EXCEL Debate: A Challenger Pushes Back, Societies Wade in Deeper

December 24, 2019

Thoracic surgery societies on both sides of the Atlantic have released new statements on a continuing controversy dogging the EXCEL trial, one that has fueled a highly public war of words over the how the study was conducted, interpreted, and reported by its investigators.

In a statement dated December 19, the European Association for Cardio-Thoracic Surgery (EACTS) offers new details on why it withdrew its endorsement of the 2018 EACTS-European Society of Cardiology (ESC) clinical guidelines section covering left-main coronary disease.

That part of the guideline had relied in part on 3-year outcomes from EXCEL, which were published in the New England Journal of Medicine in 2016 and are central to the ongoing dispute. The trial in essence was a comparison of percutaneous coronary intervention (PCI) and coronary bypass surgery (CABG) in left-main disease.

The new statement, signed by the society's secretary general Domenico Pagano, MD, also calls for a new EACTS-ESC evidence review and development of updated recommendations for left-main disease "as a matter of urgency."

For its part, the ESC had earlier declared its continuing support for the full guideline but hinted that might change pending further details on EXCEL yet to be made public.

The EACTS statement follows the society's earlier announcement, previously covered in detail by theheart.org | Medscape Cardiology, that it would pull support of the guideline section on left-main disease in response to a December 9 news report from BBC Newsnight that was critical of the EXCEL trial's conduct.

The news story made a number of allegations regarding the interpretation and reporting of EXCEL based largely on unpublished data it had obtained through unofficial channels.

Key among them, also as previously reported, was that reanalysis of myocardial infarction (MI) outcomes using the Third Universal Definition of MI, rather than the primarily enzymatic definition on which the reported outcomes were based, substantially raised the MI count in the PCI group compared with those who had CABG.

The data for that alternative analysis, which had not been publically reported, seemed to recast the published EXCEL primary outcome from one of parity for PCI and CABG in left-main disease to one that significantly favored CABG, notes the BBC Newsnight story.

Also as previously noted by theheart.org | Medscape Cardiology, the news story claimed that EXCEL investigators had promised to publicly release the trial's data based on the Third Universal Definition of MI, but had not done so, and had not adequately heeded concerns raised by its Data Safety Monitoring Board (DSMB) over signs of an apparently increased mortality risk from PCI.

Another Society Weighs In

The unreported data and other issues have led the American Association for Thoracic Surgery (AATS) to issue a statement acknowledging the possibility of misguided treatment recommendations, and therefore patient care, stemming from incomplete reporting of EXCEL.

If there are serious concerns about the "presentation or interpretation" of clinical trials, "then the best way forward is the public release of all trial data for an independent analysis to confirm that the original trial conclusions are valid," says the statement, signed by AATS president Vaughn A. Starnes, MD, and secretary David R. Jones, MD.

"The AATS agrees with others that all of the data should be made publicly available for analysis and interpretation, as a way to resolve the current controversy around the EXCEL trial, in order to provide patients with the best possible counsel and informed consent," it states.

The BBC Newsnight story "raised legitimate questions regarding what data was/was not presented to the other EXCEL investigators and to [the] ESC/EACTS guideline committee, and what, when, and to whom were safety warnings raised by the DSMB," David Taggart, MD, PhD, told theheart.org | Medscape Cardiology by email in response to a query.

"Until these issues are resolved, both EACTS and AATS have expressed concerns about what has happened and, most importantly, the potential implications for patient safety. This stance underpins their sincerity that patient safety, genuine informed consent, and scientific integrity are amongst their highest priorities. Consequently they have my complete support," said Taggart, of University of Oxford, United Kingdom, a former EXCEL trialist who has been among the most vocal critics of how the EXCEL leadership has interpreted and reported the trial's outcomes.

"Personally, I do not feel that the current controversy over the EXCEL trial will be resolved until there is full and independent reanalysis of its data. I feel that this would be absolutely crucial in reassuring our patients, the wider medical community, and the general public of the validity of current recommendations."

An EXCEL principal investigator and prominent public voice for the trial, Gregg W. Stone, MD, Icahn School of Medicine at Mount Sinai, New York City, has not responded to theheart.org | Medscape Cardiology requests for comment on the new society statements.

Point-Counterpoint

As previously reported, allegations about EXCEL in news reports and the sometimes fiery public debate led the trialists to release a long and wide-ranging public communiqué that forcefully disputes the charges. Among them, that they were either remiss or willfully deceptive in not reporting an analysis based on the Third Universal Definition of MI.

In response, Taggart provided theheart.org | Medscape Cardiology with a toughly worded statement that disputes the EXCEL leadership's missive nearly point by point. It variously describes the assertions as "simplistic," seemingly "illogical," "disingenuous," and "factually completely incorrect," among other terms.

The document provides Taggart's perspective on how MI was defined and interpreted while he was an active member of the EXCEL trial's leadership, and alleged shortfalls in how outcomes were interpreted and reported.

In it, Taggart also wonders whether or not EXCEL leadership had possibly been aware of a tilt favoring CABG in the analysis based on Third Universal Definition of MI but "decided to supress it," and also whether the trial's sponsor, Abbott Vascular, had influenced the trial's conduct.

Despite the EXCEL leadership's communiqué, "my profound concerns remain the same and, in my opinion, the very long rebuttal response by the EXCEL investigators does not adequately respond to the core issues," Taggart writes.

He withdrew his name as an author on the trial's 5-year outcomes publication, Taggart says, because "I believed, and still do, that the final interpretation of the actual data in the [New England Journal of Medicine] manuscript did not appropriately reflect its clinical reality, and especially with regards to mortality, and would therefore have potential to do real harm to patients."

Taggart has disclosed no relevant financial relationships.

Follow Steve Stiles on Twitter: @SteveStiles2. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook

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