Baseline Ischemia Not Linked to 10-Year Events in Stable CAD: MASS II Analysis

Exercise stress test-induced myocardial ischemia in patients with multivessel CAD was not predictive of major adverse cardiovascular events or changes in left ventricular function over 10 years in the Medicine, Angioplasty, or Surgery (MASS) II study, according to long-term follow-up.

Those findings held true regardless of the type of therapeutic strategy applied in MASS II or whether any interventions subsequently implemented over follow-up, researchers led by Cibele Larrosa Garzillo, MD, PhD (Instituto do Coração [InCor], São Paulo, Brazil), report this week in JAMA Internal Medicine.

The controversial link between documented ischemia and long-term CVD outcomes in patients with stable CAD is the focus of the long-running ISCHEMIA trial, which is seeking to establish the best treatment course—coronary revascularization on top of optimal medical therapy (OMT) or OMT alone—in patients with stable coronary heart disease with moderate-to-severe ischemia on stress testing. ISCHEMIA is looking at the primary endpoint of cardiovascular death and MI, resuscitated cardiac arrest, hospitalization for unstable angina, and hospitalization for heart failure at 5 years.

This analysis of MASS II, however, offers 10 years of follow-up and according to co-author Paulo Cury Rezende, MD, PhD (InCor), should give pause. “I really think, with our study, we have a good answer,” he told TCTMD. “We are also waiting for the final results from ISCHEMIA trial, and we're very excited about that. But here we have data about this issue,” namely, that inducible ischemia on baseline stress-testing was not associated with later events.

Even in the absence of definitive trial evidence, many hospitals depend heavily on stress testing as a means of guiding the intensity of subsequent therapies for stable CAD patients, and for Rezende, these MASS II findings call into question the use of exercise stress tests for this purpose. “I think we can agree that we have to be careful with the results that we get,” he said.

Speaking with TCTMD, Leslee J. Shaw, PhD (Emory University, Atlanta, GA), principal investigator for ISCHEMIA’s Ischemia Imaging Coordinating Center, pointed out that stress imaging substudies from two prior randomized trials, COURAGE and BARI 2D, as well as an analysis from the CLARIFY registry yielded results similar to those from MASS II. “We're seeing a consistently clear pattern that ischemia is not predictive” of subsequent events, she said.

But Shaw, as well as ISCHEMIA co-chair David J. Maron, MD (Stanford University School of Medicine, CA), offered TCTMD a number of caveats, including the fact that this MASS II analysis did not have core lab-adjudicated information on the severity of ischemia, did not include longitudinal information on ischemia changes over time, and did not look separately at patients who did not receive revascularization at the time of randomization or who crossed over during the ensuing decade.

“I'm waiting to see what the ISCHEMIA trial teaches us,” Maron said. InCor, where MASS II was conducted, is one of the highest enrolling centers in ISCHEMIA, he noted.

MASS II Insights

MASS II was a 611-patient randomized trial comparing optimal medical therapy, PCI, or CABG over the long term in patients with stable multivessel CAD; the current analysis zeroes in on the association between stress-induced ischemia and the occurrence of MACE and LVEF changes over a 10-year period. Of note, the study was initiated in the late 1990s, so PCI entailed stent placement, laser angioplasty, directional atherectomy, or balloon angioplasty; CABG and intensity of medical therapy have also evolved over this period.

I'm waiting to see what the ISCHEMIA trial teaches us. David J. Maron

Here, Larrosa Garzillo and colleagues tracked 535 MASS II subjects who underwent exercise stress testing at baseline: 270 with documented ischemia and 265 without. Over the decade of follow-up, and after adjusting for initial randomization, researchers saw no link between the presence of baseline ischemia and survival free from cardiovascular events, specifically all-cause mortality, myocardial infarction, and revascularization for refractory angina (HR 1.00; 95% CI, 0.80-1.27).

