ISCHEMIA Trial Revisited: Some May Benefit From Invasive Strategy

Bruce Jancin

September 15, 2020

The landmark ISCHEMIA trial rattled the cardiology world with its message that clinical outcomes weren't significantly better with a routine initial invasive strategy than with medical therapy alone in patients with stable coronary artery disease and moderate or severe myocardial ischemia on noninvasive testing. But a new prespecified subanalysis from the randomized trial points to a subgroup that might actually benefit from immediate revascularization.

Renato Lopes

ISCHEMIA participants in the sweet spot for an initial invasive strategy were the ones with a baseline history of mild to moderate heart failure symptoms and a left ventricular ejection fraction (LVEF) of 35%–45%, Renato Lopes, MD, PhD, reported at the virtual annual congress of the European Society of Cardiology.

"An invasive approach may be beneficial in this subgroup of high-risk patients with moderate to severe ischemia and a history of heart failure and left ventricular dysfunction," declared Dr. Lopes, professor of medicine at Duke University, Durham, N.C.

He was quick to add, however, that this finding from ISCHEMIA should be considered hypothesis generating in light of the small sample size in the subgroup analysis.

The ISCHEMIA trial randomized 5,179 patients with stable CAD and at least moderate myocardial ischemia on noninvasive testing to a routine invasive or conservative management strategy. At 4 years of follow-up there was no significant between-group difference in cardiovascular outcomes (N Engl J Med. 2020 Apr 9;382[15]:1395-407).

Patients with a baseline LVEF below 35% weren't eligible for enrollment in ISCHEMIA. That's because the prior Surgical Treatment for Ischemic Heart Failure Extension Study (STICHES) showed patients with ischemic cardiomyopathy and an LVEF below 35% had a significantly lower cardiovascular death rate with surgical revascularization plus medical therapy than optimal medical therapy alone at 10 years of follow-up (N Engl J Med. 2016 Apr 21;374[16]:1511-20).

But what about the impact of immediate revascularization as compared with medical management alone in patients with milder impairment of LVEF in the 35%–45% range and/or a history of symptomatic heart failure? Theoretically, the improved blood flow to ischemic myocardium obtained via revascularization in such patients might activate hibernating myocardium and reduce ventricular dysfunction, thereby reducing the risk of cardiovascular events. The ISCHEMIA trial provided a unique opportunity to prospectively examine this question in 398 affected study participants, Dr. Lopes explained.

This 398-patient subgroup with a baseline history of heart failure and/or left ventricular dysfunction (HF/LVD) was at higher risk than patients without those features. Indeed, the primary outcome in ISCHEMIA — a composite of cardiovascular death, nonfatal MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest — occurred in 22.7% of the HF/LVD group at 4 years of follow-up, compared with 13.8% of the much larger group without HF/LVD. The HF/LVD group also had significantly higher rates of the secondary composite endpoints of cardiovascular death or MI (19.7% vs. 12.3%) and all-cause mortality or heart failure (15% vs. 6.9%).

The provocative central finding in this new subanalysis was that patients in the HF/LVD subgroup fared significantly better in terms of cardiovascular events if randomized to the initial invasive approach. Indeed, their 4-year rate of the primary outcome was 17.2%, compared with 29.3% with an initial conservative approach. The various secondary outcomes followed suit. In contrast, the primary outcome occurred in 13% of patients without HF/LVD who were randomized to the invasive strategy, not significantly different from the 14.6% rate with conservative management.

Drilling deeper into the data, Dr. Lopes and coinvestigators found that the enhanced event-free survival benefit of an initial invasive strategy was restricted to the 28 patients having both a baseline history of symptomatic heart failure and an LVEF of 35%–45%. There was no significant difference in outcomes with an invasive versus conservative strategy in the 177 patients with a history of heart failure whose LVEF was greater than 50% — that is, patients with heart failure with preserved ejection fraction — nor in the 193 participants with an LVEF of 35%-45% but no history of symptomatic heart failure.

In an interview, Mark H. Drazner, MD, commented, "this is an interesting hypothesis, for sure, that warrants further study to confirm whether it's valid. And if it is valid, there could be real implications. If this is true, I think there could be a decent number of patients out there that this would have implications for.

"The ISCHEMIA trial was a heroic effort. While there are certainly logistical hurdles involved in anybody doing an ISCHEMIA 2 trial based on this small subgroup analysis, other people could start looking at retrospective datasets and see if they can confirm these findings to build momentum to study this further," said Dr. Drazner, professor of medicine and chief of clinical cardiology at the University of Texas Southwestern Medical Center, Dallas, as well as an associate editor at Circulation.

Simultaneous with his presentation at ESC Congress 2020, Dr. Lopes' study was published online in Circulation.

Dr. Lopes reported receiving research grants from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi-Aventis as well as serving as a consultant to a handful of pharmaceutical companies, none relevant to his presentation.

Circulation. Published online August 29, 2020. Abstract

European Society of Cardiology (ESC) Congress 2020.

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