The authors reply [to: Everolimus-Eluting Stents or Bypass Surgery for Left Main Coronary Disease]

Belley-Côté et al. question the noninferiority margin in the EXCEL trial. The margin should be selected to support a reasonable conclusion of therapeutic interchangeability between the test and control treatments,1 and in an active controlled trial, the margin may be based on a putative placebo or expert consensus of the minimal clinically important difference.2 Trial feasibility often necessitates composite end points. The cardiology and surgical leadership in the EXCEL trial unanimously agreed that death, stroke, and large MI are clinically important end points and that a margin of 4.2 percentage points was acceptable. An examination of the absolute 95% confidence intervals of the 3-year difference with respect to the primary end point in the EXCEL trial (which accounts for the number of patients enrolled) shows that PCI may range from 2.7 percentage points better to 4.0 percentage points worse than CABG for treatment of left main disease, with a Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score of 32 or lower (the SYNTAX score reflects a comprehensive angiographic assessment of the coronary vasculature, with 0 as the lowest score and higher scores [no upper limit] indicating more complex coronary anatomy).
Both Belley-Côté et al. and Christiansen et al. question the appropriateness of the EXCEL protocol definition of MI. Our MI definition represents extensive myonecrosis, which has been strongly associated with subsequent death in patients who underwent PCI and patients who underwent CABG3 and avoids ascertainment bias. Periprocedural MI, as defined in the EXCEL trial, was significantly associated with death at 3 years in patients who underwent PCI (hazard ratio, 3.04; 95% confidence interval [CI], 1.39 to 6.63) and in patients who underwent CABG (hazard ratio, 2.44; 95% CI, 1.10 to 5.40), which justifies its inclusion in the composite outcome. We disagree with Christiansen et al. that repeat revascularization (which favored CABG) deserves equality with death, stroke, and large MI as a primary end-point event. Repeat revascularization is of no greater clinical consequence than many other adverse outcomes that favored PCI, such as major bleeding, renal failure, arrhythmia, or serious infection. Comparisons between the EXCEL trial and NOBLE4 are problematic because a relatively thick-strut stainless steel stent was used in NOBLE; the rate of thrombosis among the patient who received this stent in NOBLE was 4 times as high as that among the patients who received the everolimus-eluting stent used in the EXCEL trial. Moreover, in NOBLE, periprocedural MI was not routinely assessed, and a higher rate of stroke was observed in association with PCI than with CABG, which could not be explained.
Finally, Belley-Côté et al. implicate undue industry influence in the design of the EXCEL trial. Our hypotheses and end points were developed by a large group of practicing interventional cardiologists and cardiac surgeons (with guidance from the Food and Drug Administration) and were not prejudiced by the sponsor.