In an additional echocardiographic evaluation conducted in a subset of patients at baseline and after 10 years, authors found no link between baseline ischemia and subsequent left ventricular function, finding similar, modest declines in patients with versus without ischemia at baseline.

“Although the presence of documented ischemia has been identified as a possible marker of a higher-risk population and an indication for myocardial revascularization procedures to protect the myocardium from the chronic, deleterious effects of ischemia over time, the present study’s findings do not support this assumption,” the authors conclude. “The delicate imbalance between oxygen supply and demand at stress is a consequence and does not seem to be a factor for impairment of ventricular function or coronary events during a long-term follow-up.”

Yesterday, Today, Tomorrow

Speaking with TCTMD, Rezende addressed some of the concerns voiced by Shaw and Maron, clarifying that the MASS II analysis included qualitative (yes/no) information on ischemia, but not quantitative information that would speak to the degree of ischemia severity among MASS II patients. ISCHEMIA, Shaw stressed, has relied on core lab-adjudicated results to ensure that only patients with moderate-to-severe ischemia are enrolled, thereby guaranteeing an “enriched” population for the comparison of revascularization versus OMT.

To a point raised by both Maron and Shaw, namely the lack of information on inducible ischemia over the course of the follow-up and in particular following the intervention, Rezende noted that, in fact, patients in MASS II were scheduled for yearly stress tests but that missed appointments and incomplete numbers rendered this analysis impossible.

He also noted, however, that it was the baseline stress test that investigators were primarily interested in, since this reflects the way stress tests are used in practice today—that is, to help guide decision-making on whether to proceed with revascularization. And in MASS II, outcomes were no different between patients no matter what type of therapy they received.

Ischemia involves the vessels, the lesions, and the myocardium and this is a very complex situation, and ischemia is a consequence of this whole problem. Paulo Cury Rezende

“Of course, we will have the ISCHEMIA results, but maybe we should be more careful about using ischemia [when deciding whether] to revascularize our patients. This is the take-home message of this paper,” Rezende said. “Ischemia involves the vessels, the lesions, and the myocardium and this is a very complex situation, and ischemia is a consequence of this whole problem. We still have to learn and use with more caution the information we get from these tests when we are thinking about revascularizing patients.”

Beyond the results of the current analysis is the possibility that in the decades-long search to find an answer on the link between stress imaging, subsequent events, and the best treatment strategy, other modalities have emerged in the interim.

Maron pointed out that while baseline ischemia did not predict events in the COURAGE trial, anatomic severity did.

Coronary CTA results for ISCHEMIA patients at baseline, published last year, show that the trial has enrolled a high proportion of patients with multivessel disease and LAD artery involvement—in other words an anatomically complex cohort. Moreover, while ISCHEMIA has faced some flack for the use of nonimaging exercise stress tests, Maron noted the trial required coronary CTA evidence of at least 70% stenosis in a major coronary artery as well as the presence of documented ischemia at a low workload.

“The baseline paper shows that the anatomic severity of the group that qualified with nonimaging stress tests was as bad or worse than the group that qualified with stress imaging tests,” Maron clarified in a follow-up email.

As such, the MASS II analysis “helps keep us in suspense,” Maron said. “We don't have the answer and we look forward to presenting the ISCHEMIA results later this year,” most likely at the American Heart Association 2019 Scientific Sessions.

Shaw, asked whether stress tests are still the best way to determine functionally relevant disease, also emphasized the need to wait for ISCHEMIA, but she agreed that these MASS II findings appear to be “another nail in the coffin, if you will, for stress-induced ischemia,” particularly in the modern era.

She pointed to studies like FAME II that have looked at the use of invasive tests like fractional flow reserve to gauge vessel-specific ischemia as opposed to more global myocardial ischemia, as was the case with MASS II.

“There are quite a lot of differences between what goes on within the vessel and what goes on in the myocardium. Maybe this is one other piece of the puzzle suggesting that what goes on in the myocardium is less important than what goes on in the vessel,” Shaw said.