EXCEL Leaders Answer Back After BBC Exposé

Patrice Wendling

December 13, 2019

Allegations that the EXCEL investigators concealed key data and downplayed a longer-term mortality increase for patients treated with percutaneous coronary intervention (PCI) vs surgery were met with a fierce 11-page rebuttal signed by 11 members of the trial's leadership.

BBC Newsnight alleged earlier this week that the rate of myocardial infarction (MI) was 80% higher if left-main coronary lesions were treated with PCI rather than surgery when assessed under the Universal Definition of MI — a secondary outcome the trialists have not yet reported.

This prompted the European Association for Cardio-Thoracic Surgery (EACTS) to withdraw support for its left main recommendations in clinical guidelines developed with the European Society of Cardiology, although the ESC stood fast behind the guidelines.

The debate in news reports and on social media appeared similarly divided — often along surgical/interventional lines — about the suggestion of wrongdoing and whether the universal MI analysis would have changed the trial's primary finding of no difference between PCI and surgery for the composite of all-cause death, MI, or stroke. Still, the notoriously critical cardiosphere also included tweets lamenting the "sensationalist" discussions around EXCEL and calling for a return to science for the benefit of patients and healthcare professionals alike.

Scientific debate over study findings among informed parties is healthy, the EXCEL leadership wrote in their statement; "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."

They say that "reporting procedural MI rates according to Universal Definition was not possible" because it is based on the collection of cardiac troponins, which was optional in the trial and done in only a minority of patients because of cost considerations. Further, 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 [coronary artery bypass grafting], and lack of demonstrated correlation with prognosis."

David Taggart, MD, PhD, University of Oxford, United Kingdom, who withdrew his authorship from the 5-year EXCEL publication, said the trialists agreed, because of a legitimate concern over ascertainment bias, to use the previously untried and untested Society of Cardiovascular Angiography and Interventions (SCAI) definition of MI in addition to the Universal Definition (UD).

"The importance of the UD was a 'safety check' to allow comparison of these two definitions of MI within the EXCEL trial and against other trials," he told theheart.org | Medscape Cardiology via email. "However, at no time was there any agreement NOT to also present the protocol-specified UD. If so, why was the protocol not updated accordingly?"

The leadership's claim that the UD data could not be presented is "completely erroneous," Taggart asserts, because the UD definition states that creatine kinase-MB (CK-MB) values are the best alternative when troponins aren't available. "As we had that data, the question remains, Why was it not published?"

The EXCEL leaders explain that an exploratory attempt was made to assess procedural UD MI rates using troponins in some patients and CK-MB values in others. "However, this is not scientifically sound given the different sensitivities of these assays." The protocol definition of MI also strongly correlated with mortality in the trial, whereas smaller biomarker elevations included in the UD MI definition would not have been prognostic.

Although there was "absolutely no attempt to withhold meaningful data," the EXCEL leadership said they "commit to publishing a future manuscript reporting the rates and implications of MI according to numerous definitions, including the UD using CK-MB data."

Taggart said the UD data is absolutely vital because a paper reported last year in the journal Circulation that the new SCAI definition appeared to increase the incidence of MI fivefold in the CABG group and decrease it threefold in the PCI group. "This had a very real potential to change the primary composite outcome," he said. "Until this data is published, I feel that we need to be extremely cautious about interpreting the primary composite endpoint of EXCEL as 'no difference.' "

In the BBC report, at least one guideline writer said he would never have agreed the treatments were interchangeable if he had seen the leaked data. EACTS officials also expressed concern that as a result of the missing data, patients may have received the wrong clinical advice.

Underplayed Mortality Risk

The BBC Newsnight report also includes claims that emails from the trial's data safety monitoring committee (DSMC) raised concerns about a higher mortality rate among PCI-treated patients when the EACTS/ESC guidelines were being updated in 2018. They also reiterate concerns raised initially by Taggart that this risk was not given sufficient prominence in the 5-year results reported recently in the New England Journal of Medicine (NEJM).

The EXCEL leadership noted in the statement that all-cause mortality was a secondary, underpowered endpoint and that the "modest difference" between groups was not adjusted for multiplicity. It also lacked a logical basis given that the clinical events committee adjudicated the excess to be primarily as a result of sepsis and cancer.

They also point out there was no difference in mortality between drug-eluting stents and surgery at 5 years in 4394 patients in meta-analyses of four trials, including EXCEL, or at 10 years in SYNTAX, the only trial with longer-term follow-up.

However, speaking to theheart.org | Medscape Cardiology, John McMurray, MD, University of Glasgow, Scotland, pointed to a meta-analysis of 11,518 patients in 11 randomized trials that gives a clear mortality benefit to surgery over PCI.

"No matter what way MI was defined early after surgery, in my view, it is a biochemical change and not a clinical event as we usually diagnose an MI," he said. "It is hard to accept that the early excess risk of MI after CABG, defined in this way by just a biomarker change, outweighs death in importance and, later MI — true MI was less common after CABG."

There is, however, another major consideration — patient choice, he said. Patients may still make a fully informed decision to opt for PCI rather than CABG, knowingly sacrificing a small survival advantage, because they simply don't want open-heart surgery. Also, the survival benefit of surgery is a long-term benefit, with an early excess risk of death with surgery and the survival curves crossing over only after about a year.

"You probably need to have a life expectancy of at least 2 years, and maybe ideally at least 5, to realize the survival benefit of surgery," McMurray said via email. "So if you or your doctor don't think you have long to live, choosing surgery might not be such a good idea. Therefore, it is important to think about all of this from two perspectives — what the data show and how the data are used to inform joint decision-making and choice."

The difference in death rates was not 'modest' as asserted by the trialists, but both clinically and conventionally statistically significant (odds ratio, 1.38; 95% confidence interval, 1.03 - 1.85), Taggart said. "In my view, it was particularly concerning that the accelerating divergence in death at 5 years was not specifically discussed in the manuscript, and especially considering that these were relatively young patients (mean age 66 years) with low or moderate disease.

"And, indeed, the initial NEJM review stated: 'The finding of a higher mortality rate in one group than another in a clinical trial (unless the difference is clearly trivial) should receive central emphasis in the report of the results, and we would generally consider it important to include such information in the concluding statement in the final paragraph.' It is still inexplicable to me why this did not happen in the final version of the manuscript," he said.

NEJM spokesperson Jennifer Zeis told theheart.org | Medscape Cardiology via email that the "mortality results were reported in the Results section of the 2019 report's abstract, as well as in the text and in the tables and figures" and that the "NEJM editors sought to ensure that information about endpoint definitions was fully explained."

Asked whether the NEJM editors had seen the UD data leaked to the BBC, Zeis said communications with authors are considered confidential. "We consider the published paper to be an accurate description of the trial findings."

Several cardiologists declined to comment for this story, including EXCEL investigator Gregg Stone, MD, Icahn School of Medicine at Mount Sinai, New York City, who said the trial leadership will not further debate the BBC exposé in the press or on Twitter.

Follow Patrice Wendling on Twitter: @pwendl. For more from theheart.org | Medscape Cardiology, join us on Twitter and Facebook

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