Elective Revascularization, Better Long-term Survival: Meta-analysis

(UPDATED) Looking once again at a question that many cardiologists considered settled, a new meta-analysis suggests that patients with stable coronary artery disease undergoing elective revascularization are at a lower risk of dying from cardiac causes over the long term when compared with patients treated with medical therapy alone.

The findings, presented today as a late-breaking clinical trial at EuroPCR 2021, and simultaneously published in the European Heart Journal, seem to fly in the face of the randomized ISCHEMIA trial findings, published last year. In this analysis, the benefit appeared directly related to the duration of follow-up, with investigators reporting that the longer the follow-up, the lower the risk of cardiac death and spontaneous MI among those who underwent PCI or CABG surgery.

To TCTMD, lead investigator Eliano Navarese, MD (Nicolaus Copernicus University, Toruń, Poland), said he believes the results of the new meta-analysis, far from being contradictory, are actually consistent with ISCHEMIA, the landmark clinical trial comparing optimal medical therapy versus coronary revascularization in stable patients with moderate-to-severe ischemia. In that study, there was no difference in the risk of the adjusted primary composite endpoint; of death from all causes or MI, the study’s original endpoint; or of all-cause mortality, a secondary endpoint.

In a roundtable discussion following the presentation, Navarese said that based on their findings, “which are solid and consistent, I think it should be considered strongly and that it would probably be almost unethical not to offer revascularization to stable patients with coronary artery disease.”

William Boden, MD (Boston University School of Medicine/VA New England Healthcare System, MA), who led the COURAGE trial but wasn’t involved in the meta-analysis, disputes the characterization that this latest study is consistent with ISCHEMIA. In fact, he questioned why the interventional cardiology community continues to pan for nuggets when gold-standard randomized, controlled evidence is right in front of them.

“The overall trial was negative,” stressed Boden. “ISCHEMIA was a neutral/negative trial for both the five-component primary endpoint and the two-component endpoint of cardiovascular death/MI. That is the inescapable scientific fact of the trial.” Interventionalists seem to be unable to accept that the invasive strategy does not reduce the risk of hard clinical outcomes in patients with stable ischemic heart disease, he said.

For his part, Navarese stressed that ISCHEMIA was not powered to address cardiovascular mortality—the primary endpoint in this meta-analysis—and as such, there was no significant difference between the two strategies with respect to that endpoint. There were, however, fewer cumulative cardiac deaths in the revascularization study arm, a trend that might increase over time. Moreover, the intriguing crossing of the MI event curves in ISCHEMIA also hinted at a potential longer-term benefit to revascularization, he noted.  While there was no significant difference in the risk of MI between the two strategies at 4 years, the invasive strategy was associated with a higher risk of MI early while there were more MIs with the conservative strategy in longer follow-up.

For that reason, said Navarese, he and his co-investigators wanted to assess the impact of revascularization over longer-term follow-up to determine if revascularization translated into a clinical benefit.

“The point is that it’s hard to believe we should rely on trials with short follow-up, 3.2 years in the case with the ISCHEMIA trial,” he said.

The ISCHEMIA trial investigators have announced plans to study patients for an additional 5 years beyond the original trial. As part of the ISCHEMIA-EXTEND study, which now includes more than 5,000 participants enrolled in the follow-up study, investigators say they plan to assess all-cause mortality “to provide patients and clinicians with robust evidence regarding survival following the two initial management strategies over the long term (~ 10 years),” according to the ISCHEMIA trial website.

Bigger Bang With Longer Follow-Up

The retrospective meta-analysis of 25 studies included 19,806 patients with clinically stable coronary artery disease who received elective revascularization plus medical therapy or medical therapy alone. The analysis included older trials such as MASS-1, RITA-2, and COURAGE, as well as more-recent trials like ORBITA, FAME 2, and ISCHEMIA. In the analysis, clinical stability was defined by the absence of symptoms or signs of ischemia at rest. For all of these studies, the investigators assessed the primary endpoint of cardiac mortality at each study’s longest follow-up.

