The last several months have witnessed publication of long-term follow-up of major trials for left main (LM) coronary artery disease revascularization. One of the trials that reported its long-term follow-up was the PRECOMBAT trial (Premier of Randomized Comparison of Bypass Surgery vs. Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease), presented as a late-breaking trial at the 2020 American College of Cardiology Annual Scientific Sessions Together With World Congress of Cardiology.¹

The PRECOMBAT trial was a prospective open-label randomized trial that compared percutaneous coronary intervention (PCI) with sirolimus-eluting stents with coronary artery bypass grafting (CABG) in patients with LM coronary artery disease. The primary endpoint was a major adverse cardiac and cerebrovascular event (MACCE) (a composite of death from any cause, myocardial infarction [MI], stroke, or ischemia-driven target vessel revascularization [TVR]) after randomization. Patients considered eligible to participate in the study were older than 18 years of age and had received a diagnosis of stable angina, unstable angina, silent ischemia, or non-ST-segment elevation MI. All patients had newly diagnosed LM stenosis and had been judged to be suitable candidates for either PCI or CABG. This study was partially funded by the CardioVascular Research Foundation (Seoul, Korea). The sample size calculation based on an expected incidence for the primary endpoint in the CABG arm of 13% and non-inferiority margin of 7% yielded an estimation of 286 patients per group with a 72% power. Finally, 300 patients per group were randomized to either CABG or PCI.²

The mean (± standard deviation) age of the trial participants was 62.3 ± 9.7 years, 76.5% were men, and 32.0% had medically treated diabetes mellitus. Mean SYNTAX score was 24.8 ± 10.3 (low in 42.4%, intermediate in 35.3%, and high in 22.3%). Complete revascularization was achieved in 68.3% in the PCI group and 70.3% in the CABG group; 63.8% of patients underwent off-pump CABG. The 1-year MACCE (primary outcome) occurred in 8.7% and 6.7% in the PCI and CABG groups, respectively (absolute risk difference 2.0%; 95% confidence interval [CI], -1.6 to 5.6; p = 0.01 for noninferiority). At 10 years, MACCE was 29.8% in the PCI group and 24.7% in the CABG group (hazard ratio [HR] 1.25; 95% CI, 0.93-1.69). No significant differences were found with respect to death, stroke, or MI. However, the incidence of TVR was significantly higher in the PCI group.

The authors conclude that 10-year follow-up did not demonstrate significant difference in the incidence of MACCE. Yet several issues need to be considered to fully understand the generalizability of the results from this trial. As mentioned, the sample size calculated for the primary outcome estimated an incidence of MACCE in the CABG group much higher than the real outcome. Because sample size was not corrected during interim analysis, the trial was un-powered even for their primary 1-year outcome. The non-inferiority margin of 7% means that MACCE in the PCI arm could be twice as high compared with CABG and the result still be non-inferior. Therefore, the statistics involved in the sample size and non-inferiority design are flawed, rendering cautious interpretation of the primary outcome. The CONSORT diagram shows that 1,454 patients were assessed for eligibility to include the calculated sample (600 patients). This means that only 40% fell into the inclusion and exclusion criteria specified by the trial. Therefore, the external validity of the reported results is narrow, and application of the results for daily clinical practice is quite limited. Again, it should be noted that one of the inclusion criteria was that patients needed to have suitable anatomy for CABG or PCI. Open-label trials like the PRECOMBAT trial are subject to non-compliance by patients in the control group, which may explain the relatively high crossover from CABG to PCI (17%). Unfortunately, the authors do not specify the reason for such an incidence, making as-treated analysis compulsory to have a complete understanding of outcomes. As-treated and per-protocol analysis showed that PCI was inferior to CABG with respect to the primary outcome at 10 years. TVR was significantly higher in the PCI arm, and as we have seen with the EXCEL (Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial, patients who require new revascularization are at higher risk for mortality.³ Subgroup analysis, although hypothesis generating, show two interesting results. It confirms once again that the higher the number of diseased vessels, the higher the benefit of CABG. And similar to what was shown in the SYNTAX (Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery) trial,⁴ patients who receive incomplete revascularization have worse outcomes with PCI (HR 1.57; 95% CI, 0.90-2.73). Lastly, given the growing attention to conflicts of interest, it is important to note that the PRECOMBAT trial was partially funded by the CardioVascular Research Foundation, of which the founder and chairman is Seung-Jung Park, who is the senior author and principal investigator for this trial. This type of mixed participation between funding organization and principal investigator has the potential to introduce unintentional bias into the analysis of data.

In conclusion, the results from the long-term follow-up of the PRECOMBAT trial must be interpreted with caution. Patients who receive PCI (as treated analysis) will have significantly higher risk for MACCE compared with CABG. Its restricted external validity makes generalizability of its conclusions quite limited among the LM population. Because ischemia-driven revascularization was significantly higher with PCI, revascularization of patients with LM stenosis, particularly among those who are young or otherwise good surgical candidates, should be carefully reviewed with a heart team approach.

References

1. Park DW, Ahn JM, Park H, et al. Ten-Year Outcomes After Drug-Eluting Stents Versus Coronary Artery Bypass Grafting for Left Main Coronary Disease: Extended Follow-Up of the PRECOMBAT Trial. Circulation 2020;141:1437-46.
2. Park SJ, Kim YH, Park DW, et al. Randomized Trial of Stents Versus Bypass Surgery for Left Main Coronary Artery Disease. N Engl J Med 2011;364:1718-27.
3. Giustino G, Serruys PW, Sabik JF 3rd, et al. Mortality After Repeat Revascularization Following PCI or CABG for Left Main Disease: The EXCEL Trial. JACC Cardiovasc Interv 2020;13:375-87.
4. Milojevic M, Head SJ, Parasca CA, et al. Causes of Death Following PCI Versus CABG in Complex CAD: 5-Year Follow-Up of SYNTAX. J Am Coll Cardiol 2016;67:42-55.

Clinical Topics: Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Stable Ischemic Heart Disease, Atherosclerotic Disease (CAD/PAD), Aortic Surgery, Cardiac Surgery and SIHD, Interventions and Coronary Artery Disease, Chronic Angina

Keywords: Cardiac Surgical Procedures, Coronary Artery Disease, Percutaneous Coronary Intervention, Angina, Stable, Taxus, Sirolimus, Sample Size, Drug-Eluting Stents, Control Groups, Constriction, Pathologic, Prospective Studies, Follow-Up Studies, Conflict of Interest

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