VARC-3 Sets Goalpost for Future Aortic Valve Trials

Patrice Wendling

April 27, 2021

The newly updated Valve Academic Research Consortium 3 (VARC-3) definitions and endpoints proposed for transcatheter and surgical aortic valve replacement (TAVR/SAVR) research aim to add more granularity and a patient focus to a rapidly evolving field, the authors say.

Work began in 2016 to update definitions in the document to be more contemporary, as TAVR matured over the last 10 years to include younger, lower-risk patients and began moving to long-term outcomes, lead author Philippe Généreux, MD, told | Medscape Cardiology.

"The main change in VARC-3 is really that we tried to define not only procedural outcome, both for TAVR and aortic valve replacement performed by surgery, but also more the long-term outcomes mainly based on the patient — so quality of life, bioprosthetic valve failure, how do we define a valve failure, and also the need for rehospitalization," he said.

However, soon after the VARC-3 document was published on April 19 in the European Heart Journal (EHJ) and Journal of the American College of Cardiology (JACC), surgeons took to social media to highlight the writing committee's financial ties to industry and to suggest some definitions were shaped to favor transcatheter approaches.

"There's no doubt that the coauthors who participated in these guidelines are experts; nobody would argue about that but what we can argue, and I'm 100% sure about, is that we have experts outside the payroll of industry who are excellent and can be part of this guideline drafting in an unbiased way," Victor Dayan, MD, adjunct professor of cardiac surgery, National Institute of Cardiac Surgery, Montevideo, Uruguay, said in an interview.

Although the American College of Physicians recommends guideline committee members with moderate- or high-level conflicts of interest recuse themselves from authorship, he noted that one author has received more than $2 million in fees from industry in the past 4 to 5 years.

In all, 20 of 23 authors were involved in PARTNER, SURTAVI, and PORTICO, and several also write clinical guidelines for the American College of Cardiology (ACC) and American Heart Association (AHA). "So we have the same authors that are judge, jury, and attorney for these issues," Dayan said.

Commenting to | Medscape Cardiology, J. Rafael Sádaba, MD, PhD, interim secretary general for the European Association for Cardio-Thoracic Surgery (EACTS), pointed out that only three committee members are surgeons and that author disclosures took up nearly a full page of the document. "Surely they would be able to find very capable physicians with far less conflicts of interest."

Sádaba said the question to him is why professional societies like ACC and AHA don't define the endpoints for the clinical trials that will inform their guidelines.

"One could say these people are there because they're good scientists, trialists, but one at least has to ask why is this happening. Why are these people setting the rules for the trials they're running?" said Sádaba, of the Royal Navarre Hospital, Pamplona, Spain.

Généreux dismissed the Twitter comments as coming from a handful of people who engage in conspiracy theories. The VARC-3 document, he said, was created with input from 75 experts, including US Food and Drug Administration (FDA) officials, and the final document was reviewed by the FDA and underwent rigorous peer review prior to publication.

"The question is: do you believe there is bias when people are involved in studies driven by the industry? Well, this is where we derive our science in this field," he said. "We are very transparent and disclose our conflicts of interest [COI]."

Commenting further, Généreux added, "this was a very well-balanced group and to imply that because we work with industry, we don't have the best interest of the patient in mind is wrong."

Editor-in-chief of the EHJ, Filippo Crea, MD, PhD, Catholic University, Rome, said in an email that "it is not surprising that most of the authors have experience in TAVR trials. All of the authors have carefully disclosed their COIs."

He noted that the EHJ and JACC copublished the first VARC consensus in 2011, VARC-2 one year later, and that VARC-3 was reviewed by four external reviewers and two editors and was accepted for publication after two revisions.

Asked about a shot on social media that the EHJ had long ago "sold its soul" to be the scientific "arm" of industry, Crea said allegations need to be substantiated by facts.

"The wide adoption of VARC definitions implies that they have been well accepted by the scientific community and that they have stood the test of time," Crea said. "EHJ has a history of publishing high-quality science. We welcome robust arguments that may challenge previously published work. Readers who perceive gaps are encouraged to provide a detailed challenge and engage with the journal."

Defining Hospitalizations

One of the surgeons' biggest concerns is that VARC-3 now defines hospitalization or rehospitalization as "any admission after the index hospitalization or study enrolment" for at least 24 hours, including an emergency department stay.

VARC-2 and SURTAVI defined hospitalizations as those for valve-related symptoms or worsening heart failure, whereas the newly reformulated definition of hospitalization was part of the main composite endpoint in the PARTNER-3 trial, along with stroke and mortality, that drove the superiority of TAVR over SAVR at 1 year for low-risk patients, Dayan noted.

"It's not uncommon for patients who have cardiac surgery to come back for issues related to wound healing or mild pulmonary edema for a day or two, and if you include these hospitalizations in the primary endpoint, it will dilute the real benefit of SAVR versus TAVR, which is mortality and stroke," he added.

