Meta-analysis Finds No Excess Mortality Risk With Coronary Revascularization

Operators think these new data will end a controversy about PCI’s mortality risks that gained traction with ISCHEMIA-EXTEND.

Meta-analysis Finds No Excess Mortality Risk With Coronary Revascularization

PARIS, France—There is no excess risk of death from noncardiac causes in patients with chronic coronary syndromes (CCS) treated with revascularization and medical therapy when compared with those who receive medication alone, according to the results of a new meta-analysis.

The study, presented today at EuroPCR 2023 and published simultaneously in JACC: Cardiovascular Interventions, included 18 trials with 16,908 patients randomized to either coronary revascularization plus medical therapy or medical therapy alone: the noncardiac mortality rate in the two groups was 4.7% and 4.2%, respectively, and was not statistically significant.

Senior investigator William Wijns, MD (Lambe Institute for Translational Medicine and CÚRAM, Galway, Ireland), said these data should provide interventional cardiologists with “ammunition if anyone tells you that we are causing an excess risk of noncardiac mortality with PCI.”

This specific risk question first emerged 2 years ago in a different meta-analysis where investigators reported that noncardiac mortality might be higher with revascularization than with medical therapy. The question took on more urgency after extended follow-up of the ISCHEMIA trial showed there was a higher risk of noncardiovascular mortality among those randomized to the invasive strategy. Other signals of noncardiac mortality risk were observed elsewhere, including in REVIVED where there were numerically more noncardiac deaths with PCI plus optimal medical therapy versus medical therapy alone.

Whether the risk was real, or just a play of chance, has been debated, said Wijns.

Gregory Ducrocq, MD, PhD (Hôpital Bichat-Claude Bernard/Université Paris VII), one of the hotline discussants, said the interventional field was surprised by the hazard seen in ISCHEMIA-EXTEND. The new meta-analysis, he told TCTMD, should close the door on the idea that coronary revascularization increases the risk of noncardiac mortality.

Davide Capodanno, MD, PhD (University of Catania, Italy), who chaired the session, said that given the mix of findings from different trials, a meta-analysis is the best tool to address this specific question. Like others, he thinks the question is settled, saying these new data should end “once and forever” the current mortality controversy around revascularization.

Nearly 17,000 Patients in 18 Trials

The meta-analysis included patients with CCS randomized to either revascularization plus medical therapy or medical therapy alone. Among the trials, ISCHEMIA, COURAGE, and BARI-2D were the largest, but investigators also included familiar studies like DEFER, FAME-2, ORBITA, and MASS 1 and 2, among others. The average follow-up was 5.7 years.

Overall, there was no significant difference in the risk of noncardiac mortality between the two treatment strategies (RR 1.09; 95% CI 0.94-1.26). The results were consistent when investigators excluded the ISCHEMIA trial from the analysis. Similarly, when trials with CABG surgery as the mode of revascularization were excluded, there was still no excess risk seen. When trials including patients with chronic total occlusions were excluded, the results were the same.

“With the exception of one study, ISCHEMIA, there is [no trial] that showed an excess in noncardiac mortality,” said Wijns, adding the length of follow-up also didn’t reveal any signal of harm.

A Bayesian analysis showed no significant differences in noncardiac mortality between revascularization/medical therapy and medical therapy alone. In a trial sequential analysis, which investigators say allows them to control for potential type I and II statistical errors, there was no signal of excess noncardiac mortality with coronary revascularization. The trial sequential analysis also showed that the addition of other studies would be unlikely to influence the results.

“Adding further studies is not going to add information content and this speaks in favor of the robustness of this analysis,” said Wijns.

In an editorial accompanying the published paper, Harvey White, MBChB, DSc (Green Lane Cardiovascular Research Institute Auckland City Hospital, New Zealand), points out that while the meta-analysis didn’t show any signs of excess noncardiac mortality, “there seems to be something going on” based on ISCHEMIA-EXTEND and REVIVED.

White emphasizes the importance of adjudicating the cause of death in clinical trials, noting that cancer deaths accounted for the excess noncardiac mortality risk in ISCHEMIA, which raises concerns about radiation exposure.

