Authors suggest ISCHEMIA-EXTEND’s finding of noncardiac mortality excess risk observed following revascularization ‘likely due to a statistical Type I error’
There is no significant difference in non-cardiac mortality between revascularization plus medical therapy (MT) compared with MT alone in patients with chronic coronary syndrome (CCS), according to a new meta-analysis of existing trial data.
The analysis, published online Monday and in the May 22 issue of JACC: Cardiovascular Interventions, noted ongoing uncertainty over whether coronary revascularization plus MT is associated with an increase in noncardiac mortality in CCS when compared with MT alone – particularly following recent data from the ISCHEMIA-EXTEND trial, which reported a lower rate of cardiac death among patients with CCS following revascularization plus MT compared with MT alone, but a relative excess in noncardiac-related mortality in the revascularization arm, thus counterbalancing the overall mortality comparison between the groups.
“In this context, we conducted a meta-analysis of randomized trials comparing elective coronary revascularization plus MT with MT alone in patients with CCS and preserved or moderately impaired left ventricular ejection fraction to determine whether revascularization plus MT impacts noncardiac mortality at longest follow-up,” said the authors, led by Eliano P. Navarese, MD, PhD, from Nicolaus Copernicus University and SIRIO MEDICINE Research Network, both in Bydgoszcz, Poland, and the University of Alberta.
Navarese and colleagues pooled data from 18 clinical trials involving nearly 17,000 patients, finding that noncardiac mortality was similar between assigned treatment groups, without heterogeneity.
“These results lend support to the hypothesis that the noncardiac mortality excess risk observed following revascularization in a single large trial (the ISCHEMIA-EXTEND trial) is likely due to a statistical type I error,” said the authors, adding that the findings of the analysis “have public health implications when estimating the benefits of interventions to treat patients with CCS.”
Study details
The research team conducted a meta-analysis of randomized trials comparing elective coronary revascularization plus MT with MT alone in patients with CCS to determine the relative impact of revascularization on noncardiac mortality at longest follow-up.
Treatment effects were measured by rate ratios (RRs) with 95% confidence intervals (CIs), using random-effects models, they noted, adding that noncardiac mortality was the prespecified endpoint.
Data from 18 trials involving 16,908 patients randomized to either revascularization plus MT (n = 8,665) or to MT alone (n = 8,243), were analyzed.
No significant differences were detected in noncardiac mortality between the assigned treatment groups (RR: 1.09; 95% CI: 0.94-1.26; P = 0.26), with absent heterogeneity (I2 = 0%).
Furthermore, they noted that results were consistent without the ISCHEMIA trial (RR: 1.00; 95% CI: 0.84-1.18; P = 0.97), while meta-regression showed that follow-up duration did not affect noncardiac death rates with revascularization plus MT vs MT alone (P = 0.52).
“Trial sequential analysis confirmed the reliability of meta-analysis, with the cumulative Z-curve of trial evidence within the non-significance area and reaching futility boundaries,” added Navarese, noting that Bayesian meta-analysis findings were also consistent with the standard approach (RR: 1.08; 95% credible interval: 0.90-1.31).
Does cause of death matter?
Writing in an accompanying editorial, Harvey D. White, MB ChB, DSc, from the Auckland City Hospital at Te Whatu Ora–Health New Zealand, warned that the findings from the meta-analysis alert practitioners to the importance of adjudicating causes of death in clinical trials.
“This is often difficult, for example, sepsis in a patient with MI [myocardial infarction],” he noted, adding that the current trial-level meta-analysis “may seem to dispel concerns about increases in noncardiac and cardiovascular deaths seen in some revascularization trials, but paradoxically, it has raised the need for more and careful analysis of causes of death.”
“Although this meta-analysis did not show an overall increase in noncardiac or non-cardiovascular deaths, there appears to be a signal from ISCHEMIA EXTEND and REVIVED that we should pay attention to and explore the possibility that increased radiation doses with PCI [percutaneous coronary intervention] may cause increased rates of cancer,” said the editorialist, adding that in this context, other data should be examined including the radiation doses in these trials and in available registries.
“Longer follow-up will also be required,” he said. “In future trials, it will also be important to collect quality-of-life data including cognitive function and patient-focused outcomes such as days alive out of hospital.”
Indeed, the expert commentator noted that the cause of death in cardiovascular trials “probably doesn’t matter much” to patients.
“What matters to patients is the longevity and quality of life before death,” he noted, adding that metrics such as the Seattle Angina Questionnaire and the Kansas City Cardiomyopathy Questionnaire have been used to study the quality of life as well as the patient-focused metric days alive out of hospital, but have rarely been used in revascularization trials.
“Why then the focus on cardiac death and noncardiac death in revascularization trials, and not quality of life or total mortality?”
Sources:
Navarese EP, Lansky AJ, Farkour ME, et al. Effects of Elective Coronary Revascularization vs Medical Therapy Alone on Noncardiac Mortality: A Meta-Analysis. JACC Cardiovasc Interv 2023;16:1144-1156.
White HD. Does it Matter What the Cause of Death Is in Revascularization Trials? JACC Cardiovasc Interv 2023;16:1157-1159.
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Editor's note: This story has been updated to reflect the following correction: A summary headline incorrectly stated a finding from the ISCHEMIA-EXTEND trial. The finding that the meta-analysis points out as a likely Type I statistical error was noncardiac mortality excess risk observed following revascularization in the ISCHEMIA-EXTEND trial compared to medical therapy alone. The meta-analysis did not find a lower incidence of cardiac related death.