The investigators of the anticipated ISCHEMIA trial have published a paper in Circulation: Cardiovascular Quality and Outcomes defending their late addition of “softer” outcomes to their primary composite endpoint.
The change occurred 99 percent of the way through the recruitment period and was called into question by a writing group from Imperial College London, which claimed the researchers were “moving the goalposts” and subjecting their results to an additional level of bias.
ISCHEMIA is a randomized trial comparing two treatment strategies for stable angina: early cardiac catheterization and revascularization (if suitable) plus medical therapy, or medication alone with invasive management reserved for when medical therapy fails.
According to the Imperial College London group, the investigators regularly touted the hard primary endpoint of death and nonfatal myocardial infarction. But in January, they added cardiac arrest and hospitalization for unstable angina or heart failure to that composite endpoint.
The critics asserted that this will water down the study, which received $84 million in funding from the U.S. National Heart, Lung, and Blood Institute (NHLBI).
“We must reflect on whether there is any meaning to the term primary endpoint when goalposts are moved after a trial has begun recruiting despite the best intentions of investigators,” wrote senior author Darrel P. Francis, MD, and colleagues. “We must learn to accept the results of trials even if they are not as we hoped. True scientists do experiments for the potential to surprise. The thousands of patients who volunteered to participate, and even more importantly the millions whose care will be informed by the reported trial results, deserve nothing less.”
Hospitalizations for unstable angina and heart failure, they noted, could be affected by the knowledge of which treatment a patient received. The power of “knowing and telling” from both a patient and physician’s perspective, they said, leaves these outcomes open to bias.
Francis and colleagues suggested when the study results are revealed, readers focus on the initially planned outcomes of death and myocardial infarction, which will be reported as a secondary endpoint.
In their response published May 11, the investigators said the five-component primary endpoint was always a “contingency plan” if it was determined they would need additional outcomes to achieve statistical power.
“This contingency plan was developed to avoid a common pitfall of other trials, namely lower than projected power because of lower than projected event rates,” wrote lead author Sripal Bangalore, MD, of New York University School of Medicine, and other ISCHEMIA investigators. “An event-driven trial was considered as an alternative but was not possible because the duration of follow-up and thus costs would be uncertain.”
The contingency plan was part of the original trial protocol in 2012, they noted. Bangalore et al. said it would take more than double the 5,179 participants enrolled to achieve 80 percent power for a 20 percent risk reduction in mortality in the allotted time. It wasn’t feasible to enroll that many patients, but they hope to receive funding to extend the study’s follow-up, which is another way to increase statistical power.
“The process … to change the primary end point was deliberate and carefully considered, involving the trial Leadership Committee, Steering Committee, National Heart, Lung, and Blood Institute program staff, statisticians, and independent experts; it took nearly a year of planning,” the investigators wrote. “As leaders of this NHLBI-funded trial, we take seriously the humbling responsibility granted to us to conduct this trial, and we are confident that the wealth of trial data, the rigor with which it is collected, and our careful adherence to standards in the conduct of clinical trials will substantially advance our knowledge about the management of patients with stable ischemic heart disease and at least moderate ischemia.”
Related ISCHEMIA Trial Content:
ISCHEMIA: Invasive therapy no better than meds for reducing CV events
‘Twitter doesn’t require peer review’: The benefits, risks of cardiology chatter on social media
Daniel joined TriMed’s Chicago editorial team in 2017 as a Cardiovascular Business writer. He previously worked as a writer for daily newspapers in North Dakota and Indiana.