N Engl J Med 2022;387:1351-1360

Background: Systolic heart failure and obstructive coronary artery disease often coexist. Some patients show improvement in left ventricular systolic function after revascularization, which led to the development of the concept of myocardial hibernation. In this state, areas of the heart that are exposed to repetitive ischemia reduce their contractility to help facilitate their survival. Restoring blood flow to these hypocontractile yet viable segments could improve outcomes. Although observational studies supported this theory, large randomized trials were still lacking. Patients with severe left ventricular systolic dysfunction were generally excluded from the seminal trials of percutaneous coronary intervention (PCI) in stable coronary artery disease.

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The Revascularization for Ischemic Ventricular Dysfunction (REVIVED) trial sought to test the hypothesis that revascularization with PCI plus medical therapy is superior to medical therapy alone in patients with left ventricular systolic dysfunction, obstructive coronary artery disease and viable myocardium.

Patients: Eligible patients had left ventricular ejection fraction of 35% or less, obstructive coronary artery disease, in addition to viability in at least four dysfunctional myocardial segments that are amenable to revascularization by PCI. Viability could be determined by any imaging modality and was adjudicated based on local experts.

Major exclusion criteria were myocardial infarction within 4 weeks, sustained ventricular arrhythmias within 72 hours, acutely decompensated heart failure requiring inotropic support, invasive or non-invasive ventilation or mechanical circulatory support within 72 hours, glomerular filtration rate <25 ml/ min (unless already on dialysis) or life expectancy less than 1 year due to noncardiac disease.

Baseline characteristics: The trial randomized 700 patients—347 randomized to the PCI plus medical therapy arm and 353 randomized to the medical therapy alone arm.

The average age of patients was 69 years and 88% were men. The average body mass index was 29 kg/m2. Approximately 56% had hypertension, 41% had diabetes, 53% had prior myocardial infarction, 20% had prior PCI, 5% had prior CABG, and 73% were current or previous smokers. Seventy four percent had NYHA class I or II. Sixty seven percent had no angina.

The average left ventricular ejection fraction was 27%. Approximately 14% had left main disease, 40% had 3-vessel disease and 49% had 2-vessel disease. Proximal left anterior descending artery disease was present in 58% of the patients.

Procedures: Patients were randomized in an open-label way to undergo PCI plus medical therapy or medical therapy alone. In the PCI group, revascularization was to be attempted on all diseased coronary arteries supplying areas of viable myocardium. Medical therapy was provided by heart failure specialists in accordance with guideline recommendations.

The minimum intended follow up time was 24 months.

Endpoints: The primary outcome was a composite of death from any cause or hospitalization for heart failure. Secondary outcomes included left ventricular ejection fraction at 6 and 12 months, functional status using the NYHA classification and quality of life based on the Kansas City Cardiomyopathy Questionnaire (KCCQ) summary score. The endpoints of death, hospitalizations for heart failure, myocardial infarctions or unplanned revascularizations were adjudicated by a committee unaware of treatment assignment.

Analysis was performed based on the intention-to-treat principle. The estimated event rate of the primary outcome in the medical therapy arm was 36% at 24 months. A sample size of 700 patients was needed to ensure 85% power with a 5% alpha, based on an assumed 30% relative risk reduction for the primary outcome with PCI.

Results: The median follow up time was 41 months and data on the primary outcome were available from 99% of the patients. Among the patients assigned to undergo PCI, 334 (96.3%) underwent the procedure.

PCI plus medical therapy did not significantly reduce the primary outcome compared to medical therapy alone (37.2% with PCI vs 38.0% with medical therapy, HR: 0.99; 95% CI: 0.78 - 1.27; p= 0.96). Similarly, there was no significant difference in death from any cause (31.7% vs 32.6%, HR: 0.98, 95% CI: 0.75 - 1.27), hospitalizations for heart failure (14.7% vs 15.3%, HR: 0.97; 95% CI: 0.66 - 1.43) or acute myocardial infraction (10.7% vs 10.8%, HR: 1.01, 95% CI: 0.64 – 1.60). Unplanned revascularization was reduced with PCI (2.9% vs 10.5%, HR: 0.27, 95% CI: 0.13 – 0.53).

The change in left ventricular ejection fraction at 1 year was not significantly different between both groups (+2.0% with PCI vs +1.1% with medical therapy). Both treatment groups had improvement in quality of life based on the KCCQ summary score. This favored the PCI group at 12 months (mean difference of 4.5 points, 95% CI: 1.4 – 7.7), however, there was no significant difference at 2-years (70.6 with PCI vs 68.1 with medical therapy). The NYHA functional class and the Canadian Cardiovascular Society Angina class were comparable between both groups on follow up.

There were no significant subgroup interactions for the primary outcome.

Note to readers: The KCCQ summary score ranges from 0 – 100 with higher scores indicating better quality of life. Generally speaking, a change of 5 is considered small but clinically important, whereas a change of 10 is considered moderate to large and a change of 20 is considered large to very large.

Conclusion: In patients with moderate to severe left ventricular systolic dysfunction, obstructive coronary artery disease and viable myocardium, PCI did not reduce death or heart failure hospitalization compared to medical therapy alone, over a median follow up of 41 months. Additionally, PCI did not significantly improve left ventricular ejection fraction, quality of life or symptoms compared to medical therapy alone.

The trial included high risk patients. For comparison, mortality in the medical arm in this trial was 32.6% at 41 months, compared to 8.3% at 5-years in the ISCHEMIA trial.

This is an important trial. The authors chose high-risk patients who were theoretically likely to benefit from revascularization with PCI - those with left ventricular dysfunction, obstructive coronary artery disease (with 58% having proximal left anterior descending artery disease) and viable myocardium. However, PCI was not more effective compared to medical therapy alone. This is the second negative trial of revascularization in patients with ischemic cardiomyopathy, after the STICH trial. Taken together, these trials underscore the complexity of coronary artery disease, showing it's not only a localized problem. It also reinforces the importance of randomized trials, as treatments that seem logical don't always work.

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