Planning and Conducting the ISCHEMIA Trial
Authors: David J. Maron, Robert A. Harrington, Judith S. Hochman
Journal: Circulation (2018)

s members of the leadership of the ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), 1 a large, international, ongoing National Institutes of Healthfunded clinical trial, we write to provide insight into why the study group made certain trial design decisions after the trial started enrolling patients.These decisions were made to preserve the trial's ability to address the primary aim in our grant proposal to the National Heart, Lung, and Blood Institute (NHLBI): "The primary aim of the ISCHEMIA trial is to test the hypothesis that in patients with moderate-severe ischemia on stress imaging, a routine early invasive strategy (INV) with cath followed by optimal revascularization plus OMT [optimal medical therapy] is superior to a conservative strategy (CON) of OMT, with cath and revascularization reserved for those with refractory symptoms or deterioration in clinical status for reducing the incidence of cardiovascular death, MI [myocardial infarction], or hospitalization for unstable angina, resuscitated cardiac arrest, or heart failure (acute cardiac event) in patients with moderatesevere myocardial ischemia and left ventricular ejection fraction ≥35% over an average 3.7 years of follow-up."The grant to conduct the trial with that primary aim was awarded by NHLBI in 2011. 2 When designing and conducting a large randomized clinical trial, after settling on the primary hypothesis and target patient population, choices must be made early in the process that may subsequently impact the ability of the trial to achieve its specific aim.These decisions are based on several assumptions, including importance to patients, anticipated event rate and effect size used to calculate an adequately powered sample size, and potential for bias in event ascertainment and reporting.Often there is limited evidence during the planning phase of a trial on which to base these assumptions.Investigators must estimate the number of sites required to meet recruitment milestones, determine an adequate period of followup for events to accrue, and consider rates of nonadherence to the protocol and potential loss to follow-up.Investigators must decide whether the design should be a pragmatic effectiveness trial, mimicking routine clinical practice as closely as possible, or an efficacy trial, with core laboratory review of entry criteria and central monitoring of protocol adherence.The drivers of these decisions are clinical, statistical, operational, financial, and sociocultural factors that may only emerge after the study transitions from the theoretical phase (grant application process) to the applied phase (grant award).As the trial progresses, factors such as actual recruitment rates, aggregate event rates, and external evidence from other published research may provide insights to investigators, leading to modification of design elements to preserve the ability of the trial to answer the primary research question.It is the trial leadership's responsibility to anticipate these challenges, make decisions based on the best available information, and adjust as challenges arise in