Bayesian Re-Analysis of EXCEL Trial
- The EXCEL study showed PCI was noninferior to CABG for treatment of LM disease.
- Bayesian analysis of the EXCEL trial on its own and with inclusion of other RCTs suggest contrary results.
- The author concludes there is high certainty that PCI for LM disease is associated with increased risk of death, MI, and stroke compared to CABG.
Does a Bayesian re-analysis change the interpretation of the EXCEL (Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial findings?
A systematic review was performed to identify all randomized clinical trials (RCTs) from January 1996 to January 2020 comparing coronary artery bypass grafting (CABG) to percutaneous coronary intervention (PCI) for treatment of patients with left main (LM) coronary artery disease and with 5-year follow-up data. With the use of Bayesian methods, the largest and most publicized RCT (EXCEL, 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. A composite endpoint of death, nonfatal myocardial Infarction (MI), and stroke was the primary EXCEL outcome and was accordingly the primary outcome for this re-analysis. Secondary analyses were performed for isolated all-cause mortality and for the composite outcome along with repeated revascularization procedures.
When EXCEL data were analyzed using the originally stated noninferiority design, the 5-year primary outcome difference reported (2.8%; 95% confidence interval, −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 >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 death per 100 treated. A systematic review identified three 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 endpoint, which also included repeated revascularizations, there were estimated probabilities of 98% for ≥4 extra events and of 90% for ≥5 extra events per 100 patients treated with PCI.
Bayesian analysis assisted in RCT data interpretation and specifically suggested, whether based on EXCEL results alone or on the totality of available evidence, that PCI was associated with inferior long-term results for all events, including mortality, compared with CABG for patients with LM coronary artery disease.
The controversy surrounding the best treatment approach for LM disease has been a long-standing debate. The EXCEL trial with its original study design and analysis met the noninferiority cut-off to conclude that PCI and CABG were similar for the composite endpoint of death, nonfatal MI, and stroke; however, PCI was associated with higher rates of repeat revascularization over 5 years. The current re-analysis using Bayesian methods, which moves away from dichotomous result interpretation to estimating key outcome differences with direct probability measures of their uncertainty, suggests that there was a 95% probability that PCI was associated with an increased risk of the primary composite endpoint. These results are sure to keep the debate ongoing and will make shared decision-making discussions with patients more challenging.
Keywords: Bayes Theorem, Coronary Artery Bypass, Coronary Artery Disease, Myocardial Infarction, Myocardial Revascularization, Percutaneous Coronary Intervention, Randomized Controlled Trials as Topic, Stroke, Vascular Diseases
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