care alone on major cardiovascular outcomes.EXSCEL is an academically led, phase III/IV, double-blind, pragmatic placebo-controlled, global trial conducted in 35countries aiming to enrol 14,000 patients with T2DM and a broad range of cardiovascular risk over approximately 5 years.Participants will be randomized (1:1) to receive exenatide once-weekly 2 mg or matching placebo by subcutaneous injections.The trial will continue until 1,360 confirmedprimary composite cardiovascular end points, defined as cardiovascular death,nonfatal myocardial infarction, or nonfatal stroke, have occurred.The primary efficacy hypothesis is that exenatide once-weekly is superior to usual care with respect to the primary compositecardiovascularend point. EXSCEL is powered todetect a 15% relativerisk reduction inthe exenatide once-weekly group, with 85%power anda 2-sided 5%alpha.Theprimary safetyhypothesis is thatexenatideonce-weeklyis noninferior tousualcarewithrespectto the primary cardiovascular composite end point. Noninferiority will be concluded if the upper limit of the CI isb1.30.EXSCEL will assess whether exenatide once-weekly can reduce cardiovascular events in patients with T2DM with a broadrange of cardiovascular risk. It will also provide long-term safety information on exenatide once-weekly in people with T2D

Ticagrelor effects on myocardial infarction and the impact of event adjudication in the PLATO (Platelet Inhibition and Patient Outcomes) trial

Objectives This study sought to report the treatment effect of ticagrelor on myocardial infarction (MI) and the strategy for and impact of event adjudication in the PLATO (Platelet Inhibition and Patient Outcomes) trial. Background In PLATO, ticagrelor reduced cardiovascular death, MI, or stroke in patients with acute coronary syndromes (ACS). Methods A CIinical events committee (CEC) prospectively defined and adjudicated all suspected MI events, on the basis of events reported by investigators and by triggers on biomarkers. Treatment comparisons used CEC-adjudicated data, and per protocol, exCIuded silent MI. Results Overall, 1,299 (610 ticagrelor, 689 CIopidogrel) MIs reported by the CEC occurred during the trial. Of these, 1,097 (504 ticagrelor, 593 CIopidogrel) contributed to the primary composite endpoint. Site investigators reported 1,198 (580 ticagrelor, 618 CIopidogrel) MIs. Ticagrelor significantly reduced overall MI rates (12-month CEC-adjudicated Kaplan-Meier rates: 5.8% ticagrelor, 6.9% CIopidogrel; hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.75 to 0.95). Nonprocedural MI (HR: 0.86; 95% CI: 0.74 to 1.01) and MI related to percutaneous coronary intervention or stent thrombosis tended to be lower with ticagrelor. MIs related to coronary artery bypass graft surgery were few, but numerical excess was observed in patients assigned ticagrelor. Analyses of overall MIs using investigator-reported data showed similar results but did not reach statistical significance (HR: 0.88; 95% CI: 0.78 to 1.00). ConCIusions In patients with ACS, ticagrelor significantly reduced the incidence of MI compared with CIopidogrel, with consistent results across most MI subtypes. CEC procedures identified more MI endpoints compared with site investigators. (A Comparison of Ticagrelor [AZD6140] and CIopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872) (C) 2014 by the American College of Cardiology Foundatio

Rationale and design of the EXenatide study of cardiovascular event lowering (EXSCEL) trial

Exenatide once-weekly is an extended release formulation of exenatide, a glucagon-like peptide–1 receptor agonist, which canimprove glycemic control, body weight, blood pressure, and lipid levels in patients with type 2 diabetes mellitus (T2DM). TheEXenatide Study of Cardiovascular Event Lowering (EXSCEL) will compare the impact of adding exenatide once-weekly to usualcare with usual care alone on major cardiovascular outcomes.EXSCEL is an academically led, phase III/IV, double-blind, pragmatic placebo-controlled, global trial conducted in 35countries aiming to enrol 14,000 patients with T2DM and a broad range of cardiovascular risk over approximately 5 years.Participants will be randomized (1:1) to receive exenatide once-weekly 2 mg or matching placebo by subcutaneous injections.The trial will continue until 1,360 confirmedprimary composite cardiovascular end points, defined as cardiovascular death,nonfatal myocardial infarction, or nonfatal stroke, have occurred.The primary efficacy hypothesis is that exenatide once-weekly is superior to usual care with respect to the primary compositecardiovascularend point. EXSCEL is powered todetect a 15% relativerisk reduction inthe exenatide once-weekly group, with 85%power anda 2-sided 5%alpha.Theprimary safetyhypothesis is thatexenatideonce-weeklyis noninferior tousualcarewithrespectto the primary cardiovascular composite end point. Noninferiority will be concluded if the upper limit of the CI isb1.30.EXSCEL will assess whether exenatide once-weekly can reduce cardiovascular events in patients with T2DM with a broadrange of cardiovascular risk. It will also provide long-term safety information on exenatide once-weekly in people with T2D