Latest Commentary on ISCHEMIA Trial Temporarily Withdrawn

Patrice Wendling

June 27, 2018

UPDATED June 29, 2018, with new content // In an atypical and surprising move, the latest commentary on the controversial ISCHEMIA trial was temporarily taken down from the American Heart Journal (AHJ) website.

"There was an outsized reaction for what are mostly fair criticisms," Venkatesh Murthy, MD, PhD, who coauthored the commentary with Kim Eagle, MD, both from the University of Michigan, Ann Arbor, told theheart.org | Medscape Cardiology. "Our commentary was actually accepted months ago and Dr Mark has been deeply involved in the management of our commentary."

Daniel B Mark, MD, from Duke University Medical Center, Durham, North Carolina, is the AHJ editor-in-chief and also an investigator for the long-awaited ISCHEMIA trial and a coauthor of the ISCHEMIA methods paper, also just published by AHJ. The long-awaited trial has been embroiled in controversy after outside sources recently revealed that its primary end point had been changed 5 years after its launch.

The CardioTwitter community was quick to respond after Medscape detailed the decision, with some cardiologists calling it "shameful" and "DEEPLY CONCERNING editorial behavior." While some bemoaned the recent trend of withdrawing papers once accepted by peer review, others suggested the reaction to the temporary take-down itself was overblown.

The commentary was subsequently reposted, unchanged. Revisions to the text have been sent by the authors to AHJ and the corrected version is expected soon. At press time, Mark had not yet responded to requests from Medscape as to exactly when that might be or why, if the paper was so flawed as to be taken down, it was reposted in its original form.

A March 12, 2018 perspective by senior author Darrel Francis, MD, and his colleagues at Imperial College, London, accused the ISCHEMIA investigators of "moving the goalposts" by expanding the primary end point from the hard end points of cardiovascular death and myocardial infarction to include resuscitated cardiac arrest, hospitalization for unstable angina, and hospitalization for heart failure.

The Twittersphere erupted again, and ISCHEMIA cochair David Maron, MD, from Stanford University School of Medicine, California, offered a rebuttal at the American College of Cardiology 2018 Scientific Sessions. He noted that the potential to revise the primary end point was part of the original protocol and necessary to preserve study power. Also, an independent advisory panel (IAP) recommended the five-component primary end point in May 2017, and the recommendation was accepted the next month by the National Heart, Lung, and Blood Institute (NHLBI), which is funding the study to the tune of $108 million.

ISCHEMIA is not just any trial, but one designed to address the role of revascularization in stable coronary artery disease (CAD), which was called into question after the COURAGE trial showed no benefit of percutaneous coronary intervention (PCI) over optimal medical therapy alone for preventing future events in this setting. The use of PCI shifted away from stable CAD in its wake, but the issue remains central to the cardiology community, with millions of dollars at stake in a possible reversal of its findings.

Temporary Withdrawal

Mark told theheart.org | Medscape Cardiology in an email that the Murthy/Eagle commentary on the AHJ website was the preproduction pdf submitted by the authors.

"The authors are considering a few edits to that version, and so the Elsevier/AHJ production team, at my request, put a hold on production work until we receive the updated version," Mark said. "The production team leader suggested taking the manuscript pdf that is to be replaced down from the web site to avoid confusion between versions. I thought that made sense and that is why the manuscript is temporarily down."

He added that the updated perspective will be published when the authors are fully satisfied with their manuscript and that "This temporary hold has no effect on or implications regarding that status."

Murthy said the journal raised "minor factual inconsistencies and then there are some differences of opinion."

In the former category is a comment that a protocol addendum issued in September 2015 "simultaneously reduced the sample size by 30% and follow-up duration by 25%." The planned enrollment was reduced from 8000 patients to between 5000 and 6000 patients, but the mean follow-up will be 3.5 years, which is not a 25% reduction from the 4- to 3-year estimated projections.

Murthy and Eagle made a comment about the "moral hazard" induced by the use of free stents in the trial, stating that "In order to remove financial considerations from choice of revascularization strategy, trial investigators arranged for no cost drug-eluting stents for participants."

The journal has countered that those donated stents were for use in the protocol-assigned initial invasive procedure and were not available for crossover procedures, Murthy said.

Also coming under fire were statements by Murthy and Eagle that the "IAP had some knowledge about the trial results. Clearly, the trial was not terminated early by the DSMB [data safety monitoring board] by the time the IAP met in 2017." The journal took issue with the idea that the IAP had information that they could use to speculate on how the trial was going, noting that the DSMB had not done any interim analyses of the data prior to the IAP meeting.

