European Left Main Guidelines in Disarray After EXCEL Cover-up Alleged

Patrice Wendling

December 11, 2019

The European Association for Cardio-Thoracic Surgery (EACTS) has withdrawn support for its left main coronary artery disease recommendations following an exposé by BBC Newsnight alleging key data from the EXCEL trial were concealed.

Joint EACTS and European Society of Cardiology (ESC) guidelines for myocardial revascularization were updated in 2018 based partly on 3-year data from EXCEL. The data showed no difference in risk for the primary endpoint of death, myocardial infarction (MI), or stroke between percutaneous coronary intervention (PCI) and coronary artery bypass surgery (CABG) in patients with left main lesions of low to intermediate anatomic complexity.

Citing leaked "unpublished" data, however, Newsnight reported this week that under the Third Universal Definition of MI, the rate of MIs was 80% higher among patients who had undergone PCI rather than surgery.

Further, the report notes that the investigators failed to fulfill a promise to make public the Universal MI data and downplayed concerns about a higher mortality rate with PCI that were raised by the trial's data safety monitoring board while the guidelines were being written.

"It is a matter of serious concern to us that some results in the EXCEL trial appear to have been concealed and that some patients may therefore have received the wrong clinical advice," EACTS secretary general Domenico Pagano, MD, wrote in a statement.

Following consideration of the Newsnight analysis, the EACTS council unanimously decided, with immediate effect, to withdraw support for the left main chapter of the 2018 EACTS-ESC clinical guidelines.

The guidelines had kept a class Ia recommendation for CABG in all patients with left main disease regardless of anatomic complexity, but upgraded PCI to a class Ia indication for patients with a low SYNTAX score and gave a class IIa and III recommendation for those with intermediate and high SYNTAX scores.

"If the information on the trial is proven to be correct, the recommendation is unsafe," Pagano said.

Guideline committee member Professor Nick Freemantle, MD, told Newsnight he would "never" have agreed the treatments were interchangeable if he had seen the leaked data.

ESC, however, told Newsnight it stands by its guidelines. Commenting in a statement to | Medscape Cardiology, ESC says its guidelines were based on the "totality of peer-reviewed, published data available at the time" and learned in the past few days that there may be "additional findings" from one study not included in the original publication or shared with the ESC or its guidelines task force.

A review is planned with their surgical colleagues at EACTS and "will begin as soon as we can obtain the additional data," ESC communications director John McKenzie said.

The leaked data was shot down as "fake information" by the EXCEL trialists, according to Newsnight.

A statement on the findings will be forthcoming in a day or two, EXCEL investigator Gregg Stone, MD, Icahn School of Medicine at Mount Sinai, New York City, told | Medscape Cardiology.

Just weeks ago, Stone and colleagues vehemently denied accusations by one of their own executive committee members who publically said the data had been "manipulated," using a changed definition of MI, to try and prove no difference between PCI and surgery for the primary composite endpoint.

As reported at the time, David Taggart, MD, PhD, University of Oxford, United Kingdom, who resigned from the trial, also alleged that a higher risk for all-cause mortality with PCI was downplayed in the recently published 5-year results.

Rod Stables, BMBCh, Liverpool Heart and Chest Hospital, United Kingdom, who served as an EXCEL investigator, told | Medscape Cardiology that Taggart was "barking up the wrong tree" and that the "design of the trial, the composite, was noble, positive, scientific, informative, and to be applauded."

The real issue, he suggests, is that the secondary outcome of MI rates per universal definition has not been reported, as specified in the protocol.

"If the BBC's claims are to be believed, they have obtained a copy of the trial database at 3 years and have run analyses on it, which they believe have proved it credible and matches all the results one might expect in the published arena, and that contained within that database is the MI rate by universal definition," Stables said. "And, as you've seen reported in the public arena, they believe that the result that emerges favors surgery and that this would have impacted, I believe, the way the overall trial package of results would have been interpreted.

"Of course the covert accusation, which I suspect they are making — but I'm not making — is that in some way this secondary measure has been deliberately suppressed."

It's possible that the MI data was incomplete or the data collection tools insufficient to adjudicate MI by the universal definition, suggested Stables, also a clinical lead for research at the British Heart Foundation.

The EXCEL protocol used a version of the Society for Cardiovascular Angiography and Interventions (SCAI) definition for periprocedural MI and the "universal definition" for spontaneous MIs, which does not include enzymatic criteria such as those in the SCAI definition.

While Stables has not seen the leaked data, he stressed that a key takeaway from EXCEL is not that "the left main is in some way a special case" but the importance of calculating the SYNTAX score before choosing PCI or CABG.

"I suspect that the findings of the trial will mirror SYNTAX and the various meta-analyses by suggesting that in a patient who has more complex disease, especially if they have diabetes, then there is genuine and worthwhile advantage with surgery," he said.

In a statement released yesterday, SCAI officials said its definition of MI has been used in multiple clinical trials because it "avoids the pitfall of tabulating MI events that are small enough to have little clinical impact" and, instead, permits assessment of MI events "likely to be clinically relevant." Although 5-year follow-up data show all-cause mortality remains higher for PCI-treated patients (13% vs 9%), there was no difference in cardiovascular death (5% vs 4.5%), they noted.

"SCAI respectfully disagrees with EACTS regarding EXCEL," the statement says. "While all-cause mortality is an important endpoint to follow, the EXCEL trial was neither designed nor powered to assess differences in this endpoint. Lethal differences in treatment effectiveness would be expected to manifest as differences in cardiovascular death rates; while this was also an unpowered observation, the lack of any difference in definite cardiovascular death at 5 years is reassuring."

They go on to say, "SCAI endorses the guidelines in Europe and the United States that support use of coronary stents for treatment of left main coronary artery disease in appropriately selected patients."

In a statement shared with | Medscape Cardiology, the British Heart Foundation said the EXCEL results only apply to patients with left main coronary disease and appeared to minimize concerns patients may have about the leaked data.

"It's important that all clinical trials are reported on and communicated in an open and transparent way, as they help doctors to decide, using the latest evidence, which treatments are best for each individual patient," said BHF associate medical director Sonya Babu-Narayan, MD.

"People who have undergone heart surgery in the past should not be concerned by these findings, as we know that both stents and bypass grafts are effective treatments."

EXCEL was sponsored by Abbott Vascular. Disclosures for the authors of the EXCEL 5-year report are available at Stables reports advisory board and educational support from Abbott within the last 5 years.

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