ISCHEMIA Patients: High Rates of Severe-to-Moderate Ischemia, Multivessel CAD

If the stars align, the full results of the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial should be published and presented late this year, but a new publication will give those eagerly anticipating the results something to chew on for the time being.

Published February 27, 2019, in JAMA Cardiology, the paper by ISCHEMIA investigators provides a detailed look at the baseline characteristics and risk profiles of patients with stable ischemic heart disease enrolled in the trial, noting that the vast majority have moderate-to-severe ischemia on stress testing and most have multivessel coronary artery disease.

The motivation behind the study design “to include moderate-to-high risk patients is really to define a group of patients who would benefit from revascularization,” William Boden, MD (VA New England Healthcare System, Boston, MA), one of ISCHEMIA’s principal investigators, told TCTMD. “Most of us are of the opinion that if we can’t show in ISCHEMIA that revascularization works for patients who are symptomatic and also have moderate-to-severe ischemia at baseline—if we can’t show that bypass surgery works, or PCI works—then we’re never going to be able to show it. This is precisely the group in whom you’d expect to see a clinical benefit.” 

Boden said they published this current paper because follow-up for ISCHEMIA is expected to be completed on June 30, 2019, and the hope is that the database will be cleaned up and locked later in the summer. If all goes well, they aim to present the data as a late-breaking clinical trial at the American Heart Association Scientific Sessions in November.

“Given that timeline, we felt that it would be important to get the baseline paper out there in advance of the publication coming, maybe, later this year,” said Boden. “It would give the cardiology community, the academic community, an opportunity to look at the dataset and see how it compares and contrasts with the previous studies, notably BARI 2D, COURAGE, and FAME 2, among others.”

Sripal Bangalore, MD (NYU Langone Medical Center, New York, NY), the lead investigator of the ISCHEMIA ancillary study of patients with advanced chronic kidney disease, told TCTMD that a quick comparison of the major trials of optimal medical therapy versus coronary revascularization shows that the proportion of patients with 3-vessel disease in ISCHEMIA is higher than in COURAGE, BARI 2D, and FAME 2. Similarly, the proportion of patients with proximal left anterior descending (LAD) artery involvement is higher in ISCHEMIA than in those other trials. Overall, 79.0% of patients in ISCHEMIA have multivessel CAD and 86.8% have a stenosis involving the LAD.

“If you are a believer in the ‘ischemia’ hypothesis—greater ischemia, worse outcomes—the trial has enrolled such a cohort,” said Bangalore. “If you are a believer in the ‘anatomy’ hypothesis—more severe CAD, worse outcomes—the trial has enrolled such a cohort. If you are a believer in both, the trial has enrolled such a cohort. What remains to be seen is whether an invasive strategy in such patients is beneficial.”

To TCTMD, Boden added that the current publication shows the ISCHEMIA investigators “included exactly the kinds of patients that everybody has been clamoring for these past 10 years.”

ISCHEMIA Trial Previously Under Fire

The National Heart, Lung, and Blood Institute (NHLBI)-sponsored ISCHEMIA study is being closely watched not just for its $100 million price tag, but because experts are hoping it will finally determine whether moderate-to-severe ischemia is a driver of adverse cardiovascular events that justifies referring such patients for coronary revascularization with PCI or CABG surgery.

The trial has come under criticism, particularly when investigators expanded the primary endpoint to include resuscitated cardiac arrest, hospitalization for unstable angina, and hospitalization for heart failure in addition to the hard endpoints of cardiovascular death and MI. Others have criticized the use of exercise stress testing for identifying and defining ischemia.  

“Although there may be slight changes before we lock the database, we don’t expect any significant changes from here on out, so we thought it was a good time to publish,” David Maron, MD (Stanford University, CA), the co-chair of ISCHEMIA, told TCTMD in an email. “Also, there has been discussion on social media about our inclusion of patients with nonimaging exercise stress tests, so we thought that getting these data out in the public domain would satisfy the curiosity and speculation we have heard about this subset.”    

It’s far and away the largest study done to date, and hopefully it will answer the question we’ve all been waiting for. William Boden

In total, 5,179 patients with stable ischemic heart disease were randomized to optimal medical therapy alone or in combination with coronary revascularization. The average age of patients was 64 years, 22.6% were women, 41% had diabetes, and 89.7% had a history of angina. The trial included 1,726 nonwhite and 748 Hispanic participants.

Regarding the assessment of ischemia, 3,909 participants were randomized into the trial following stress imaging (nuclear perfusion imaging, dobutamine stress echocardiography, or cardiac magnetic resonance imaging) and 1,270 were randomized after exercise treadmill testing. For those randomized after stress imaging, core laboratory-assessed ischemia was classified severe and moderate in 44.8% and 41.0% of subjects, respectively. With exercise treadmill testing, 83.0% and 8.0% had severe and moderate ischemia, respectively.

To TCTMD, Maron noted that despite the concerns over including patients on the basis of exercise stress testing, these patients had a higher proportion of three-vessel CAD and more proximal LAD disease than participants undergoing stress testing.

Critical Issues for Statistical Power

In an editorial, Raymond Gibbons, MD (Mayo Clinic, Rochester, MN), writes that ISCHEMIA is the largest trial ever conducted in patients with stable CAD and includes more patients than COURAGE and BARI 2D combined. Exercise stress testing was used to encourage participation in countries where cardiac imaging was not commonly performed. While patients randomized on the basis of an exercise electrocardiogram did have more severe CAD, they were also younger and had less prior MI, PCI, CABG surgery, and PAD. As a result, these subjects might not have similar rates of hard cardiac events, “which is a critical issue for the statistical power for the trial,” he notes.

One additional concern for Gibbons is the inclusion of patients with less-than-moderate ischemia on stress imaging or exercise testing. These patients were randomized by the enrolling centers and then later shown to have inadequate ischemia when reviewed by the core laboratory. This also could potentially reduce the power of the ISCHEMIA trial, according to Gibbons.   

Boden said they did not want to slow down the enrollment process by having every test for ischemia verified by the core laboratory prior to randomization into the trial. The discrepancy between the extent of moderate-to-severe ischemia identified by the core lab and individual sites is a consequence of that decision.

“It’s the price you pay for having a hard trial not go on forever,” said Boden. “If you put too many impediments in the path of investigators, they’re going to lose interest. They’re going to say it’s too hard to enroll. They’ll find reasons not to put patients into the trial.”

Nonetheless, Boden said it was critical to publish this detailed snapshot of the ISCHEMIA patients at this point given the importance of the trial. “We wanted to get the baseline characteristics out there so that people can digest it and have them see exactly the profile of the patients,” he said. “I would hope that people would say, ‘Wow, this is a really well-done study.’ It’s far and away the largest study done to date, and hopefully it will answer the question we’ve all been waiting for.”