Finally, Murthy and Eagle point out that, initially, the trial insisted only on stress imaging tests with rigorous core lab adjudication of ischemic burden prior to randomization but that the criteria were expanded to permit inclusion based on concerning EKG changes during exercise testing without imaging. Patients with typical angina or chest pain during exercise stress testing who demonstrate at least 5% ischemia on nuclear perfusion imaging at low levels of exertion are also eligible.

They argue that the correspondence between ST-segment depression on exercise EKG and ischemia on stress testing is poor, the algorithm used in ISCHEMIA has not been well validated, and that patients who can undergo exercise testing represent a lower risk population than those who undergo pharmacologic stress.

Murthy and Eagle go on to say, "In addition, 5% ischemia corresponds to approximately two moderately abnormal myocardial segments, has been used as a normalcy threshold, and corresponds to a range where prior data suggest harm from revascularization." The journal suggested this could be misunderstood by readers, Murthy said.

Rules of Engagement

"A lot of these points were brought up during the peer review process and we did our best to understand what was going on with the study," Murthy said. "It's unfortunate but the ISCHEMIA trialists have gotten the wrong impression. I don't know, but I don't think we were intending to put out any inaccurate information or personally go after anyone."

He continued, "These are folks who are of high integrity, they've worked very hard, they're very accomplished, and I have tremendous respect for them, and I think I can speak for Dr Eagle in that regard. But I also think it's important we can have an open academic debate about these issues.… We need some rules of engagement of what's acceptable and what's not acceptable and that's for both sides."

Maron told theheart.org | Medscape Cardiology he was aware the AHJ commentary had been pulled down but was not aware of all the details. He said he does not have a Twitter account and acknowledged being surprised by the comments following the publication of the first commentary.

"It's disappointing to me that there's so much discussion before we have results to report," he said. "I think it's destined to generate a lot of interest and I hope people will wait to see the results and keep an open mind."

Asked why they didn't include the contingency plan for the primary end point when the original protocol was posted on clinicaltrials.gov, Maron said it was something they simply didn't consider at the time.

The investigators may have headed off some of the controversy by at least making a public announcement when the primary end point was changed, rather than leaving the UK group and others to discover it had been updated on clinicaltrials.gov in January 2018.

"This was discussed at investigator meetings but we did not issue a press release," he said. "Again, it's not something that we considered we should do. Everything we have done we have done by the book. Even any changes we have made on clinicaltrials.gov we made within the guidelines that clinicaltrials.gov requires. I'm sorry I don't have a good sound bite for you."

Asked whether there has been any outside pressure with regard to the primary end point revision, Maron firmly replied, "None. I have not been aware of any pressure from industry regarding trial design or conduct."

Murthy and Eagle call for disclosure of trial resources and data as one way to mitigate some of the controversy that is sure to surround the ISCHEMIA results, expected late 2019 or early 2020. The recommendation is sound in light of the rash of recent retractions and corrections including those for the pivotal PREDIMED trial. The ORBITA trial, the first sham controlled trial of PCI, made its angiograms accessible to the public; however, that did not appear to reduce the often-shrill commentary on Twitter.

A baseline paper is expected to be published in the near future and the investigators will comply with the NHLBI rules regarding data sharing, Maron said. "At this time, we do not plan to release the database before the NHLBI rules indicate we need to."

The seemingly endless controversy over the ISCHEMIA trial before its results are even released highlight what's at stake for the cardiology community and the need to answer this central question regarding the value of revascularization in stable CAD.

"I don't know if there will ever be a better opportunity to conduct a clinical trial of this magnitude on this topic," Maron said. "We feel a tremendous responsibility, we the trial leadership, to do this right, to be faithful to the research question we are trying to answer and to be good stewards of the taxpayer dollars and to follow clinical trial standards in the way we conduct the trial and approach this with equipoise, meaning we just want to find the truth and let the chips fall where they may."

Murthy reports owning stock in General Electric, Medtronic, Johnson & Johnson, Amgen, and Cardinal Health; receiving consulting fees and serving on the advisory board for Ionetix; and receiving research grants support from Siemens Medical Imaging and Ionetix. He is also supported by R01HL136685 from the National Heart, Lung, and Blood Institute.

Follow Patrice Wendling on theheart.org | Medscape Cardiology and Twitter @pwendl.  

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