ISCHEMIA in Print: New MI Data and More Calls for Longer Follow-up

With timing that would horrify a trapeze troupe, the ISCHEMIA and ISCHEMIA-CKD trials, as well as their quality-of-life analyses, are all in print today in the New England Journal of Medicine.

The four papers were published as COVID-19 infection rates continue to make headlines and—by intent—on the last day of the virtual American College of Cardiology (ACC) 2020 Scientific Session. The printed studies lay out, in full, the results that were first presented during last year’s American Heart Association (AHA) 2019 Scientific Sessions, as reported by TCTMD.

ISCHEMIA primary investigator David J. Maron, MD (Stanford University School of Medicine, CA), speaking with TCTMD, highlighted new analyses only partially captured in the published paper.

One, fleshed out in a supplement, uses a prespecified secondary definition of MI incorporating more periprocedural MIs; in this analysis, the conservative strategy looks better than the invasive approach. The second, however, presented as part of the ACC 2020’s “on demand” program and alluded to in the NEJM paper, indicates that spontaneous MIs were associated with worse outcomes than procedural infarcts in the trial.

“The bottom line is that the results really don’t change,” Maron said. “The secondary definition of procedural MI was not related to subsequent cardiovascular death or all-cause death, and so we really need to follow up what happens. As the editorial accompanying the paper notes, it’s unlikely that this trial is going to be repeated and there is this suggestion that outcomes are better if you have an intervention or revascularization. But over the period of time that we had to follow patients out, there was absolutely no difference in death. And if there really is a difference then we should see it in [later] follow-up.”

Investigators for the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial have submitted a grant to the National Institutes of Health, which funded the original trial, hoping to extend follow-up out to 10 years. “We’re still waiting” for a response, Maron said. “We have our fingers crossed.”

The editorialists also stress the need for further follow-up.

“Although there is some uncertainty regarding the interpretation of the ISCHEMIA results—given that the difference in outcomes between the two strategies is driven by results for myocardial infarction, and those results depend on the definition used in the analysis—the invasive strategy does not appear to be associated with clinically meaningful differences in outcomes during 4 years of follow-up,” write Elliott Antman, MD, and Eugene Braunwald, MD (both Brigham and Women’s Hospital, Boston, MA). “This finding underscores the benefits of disease-modifying contemporary pharmacotherapy for coronary artery disease.

“Thus, provided there is strict adherence to guideline-based medical therapy,” they continue, “patients with stable ischemic heart disease who fit the profile of those in ISCHEMIA and do not have unacceptable levels of angina can be treated with an initial conservative strategy. However, an invasive strategy, which more effectively relieves symptoms of angina (especially in patients with frequent episodes), is a reasonable approach at any point in time for symptom relief.”

The details on symptom relief are detailed in the quality-of-life paper and echo what was presented at the AHA last year.

“Ironically, I think that the pandemic has accelerated the translation of our results, because I believe that around the country, if not around the world, we’re doing fewer or no elective cases for stable coronary disease,” Maron commented. “This should provide reassurance that as long as we’re instituting guideline-based medical therapy, we are not exposing our patients to increased risk of cardiovascular events.”

ISCHEMIA in NEJM

As previously noted, the primary ISCHEMIA trial was conducted at 320 sites in 37 countries and enrolled 5,179 patients with stable CAD, preserved ejection fraction, and moderate-to-severe ischemia based on either stress imaging or exercise tolerance test. In all, more than 50% of patients in the trial had severe inducible ischemia at baseline, 33% had moderate, and 12% had mild.

All were randomized to a strategy of invasive coronary angiography followed by revascularization, if needed, on top of optimal medical therapy (OMT) or to an initial conservative strategy of OMT alone. Randomization was done prior to angiography and blinded CT angiography was done in approximately two-thirds of the enrolled patient cohort either to exclude life-threatening left main disease or other severe disease or to verify that CAD was, in fact, present.

The principal published results largely echo the findings presented by study chair Judith Hochman, MD (NYU Langone Medical Center, New York, NY), at AHA 2019, although with additional details on cumulative event rates.

Cumulative rates of the primary composite endpoint at 6 months were 5.3% in the invasively treated patients as compared with 3.4% in the conservative-strategy group (95% CI 0.8-3.0); by 5 years, the cumulative event rates were 16.4% and 18.2%, respectively (95% CI −4.7 to 1.0).

“Over a median of 3.2 years of follow-up, among patients with stable coronary disease who had moderate or severe ischemia on stress testing, an initial invasive strategy, as compared with an initial conservative strategy, did not reduce the rates of the primary or key secondary composite outcomes,” the authors conclude. “Patients in the invasive-strategy group had more procedural infarctions, and they had fewer nonprocedural infarctions during follow-up. The incidence of death from any cause was low and similar in the two groups.”

It’s in the online supplement that readers can find details on all of the definitions used in the ISCHEMIA trial, as well as a veritable cornucopia of different analyses many commentators on the trial had hoped to see. These include comparisons of different medication use, cardiac catheterization, and PCI over the course of the trial; time-to-event curves; and the aforementioned analysis using a prespecified secondary definition of myocardial infarction that was more sensitive to procedural MI and believed at the time of the study design to carry more prognostic significance.

