December 12, 2019
EXCEL Investigators Issue Detailed Response to BBC and EACTS Claims on Trial Conduct and Data Interpretation
December 12, 2019—Gregg W. Stone, MD, et al on behalf of the EXCEL leadership issued a response to the recent news reports and society statements questioning the conduct and data of the EXCEL trial.
EXCEL compared coronary artery bypass graft (CABG) surgery with percutaneous coronary intervention (PCI) in patients with left main coronary artery disease (LMCAD). The EXCEL investigators had concluded that there was no significant difference in patient outcomes, regardless of which treatment option was used.
The EXCEL investigators stated that a “misleading narrative” was engendered by certain members of the cardiovascular surgical community; broadcast in a BBC Newsnight program; and promulgated by European Association for Cardiothoracic Surgery (EACTS) withdrawing from guidelines—"without so much as even asking the EXCEL study group for clarification.”
As reported on December 9 by Cardiac Interventions Today, the EACTS issued a statement after consideration of a report criticizing the EXCEL trial by the United Kingdom’s BBC Newsnight. The BBC Newsnight report called into question the methods and conclusions of the EXCEL trial. One key issue is that the definition of myocardial infarction (MI) used in the EXCEL trial differed from the Universal Definition of Myocardial Infarction ("Universal Definition").
EACTS advised it was withdrawing its support for the current guidelines related to myocardial revascularization for LMCAD that were informed by the EXCEL data. The guidelines were established jointly by EACTS and the European Society of Cardiology (ESC) with the special contribution of the European Association for Percutaneous Cardiovascular Interventions (EAPCI). The 2018 EACTS/ESC clinical guidelines for myocardial revascularization were published by Franz-Josef Neumann, MD, et al in the European Heart Journal (2019;40:87–165).
In contrast to EACTS, the ESC rejected the BBC report's claim that the guidelines may have caused harm to patients and stands by the guidelines, which ESC says were based on more than the EXCEL trial. Additionally, the Society for Cardiovascular Angiography and Interventions (SCAI) countered the findings of the BBC report and disagreed with the EACTS' action. The SCAI continues to endorse the European and United States treatment guidelines.
As summarized in their response, the EXCEL investigators address the following issues and claims:
- Choice of the procedural MI definition. EXCEL investigators response in brief: “It was agreed by all involved (including surgical colleagues) that the Universal Definition was not suitable because of ascertainment bias, different criteria for PCI and CABG, and lack of demonstrated correlation with prognosis. The protocol definition of procedural MI that met these criteria was thus selected and agreed to by unanimous consent.”
- The protocol MI definition changed. EXCEL investigators response in brief: “This is absolutely incorrect—the principal definition of MI never changed throughout the course of the trial.”
- The rate of procedural MI according to Universal Definition has been deliberately withheld. EXCEL investigators response in brief: “Procedural MI according to Universal Definition was listed in the protocol as one of approximately 35 exploratory secondary endpoints. This definition is based on troponins, the collection of which was optional in EXCEL and was unfortunately infrequently performed. Thus, reporting procedural MI rates according to Universal Definition was not possible. An exploratory attempt was made to assess procedural Universal Definition of Myocardial Infarction rates using troponins in some patients and CK-MB measures in others. However, this is not scientifically sound given the different sensitivities of these assays. EXCEL has published data that the protocol definition of MI was strongly correlated with subsequent mortality within the trial, whereas smaller biomarker elevations (as included in the Universal Definition criteria) would not have been prognostic. And until these recent events there had been no requests from any source to prioritize reporting procedural MI according to Universal Definition. Thus, there was absolutely no attempt to withhold meaningful data. Nonetheless, EXCEL commits to publish a future manuscript reporting the rates and implications of MI according to numerous definitions, including the Universal Definition using CK-MB data.”
- The all-cause mortality data from EXCEL was not strongly enough emphasized. EXCEL investigators response in brief: “All-cause mortality was a secondary underpowered endpoint and the modest difference noted between groups was not adjusted for multiplicity and is therefore statistically uncertain. In addition, it has no biological basis given that the clinical events committee adjudicated the excess to be principally due to sepsis and cancer occurring years after randomization. Meta-analyses of 4,394 patients from four trials of drug-eluting stents versus CABG (including EXCEL) show there is no difference in 5-year mortality between PCI and surgery for left main disease. Even longer-term data (10-year follow-up from the SYNTAX trials) shows no difference in mortality. The distinction between all-cause mortality and cardiovascular mortality (which was very similar between PCI and CABG in EXCEL) was unfortunately not mentioned in the broadcast.”
- The DSMC raised concerns that were not adhered to. EXCEL investigators response in brief: “The independent Data Safety and Monitoring Committee (DSMC) met frequently to review unblinded EXCEL data, each time recommending that the study continue as planned without modification.”
- The ESC/EAPCI/EACTS guidelines are unsafe. EXCEL investigators response: “Guidelines are made on summated evidence from multiple trials and data input by independent experts in the field. The existing guidelines which EXCEL helped to inform suggest stenting may be considered as a treatment for selected patients with left main stem coronary disease.”
In closing, the EXCEL investigators stated:
“A large academic study group consisting of prominent surgeons, interventional cardiologists, general cardiologists, statisticians and two academic research organizations drove EXCEL, a trial that has consumed > 10 years, and which we believe sets a new standard for cooperation between the cardiac surgical and interventional cardiology subspecialties in a search for the truth to improve outcomes of patients with coronary artery disease.
“Every important study raises new questions, and some of the findings will rightfully foster scientific debate – such deliberations are healthy, and we openly welcome this from all informed parties.
“To suggest, however, that hundreds of EXCEL investigators, including cardiologists, surgeons, statisticians, and entire academic research organizations conspired to change definitions or withhold important study findings is offensive and without merit. Specifically, the surgical instigator of these concerns has now retracted several of his original grievances as being unfounded – whether his original statements were intentional mistruths or unintentional errors and exaggeration is not for us to speculate. We are equally concerned that journal editors, leaders of societies, social media followers, broadcasters, and others appear to accept one-sided declarations without requesting a full accounting of the facts.
"Regardless of the motivations and actions of others, the EXCEL leadership will continue to exercise the highest scientific principles and ethics of our profession.”