Editor's Note: This Expert Analysis is part of a series presenting perspectives on major ESC Congress 2019 trials. Please follow this link for the companion articles.

During the European Society of Cardiology Congress 2019 (ESC Congress 2019), one of the highly anticipated late-breaking clinical trials was SYNTAXES (SYNTAX Extended Survival Study), the 10-year follow-up results of the SYNTAX (Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery) trial. The SYNTAX trial, published in 2009,¹ has often been cited as strengthening our understanding of who benefits the most from coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI) based on the complexity of coronary disease. The original trial demonstrated that the primary endpoint of major adverse cardiac and cerebrovascular events (MACCE) was lower in CABG compared with PCI.² However, as with many cardiovascular randomized trials, the primary endpoint was assessed at 1 year, leading to ongoing questions about the long-term consequences of SYNTAX.

In 2015, the 5-year results of SYNTAX showed that MACCE was still significantly higher in PCI compared with CABG (37.3% vs. 26.9%, respectively).³ Moreover, the results showed that PCI was associated with a significantly higher risk of repeat revascularization and myocardial infarction (MI), although the risk of stroke was higher with CABG. Although there was no difference in all-cause mortality between groups, patients who received CABG had lower rates of cardiovascular-specific mortality and MI-related mortality. This 5-year trial again provided favorable results for CABG among patients with complex, multivessel coronary artery disease, but questions remained about additional longitudinal follow-up.

In SYNTAXES, vital status data on all-cause mortality was collected on most patients enrolled in the original SYNTAX trial. The authors report that at 10 years, there was no significant difference in all-cause mortality between PCI and CABG, but CABG provided a significant survival benefit in patients with three-vessel disease but not those with left main disease. Unlike the original SYNTAX and the 5-year SYNTAX trial, this new analysis has several unique limitations that warrant consideration when interpreting findings.

First, SYNTAXES analyzed only all-cause mortality, whereas previous SYNTAX data reported both overall and cardiovascular-specific mortality. We know from the 5-year SYNTAX data that patients who received PCI had higher rates of repeat revascularization, MI, and cardiovascular-specific death. Therefore, it is certainly possible that 10-year data may have favored CABG if cardiovascular rather than all-cause mortality had been analyzed. Additionally, SYNTAXES reported no information on the original primary endpoint (MACCE), the endpoint for which the trial was originally powered, or its components such as MI, stroke, and repeat revascularization. At 5 years, MACCE was higher in PCI patients, and it is possible that the same trend would have been observed at 10 years if the data were available. Lastly, although there was no difference in all-cause mortality between groups at 10 years, at maximum follow-up, CABG was associated with a survival benefit compared with PCI.

In an editorial published simultaneously in The Lancet, David P. Taggart provides additional observations on the limitations of SYNTAXES.⁴ The first major issue regarding the original SYNTAX population was the study cohort. Among the 3,075 patients enrolled, 59% were randomized and 41% were entered into a registry, of which 84% underwent CABG due the complexity of their disease. Although the results of SYNTAXES for multivessel disease demonstrate a survival benefit for CABG, which is consistent with the literature, Dr. Taggart brings into question the left main findings, which showed no difference in survival between groups. As noted in the editorial, left main disease is heterogenous, and only 91 patients had isolated left main disease, which greatly influences statistical power. Lastly, Dr. Taggart questions the lack of a survival benefit of CABG among diabetics in SYNTAXES, which is at odds with several meta-analyses and the results of the FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) trial. The finding may again be due to inadequate power to detect differences in subgroup analyses.

Overall, SYNTAXES deserves recognition for something often lacking in cardiovascular randomized trials: longitudinal follow-up data. Unfortunately, when the longitudinal data collected is only one component of the composite endpoint, interpretation of findings becomes challenging. For now, patients with complex, multivessel coronary artery disease appear best served with CABG. For patients with left main or less complex coronary disease, a collaborative heart team approach provides the greatest benefit to patients.

References

1. Thuijs DJFM, Kappetein AP, Serruys PW, et al. Percutaneous coronary intervention versus coronary artery bypass grafting in patients with three-vessel or left main coronary artery disease: 10-year follow-up of the multicentre randomised controlled SYNTAX trial. Lancet 2019;394:1325-34.
2. Serruys PW, Morice MC, Kappetein AP, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360:961-72.
3. Mohr FW, Morice MC, Kappetein AP, et al. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial. Lancet 2013;381:629-38.
4. Taggart DP, Pagano D. Expansion or contraction of stenting in coronary artery disease? Lancet 2019;394:1299-1300.

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