“Patients in the ISCHEMIA trial were exposed to an accumulative radiation dose related to previous investigations, nuclear stress imaging for those who qualified with this stress test modality, cardiac computed tomography angiography for selection of patients, at the time of diagnostic invasive angiography, and if appropriate, PCI, and with recurrent procedures,” he writes. “Some patients may have had up to three PCI interventions for chronic total occlusions.”

The typical time frame from carcinogen exposure to cancer is 5 to 40 years for solid tumors but can be less for hematological cancers. Although the meta-analysis didn’t show any heightened risk of noncardiac mortality, the signals from ISCHEMIA-EXTEND and REVIVED suggest physicians should pay attention and “explore the possibility that increased radiation doses with PCI may cause increased rates of cancer,” writes White.

To TCTMD, Ducrocq said today’s interventional cardiologists strictly monitor the amount of contrast and radiation exposure during procedures, the aim being as little as possible. “The risk of cancer after angioplasty has not been found in other trials,” he said. “For me, this is a hypothesis that has not been validated.” Except in the case of very complex PCI, use of radiation is very low, he added.  

PCI and Radiation Exposure

Michael Joner, MD (Deutsches Herzzentrum München, Munich, Germany), one of the discussants during the EuroPCR session, said these data ultimately reassure on the matter of noncardiac mortality risk with revascularization. However, the findings raise another question: should clinical trials opt instead for all-cause mortality instead of cardiac mortality?

Panelist Bernard de Bruyne, MD, PhD (Cardiovascular Research Center Aalst, Belgium), said that clinical trials would need to double or triple in size if they were only focused only on all-cause mortality, which is out of the question. Wijns believes trials should collect both all-cause and cardiac-specific mortality, but he also worries about focusing exclusively on total mortality.

“As the outcomes of interventions, particularly in chronic coronary syndromes, gets better, if you go for all-cause mortality, you’re likely to give more weight to these events that have nothing to do with the procedure you’re looking at,” said Wijns. “I would vote with cardiac mortality as [part of] the primary endpoint.”

Likewise, Ducrocq said cardiac mortality is a more logical endpoint, noting that it adds significant power to the study’s endpoint and reduces the number of patients required in trials. Adjudication of deaths remains the big challenge when they occur outside the hospital, he said.  

Michael O’Riordan is the Managing Editor for TCTMD. He completed his undergraduate degrees at Queen’s University in Kingston, ON, and…

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  • Navarese EP, Lansky AJ, Farkouh ME, et al. Effects of elective coronary revascularization vs medical therapy alone on noncardiac mortality: a meta=analysis. J Am Coll Cardiol Intv. 2023;Epub ahead of print.

  • White DH. Does it matter what the cause of death is in revascularization trials? J Am Coll Cardiol Intv. 2023;Epub ahead of print.

  • Navarese reports research grants from Abbott and Amgen; and lecture fees/honoraria from Amgen, AstraZeneca, Bayer, Pfizer, and Sanofi-Regeneron.
  • White reports grant support paid to the institution and fees for serving on steering committees of the ODYSSEY trial from Sanofi and Regeneron Pharmaceuticals, the ISCHEMIA and MINT studies from the National Institutes of Health, the STRENGTH trial from Omthera Pharmaceuticals, the HEART-FID study from American Regent, the DAL-GENE study from DalCor Pharma UK Inc., the AEGIS-II study from CSL Behring, the CLEAR OUTCOMES study from Esperion Therapeutics Inc, and the SOLIST-WHF and SCOREDS trials from Sanofi Aventis Australia Pty Ltd.



Bogdan Borz

11 months ago
At the end of the discussion, it is suggested by dr Joner that trials should focus on all-cause mortality instead on cardiac mortality. Dr de Bruyne replied that if clinical trials did that, they would need to double or triple in size. This is mistaken. If the clinical end point includes total mortality, instead of cardiac mortality (and there are plenty of trials that do), the number of events automatically increases since cardiac mortality is only a subset of total mortality. Therefore, the size of the trial population will decrease, not increase, if cardiac mortality is replaced by total mortality in the composite end-point. Trial size increases only if the the composite EP is replaced by total mortality. But total mortality should be our main concern. It is more robust and precise end-point. What changes for the patient if all-cause mortality is identical after the stent, but cardiac mortality decreases? "Doc, am I less likely to die after your stent? No, just as likely, but be glad that it won't be from a cardiac cause."