In choosing the broader definition, Généreux said they borrowed from heart failure studies that take a granular approach and account for every hospitalization, be it for a medication change or adjustment. "We cannot pick and choose which hospitalization we are going to consider or ignore."

VARC-3 proposes criteria for identifying and diagnosing hypoattenuated leaflet thickening (HALT) and reduced leaflet motion and features a detailed chart of the new classification scheme for bioprosthetic valve dysfunction and failure.

Bioprosthetic valve dysfunction includes structural valve deterioration, nonstructural valve dysfunction (including abnormalities not intrinsic to the valve such as paravalvular regurgitation or prosthesis–patient mismatch), thrombosis, and endocarditis. VARC-3 proposes a five-class grading system for paravalvular regurgitation (mild, mild–moderate, moderate, moderate–severe, severe).

The document updates what the authors call a "previously vague definition" of valve thrombosis proposed in 2011 to now include "clinically significant" prosthetic valve thrombosis. This requires clinical sequelae of a thromboembolic event (stroke, transient ischemic attack, retinal occlusion, or other evidence of thromboembolism) or worsening valve stenosis/regurgitation and either hemodynamic valve deterioration stage 2 or 3 or confirmatory imaging (CT evidence of HALT or transesophageal echocardiographic findings). In the absence of symptoms/clinical sequelae, valve thrombosis (subclinical) can be diagnosed if there is hemodynamic valve deterioration stage 3 and confirmatory imaging.

Bioprosthetic valve failure is divided into three stages, with stage 1 taking into account clinical factors along with valve dysfunction, stage 2 being reintervention, and stage 3 being valve-related death.

"For us, bioprosthesis valve failure is not only the need for reintervention, but it's also mortality, it's also a significant increase in gradient or the occurrence of paravalvular leak," said Généreux, of the Morristown Medical Center, New Jersey. "So it's much more clinical."

Stroke, Myocardial Infarction

VARC-3 provides detailed definitions of neurologic events and, in an attempt to harmonize with the Neurologic Academic Research Consortium, recommends combining assessment of neurologic symptoms with tissue-based criteria (pathology or neuroimaging, ideally diffusion-weighted MRI) to define stroke and other central nervous system injury.

It also recommends that assessment be performed 30 to 90 days after a neurologic event and that assessment of neurologic deficits for cerebral embolic protection trials be performed by a neurologist.

VARC-3 endorses the fourth Universal Definition of Myocardial Infarction for MI types 1 to 3, 4B, and 4C.

For periprocedural MI after percutaneous coronary intervention (PCI), coronary bypass graft surgery, TAVR, and SAVR, however, it endorses the modified Society for Cardiovascular Angiography and Interventions (SCAI) and Academic Research Consortium-2 definition, which uses troponin or creatine kinase-MB thresholds.

"Given that most current and future studies related to AVR strategies will involve long-term follow-up, with patients frequently suffering from coronary artery disease, VARC-3 believes that these definitions will allow the most appropriate characterization and classification of types of MI occurring in this population," the committee writes.

The decision comes after last year's controversy surrounding the Abbott-sponsored EXCEL trial, which used a modified version of the SCAI definition for periprocedural MI as part of its primary composite endpoint of death, stroke, and MI.

Initial reports showed nearly twice the rate of periprocedural MI with cardiac surgery as with PCI, but after a BBC investigation involving leaked data and an onslaught of criticism from surgeons, later results using the third universal definition showed surgery had the advantage.

The debacle frayed relations between surgeons and interventionalists and prompted EACTS to withdraw its support for treatment recommendations for left main coronary artery disease.

Dayan applauded VARC-3 for incorporating more detailed information on stroke and neurologic events, but said the use of the SCAI definition in the final published document is in "total disregard" to the controversy generated among surgeons and interventionalists.

"The main concern for surgeons is defining periprocedural MI just by biochemical definitions, without any additional criteria like ECG, angiographic," he said. "This is totally new and goes against what surgeons have been advocating for years around EXCEL."

Sádaba was troubled by the definitions of MI and hospitalization, but also questioned other changes, like lumping vascular complications together with access-related complications. "The sense is a lot of what they've put here favors one type of intervention over the other."

Généreux reports he has received consultant fees from Abbott Vascular, Abiomed, Boston Scientific, Cardinal Health, Cardiovascular System Inc., Edwards Lifesciences, Medtronic, Opsens, Siemens, SoundBite Medical Solutions, Sig.Num, Saranas, Teleflex, Tryton Medical, and has equity in Pi-Cardia, Sig.Num, SoundBite Medical Solutions, Saranas, and Puzzle Medical. Disclosures for coathors appear in the paper. Crea reports personal fees from Novartis, BMS, Amgen, and AstraZeneca, and is a member of the advisory board of GlyCardial Diagnostics. Dayan and Sádaba report no relevant conflicts of interest.

J Am Coll Cardiol. Published online April 19, 2021. Full text

Eur Heart J. Published online April 19, 2021. Full text

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