Researchers observed a 21% lower risk of cardiac mortality (rate ratio [RR] 0.79; 95% CI 0.67-0.93) among patients who underwent coronary revascularization compared with medical therapy alone. They also conducted a prespecified sensitivity analysis to exclude trials with post-ACS patients deemed stable (ie, without significant ischemia at rest), patients with chronic total occlusions, or patients undergoing CABG surgery. In that analysis, the lower risk of cardiac mortality with revascularization remained significant.

Moreover, Navarese said, time since randomization appeared to make a difference. “For each 4-year increase in follow-up, the risk of dying from cardiac causes declined significantly by 19% with allocation to revascularization versus medical therapy alone.”

All-cause mortality was not significantly different between the two treatment strategies (RR 0.94; 95% 0.87-1.01), but there was evidence to suggest a benefit when studies with very high crossover rates were excluded, said Navarese. He added that cardiac mortality is a better endpoint to analyze in comparisons of medical therapy versus revascularization as it’s more directly related to the procedure/treatment. All-cause mortality in long-term follow-up might be biased toward the null given the competing risks of noncardiac death.

For the secondary endpoint of spontaneous MI, there was a 26% lower risk among patients who were treated with coronary revascularization (RR 0.74; 95% CI 0.64-0.86), and each 3% absolute reduction in the risk of MI was associated with a significant 14% relative reduction in cardiac mortality.

Davide Capodanno, MD, PhD (University of Catania, Italy), one of the moderators during the press briefing, told TCTMD that the present study, despite solid evidence from the ISCHEMIA trial, stems from suggestions the clinical event curves in that trial may be separating over time. And while the rationale for the meta-analysis makes sense, there are limitations to what answers it can provide.

For example, the meta-analysis included clinical trials that spanned from 1979 to 2020, and five of those trials had a weight greater than 10% on the overall results. Two trials reported a significant reduction in cardiac death, and both are important drivers of the final results, said Capodanno. One of those trials was the European Coronary Surgery Study (ECSS), which was published in 1988 and included follow-up of 12 years. The second was the Medicine, Angioplasty, or Surgery Study (MASS) 2, which was published in 2010 and reported outcomes at 10 years.

“The authors conducted several sensitivity analyses, including exclusion of those trials, to dispel the concern that the results are due to older trials, or due to inclusion of CABG trials, and should be congratulated for that,” said Capodanno. “However, longer-term results from more-contemporary trials or an individual patient-level meta-analysis are key steps in moving forward, to inform future guidelines and to ascertain if the suggested reduction in cardiac death is something more than a plausible association.”

Speaking during the media briefing, Navarese said he believes the reduction in cardiac mortality to be biologically plausible given the reduction in spontaneous MI.

Boden, for his part, isn’t buying it, and expressed dismay at what he characterized as the continued onslaught of analyses—including a recent ISCHEMIA “completeness” analysis—attempting to glean some evidence of benefit with the invasive approach.

In the roundtable discussion, Rasha Al-Lamee, MBBS (Imperial College London, England), joked that many seeing the study results “will suddenly breathe a sigh of relief because we’ve suddenly saved intervention.” However, like the others she noted the meta-analysis included trials spanning 40 years, a time when medical therapy really changed and interventional revascularization techniques improved, and yet its sensitivity analysis suggested the benefit wasn’t related to the dates of the trials.

Navarese acknowledged that one of the criticisms of their study is that optimal medical therapy, which should include pharmacologic therapies aimed at aggressive risk factor control as well as lifestyle changes, was rarely used in those older trials. He stressed, though, that medical therapy, however it was defined at the time of the study, was also given in those who underwent revascularization. “The percentage of medical therapy was generally comparable between the two arms,” he said. “This allowed us to preserve the capacity to assess the role of revascularization on top of medical therapy.”