The EXCEL (Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial is the largest study comparing coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI) in the treatment of low-complexity left main disease. The 5-year outcomes have recently been published. The composite primary outcome occurred in 22.0% of the PCI patients and in 19.2% of the CABG patients (95% confidence interval, -0.9-6.5; p = 0.13), and the authors conclude that there is no significant difference between the two treatments.¹

However, in the EXCEL trial, there was a significant excess mortality in the PCI arm (13.0% vs. 9.9%, odds ratio 1.38 [1.03-1.85]). The authors attribute this difference to chance because no difference was found in definite cardiovascular deaths. Although we agree that the analysis is underpowered and there was no adjustment for multiple testing, the large difference in the most important outcome cannot be simply ignored, especially because adjudication of the cause of death in open-label trials is notoriously open to bias.²

In addition, in the EXCEL trial, perioperative myocardial infarction (MI) was a main driver of the primary outcome at 3 and 5 years, being in large part the cause of non-proportional hazards at 5 years and of the neutral results. In the EXCEL trial, the authors used an original definition that allows a purely enzymatic diagnosis of perioperative MI and increases by 100% the enzymatic threshold in the PCI group but not in the CABG group, clearly disadvantaging surgery. In fact, the rate of perioperative MI after surgery in similar trials that used the generally adopted universal definition were clearly lower: 1.7% in FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) and 2.9% in SYNTAX (Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery) versus 6.2% in the EXCEL trial.

It is important to highlight that 1) all the cardiac outcomes in the EXCEL trial (including non-periprocedural MI whose definition was not substantially modified) are in favor of surgery, and 2) although the main rationale provided by the authors for the definition used was the prognostic relevance of periprocedural MI, in the EXCEL trial, no excess death was found in the surgical group despite a significantly higher incidence of perioperative MI.

Other relevant considerations come into play when interpreting the EXCEL results. Unlike the homogeneous PCI treatment arm in which all patients received everolimus-eluting stents, the CABG arm has important variations that should be factored in. Approximately 30% of patients in the surgical arm of the EXCEL trial underwent off-pump CABG, which, compared with on-pump CABG, was associated with a significantly increased risk of 3-year all-cause mortality (8.8% vs. 4.5%; hazard ratio 1.94; 95% confidence interval, 1.10-3.41).³ In addition, despite guideline recommendations for multiarterial grafting,^4,5 only 24% of EXCEL patients received bilateral internal thoracic artery grafts, and fewer than 7% received radial artery grafts.⁶

In summary, the EXCEL results are to be interpreted with caution because of the study design features that disadvantage CABG. The modern-day CABG that achieves complete revascularization with multiarterial grafting remains a very competitive and durable therapy if not the gold standard intervention for patients with left main disease.

References

1. Stone GW, Kappetein AP, Sabik JF, et al. Five-Year Outcomes after PCI or CABG for Left Main Coronary Disease. N Engl J Med 2019;Sep 28:[Epub ahead of print].
2. Lauer MS, Blackstone EH, Young JB, Topol EJ. Cause of death in clinical research: time for a reassessment? J Am Coll Cardiol 1999;34:618-20.
3. Benedetto U, Puskas J, Kappetein AP, et al. Off-Pump Versus On-Pump Bypass Surgery for Left Main Coronary Artery Disease. J Am Coll Cardiol 2019;74:729-740.
4. Aldea GS, Bakaeen FG, Pal J, et al. The Society of Thoracic Surgeons Clinical Practice Guidelines on Arterial Conduits for Coronary Artery Bypass Grafting. Ann Thorac Surg 2016;101:801-9.
5. Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;124:e652-735.
6. Thuijs DJFM, Head SJ, Stone GW, et al. Outcomes following surgical revascularization with single versus bilateral internal thoracic arterial grafts in patients with left main coronary artery disease undergoing coronary artery bypass grafting: insights from the EXCEL trial. Eur J Cardiothorac Surg 2019;55:501-10.

Keywords: Odds Ratio, Taxus, Radial Artery, Confidence Intervals, Mammary Arteries, Drug-Eluting Stents, Coronary Artery Disease, Cause of Death, Percutaneous Coronary Intervention, Coronary Artery Bypass, Myocardial Infarction, Stents, Diabetes Mellitus

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