Bayesian Interpretation of the EXCEL Trial and Other Randomized Clinical Trials of Left Main Coronary Artery Revascularization

Abstract

IMPORTANCEPatients with left main coronary artery disease have improved outcomes with coronary revascularization compared with medical therapy, but the choice of optimal revascularization technique is unresolved. OBJECTIVETo use bayesian methods to analyze the risk differences for patients with left main coronary artery disease randomized to treatment with coronary artery bypass surgery (CABG) compared with those randomized to percutaneous coronary intervention (PCI) in recent randomized clinical trials (RCTs). DESIGN, SETTING, AND PARTICIPANTSA systematic review using the PubMed database with the query string "(left main disease) and (PCI or CABG) and (5-year follow-up) and (clinical trial)" identified all RCTs from January 1996 to January 2020 comparing CABG to PCI for treatment of patients with left main coronary artery disease and with 5-year follow-up data. With the use of bayesian methods, the largest and most publicized RCT (EXCEL; Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; 2019) was reanalyzed (1) as an isolated entity using noninformative priors and (2) in the context of previous knowledge using informative priors derived from similar trials. Published aggregate data were used with assignments from each trial following the original intention-to-treat principle. Combining EXCEL data with varying levels of prior information using Bayes theorem provided final (posterior) probability distributions for primary and secondary outcomes. MAIN OUTCOMES AND MEASURESA composite end point of death, nonfatal myocardial infarction, and stroke was the primary EXCEL outcome and was accordingly the primary outcome for this reanalysis. Secondary analyses were performed for isolated all-cause mortality and for the composite outcome along with repeated revascularization procedures. RESULTSWhen EXCEL data were analyzed using the originally stated noninferiority design, the 5-year primary outcome difference reported (2.8%; 95% CI, −0.9% to 6.5%) exceeded the predefined 4.2% noninferiority margin; thus, the null hypothesis of PCI inferiority could not be rejected. By contrast, the present bayesian analysis of the EXCEL primary outcome estimated 95% probability that the 5-year primary outcome difference was increased with PCI compared with CABG and 87% probability that this difference was greater than 1 extra event per 100 patients treated. Bayesian analyses also suggested 99% probability that EXCEL total mortality was increased with PCI and 94% probability that this absolute difference exceeded 1 extra deaths per 100 treated. A systematic review identified 3 other RCTs that studied the same question. The incorporation of this prior knowledge reduced the estimated probability of any excess mortality with PCI to 85%. For the secondary composite end point, which also included repeated revascularizations, there were estimated probabilities of 98% for at least 4 extra events and of 90% for at least 5 extra events per 100 patients treated with PCI.CONCLUSIONS AND RELEV...

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New Revelations Ignite the EXCEL Affair and Expose the Distortion of Science

“…Further to the extensive disclosure of flagrant bias introduced into the design, analysis, and publication of the 5-year follow-up of the EXCEL trial [ 1 ] , the June edition of the Journal of American Medical Association (JAMA) Internal Medicine revealed and highlighted that the formal hypothesis testing, which in the EXCEL trial was prespecified as a demonstration of noninferiority at 3 years, was without discussion or explanation switched to a superiority test in the 5-year analysis [ 2 ] . If as prespecified, the same noninferiority analysis had been conducted at 5 years it would not have met the criteria for statistical significance, and the printed conclusion would not have been possible.…”

“…The newly identified violation follows in the wake of the controversy over data manipulation in the EXCEL trial. The article authored by Professor James M. Brophy, who is a professor of Medicine, Epidemiology, and Biostatistics at McGill University in Montreal, Canada, re-examines the design and results of the EXCEL trial and other recent randomized clinical trials related to the left main coronary artery disease (LMCAD) using Bayesian methods [ 2 ] .…”

“…He reinforces that fourteen of 34 EXCEL trial authors, including the first and last authors, had a relationship with the study sponsor (the stent maker), and that 8 authors listed an affiliation with the Cardiovascular Research Foundation (CRF) which oversaw the study. CRF received a donation of US$ 937,000 from the sponsor during the study and Professor Brophy infers that these factors may have contributed to the entirely speculative hypothesis that these conflicts of interests contributed to the biased interpretation of EXCEL [ 2 ] .…”