Revascularization Benefits ISCHEMIA Patients With Mild LV Dysfunction or HF

Patients enrolled in the ISCHEMIA trial with a history of heart failure or left ventricular dysfunction randomized to invasive management with either PCI or CABG surgery had significantly better outcomes when compared to similar patients treated with medical management, according to a prespecified analysis from the landmark trial.

The findings suggest that this higher-risk subgroup of stable patients with moderate-to-severe ischemia and evidence of mildly impaired LV function may benefit from more invasive therapy, according to lead investigator Renato Lopes, MD, PhD (Duke Clinical Research Institute, Durham, NC).

Presenting the results this weekend during a late-breaking science session at the virtual European Society of Cardiology Congress 2020, Lopes stressed the analysis is hypothesis-generating only, noting that they had a small number of patients and clinical events in the group with heart failure/LV dysfunction. For example, of 5,129 patients included in ISCHEMIA, just 4.0% had a history of heart failure and only 1.1% had a prior heart-failure hospitalization. The median left ventricular ejection fraction (LVEF) in the trial was 60.0%.

Nonetheless, Lopes highlighted the STITCHES trial, which showed heart failure patients treated with CABG surgery had a 16% lower risk of risk of death when compared with those treated with medical therapy after 10 years of follow-up. Unlike ISCHEMIA, though, STITCHES enrolled patients with an LVEF of less than 35% and those with NYHA class III or IV heart failure. While these sicker patients were excluded from ISCHEMIA, the trial “provided us with a unique opportunity to explore the potential benefit of an invasive strategy in this subgroup of patients,” said Lopes, referring to people with an LVEF between 35% and 44%.

Presented in 2019, and later published in the New England Journal of Medicine, the ISCHEMIA trial showed that an invasive strategy of angiography followed by PCI or CABG on top of optimal medical therapy failed to reduce the study’s primary composite endpoint—cardiovascular death, MI, hospitalization for unstable angina, hospitalization for heart failure, or resuscitation due to cardiac arrest—or reduce all-cause mortality/MI when compared with medical therapy. Angina relief, however, was significantly better in the invasively treated patients.  

Worse Outcomes in HF/LV Dysfunction

Although the numbers were small, Lopes reported that more patients with heart failure/LV dysfunction in ISCHEMIA had a history of hypertension, diabetes, and prior MI. The mean LVEF in those without heart failure/LV dysfunction was 66.0%, compared with 44.0% in the higher-risk subgroup. Both groups had similar rates of severe ischemia.

Overall, the patients with heart failure/LV dysfunction had a significantly higher risk of major adverse cardiovascular events than those without. The primary composite endpoint occurred in 22.7% and 13.8% of patients with and without heart failure/LV dysfunction (adjusted HR 1.43; 95% CI 1.12-1.82). Cardiovascular death/MI occurred in 19.7% and 12.3% of patients with and without heart failure/LV dysfunction (adjusted HR 1.37; 95% CI 1.06-1.78). Rates of all-cause mortality and cardiovascular mortality were also significantly higher in the higher-risk patients.

For the primary composite endpoint, there was no difference in risk among patients without heart failure/LV dysfunction randomly assigned to the invasive strategy or conservative therapy. In contrast, there was a benefit in patients with a history of heart failure or reduced heart function; here, the primary endpoint occurred in 17.2% of patients treated with PCI or CABG surgery and 29.3% of patients treated with conservative medical management (P value for interaction between subgroups = 0.055). In terms of cardiovascular death/MI, the invasive strategy was also associated with a lower risk of events than medical management in patients with heart failure/LV dysfunction (14.6% vs 25.9%), but the benefit was not observed in those without heart failure/LV dysfunction (P = 0.061 for interaction).

During the presentation, Lopes noted that revascularization in the invasive strategy was a mixture of CABG and PCI, which may differ in their acute risks and benefits as well as their long-term protection from future events. He added that further follow-up is planned for this high-risk subgroup to determine if the invasive strategy provides long-term benefits.

A Signal Raised for Future Studies

Speaking with TCTMD, Sripal Bangalore, MD (NYU Langone Medical Center, New York, NY), one of the ISCHEMIA investigators, pointed out that the trial had fairly strict inclusion/exclusion criteria and as such included very few patients with a history of heart failure or LV dysfunction. Nonetheless, these new results line up with STITCHES, this time showing a benefit to revascularization in stable ischemic patients with less severe LV dysfunction.

“Of course, this is a small subgroup of patients so it’s hypothesis-generating, but it fits the narrative that milder LV dysfunction and heart failure patients are at higher risk [than those without]. I don’t think clinicians are seeing this mild LV dysfunction and taking it as seriously,” he said. He added that most physicians would likely consider patient with a “midrange” LVEF as similar to the patient with a normal LVEF and manage them in the same manner. “This study is saying, ‘wait a minute. We might have to think of them different.’”

In such stable patients with a mildly compromised LVEF or history of NYHA class I or II heart failure, Bangalore said it might be worth considering more-invasive management with PCI or surgery.

“If you have this degree of ischemia—moderate-to-severe in ISCHEMIA—and you’re already seeing the ventricle fail or heart failure, it may denote a higher-risk group of patients,” he said. “We know that in terms of the risk-benefit ratios of studies with revascularization versus medical therapy that patients at the highest risk—the ACS patients, the shock patients—benefit the most. Maybe this falls into that continuum.” While a patient with moderate-to-severe ischemia and preserved LVEF might not derive as much benefit, “those with mild-to-moderate LV dysfunction may gain more from revascularization.”  

Despite that, Bangalore stressed the present analysis only raises a “signal,” and said that the benefit of revascularization over medical management in stable patients with less severe LV dysfunction needs to be studied further.