MI Definitions in the Spotlight

In this analysis using the more sensitive definition of MI, estimated cumulative events were higher with an invasive approach at 6 months for the primary endpoint and remained higher out to 5 years, such that the event curves do not cross as they did with the primary MI definition. That occurred as a result of more spontaneous MIs occurring in the conservative therapy arm over follow-up.

“This was significantly different,” Maron said. “If we had used the secondary definition of MI for the main results, we would conclude that the conservative strategy is superior to the invasive, and this highlights how important the definition of MI is in the interpretation of the results.”

But this secondary definition was not used for the primary analysis because, said Maron, when investigators designed ISCHEMIA, there was evidence to suggest that the prognostic importance of procedural MIs was not as great as that associated with spontaneous events, a point made at the time the trial was presented and in subsequent discussion online.

A secondary analysis, accepted for presentation at the ACC meeting by Bernard Chaitman, MD (St. Louis University Medical Center, MO), and now available on demand, bears this out, Maron said. As Chaitman’s presentation details, the primary definition of MI—but not the secondary one—was associated with subsequent cardiovascular death. Moreover, nonprocedural MIs and type 1 MIs were strongly related to subsequent mortality, and this increased risk was several times greater than that of procedural MIs, regardless of the MI definition used.

“Those results really help with the interpretation of what we’re supposed to think of this secondary definition and what is the prognosis associated with the different types of MI, and we have just one sentence in the main results paper that alludes to the difference in prognosis,” Maron explained to TCTMD. “We are grateful to the NEJM for timing the release of the publications with our release of these results at ACC, because the ACC results provide the information to support this comment.”

“Despite pronounced differences in the frequency and timing of myocardial infarctions, there was no difference between the groups with respect to mortality,” Maron, Hochman, et al conclude their paper. “Longer-term follow-up with assessment of mortality is needed to fully understand the prognostic implications of more procedural and fewer nonprocedural infarctions with an invasive strategy.”

Antman and Braunwald echoed the call for longer follow-up. “It is possible that ISCHEMIA ended before a substantial difference in favor of the invasive strategy emerged,” they write. “Since it is unlikely that ISCHEMIA will be repeated, it is especially important to extend follow-up with the patients before contact with them is lost; additional events may enhance our understanding of the effect of the trajectory of the event curves and ascertain the durability of the benefit of an invasive strategy with regard to control of angina.”

Timing Is Everything

The publication of the papers today was planned to coincide with the ACC conference, which includes a range of other ISCHEMIA analyses as well; those decisions were made before the COVID-19 outbreak and the decision to make ACC an online experience. The timing is ironic on a number of levels, Maron noted.

“I think that if people had not been practicing this way already, then they’re sort of forced to do it now [because of the COVID-19 pandemic] and can point to this evidence to reassure themselves and their patients that it’s not necessary to rush to the cath lab, that giving good medical therapy a chance is a safe thing to do,” he explained.

That said, this was a trial more than a decade in the making and the published results have been the source of eager speculation in the cardiology community ever since it was announced that there would not be a simultaneous publication at AHA last year. It’s not lost on Maron that ISCHEMIA in print will likely not get the spotlight it might have had at any other time in recent history.

“I don’t think that the lack of media coverage in any way diminishes the impact that these studies will have on guidelines and practice,” Maron said. “It would have been nice basically just for ego and pride to be recognized [with more fanfare], but that’s not really what motivated us to do the trial. We would all enjoy the recognition, but it’s very appropriate that COVID-19 is the dominant story today.”

Full Results for ISCHEMIA-CKD

The key numbers in the ISCHEMIA-CKD results published today for the 777 patients in this ancillary trial are by and large identical to those presented by principal investigator Sripal Bangalore, MD (NYU Langone Health), at AHA last year.

The rate of death or MI—the primary composite endpoint—was 36.4% with the invasive approach and 36.7% with optimal medical therapy alone (adjusted HR 1.01; 95% CI 0.79-1.29). The “key secondary outcome” was the same as the primary outcome for the main trial. Here, rates of death, nonfatal myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest also were similar: 38.5% versus 39.7%, respectively (adjusted HR 1.01; 95% CI, 0.79 to 1.29). Stroke was increased with a routine invasive strategy (HR 3.76; 95% CI 1.52-9.32) and renal outcomes were worse: the risk of the composite of death or new dialysis was higher in invasively treated patients (HR 1.48; 95% CI 1.04-2.11), driven by an increase in the risk of new dialysis. And as noted previously, ISCHEMIA-CKD patients did not derive quality-of-life benefits from revascularization, detailed in the separate NEJM paper.

New to this paper is an analysis using the new secondary MI definition. “Unlike the main ISCHEMIA trial, the results for CKD did not change even with the secondary MI definition,” Bangalore told TCTMD.

To TCTMD, John Spertus, MD (Saint Luke’s Mid America Heart Institute, Kansas City, MO), confirmed that the published quality-of-life studies include all the details from the AHA presentation but said they allow for readers to review them “much more closely than a 5-minute presentation affords, which is great.”