SAN FRANCISCO — In two forms of severe mitral valve disease with high rates of mortality and limited treatment options, multicenter trials with novel transcatheter devices produced what experts described as unprecedented symptom control and rates of survival. 

The two trials — one directed at severe mitral annular calcifications (MACs) and the other at inoperable severe mitral regurgitation — were conducted without a comparator arm because no meaningful benefit could be expected from alternatives, according to the principal investigators of each trial.

Highly selected for the severity of their mitral valve disease, the “very sick” patients enrolled in each of these studies represented “truly no-option populations,” said Roxana Mehran, MD, director of interventional cardiovascular research at Mount Sinai’s Icahn School of Medicine, New York, who was not involved in the studies.

Addressing Unmet Needs

SUMMIT-MAC, which tested Abbott’s Tendyne Transcatheter Mitral Replacement System in severe MAC, and ENCIRCLE, which tested Edwards Lifesciences’ Sapien M3 platform in severe mitral regurgitation, were presented at the Transcatheter Cardiovascular Therapeutics (TCT) 2025 meeting. 

The self-expanding Tendyne device, which was developed specifically for treating MAC, is delivered through a 36 Fr sheath for transapical implantation within the native mitral valve. The system was approved by the FDA earlier this year. The Sapien M3 device, which employs technology similar to aortic Sapien valves, is delivered transeptally and was developed for those unsuitable for transcatheter edge-to-edge mitral valve repair. It is available in Europe but not yet approved in the United State.

In SUMMIT-MAC, conducted at 37 sites in the United States and Canada, patients were required to have both severe MAC (≥ 1000 mm³) and severe mitral valve dysfunction defined as 3+ or higher mitral regurgitation with moderate or severe stenosis. The average MAC volume was 5679 mm³. A variety of comorbidities were common; 74% were in New York Heart Association (NYHA) functional class III or IV, and quality of life scores were low, the researchers reported. 

The primary endpoint was freedom from all-cause mortality and heart failure hospitalizations at 1 year with a performance goal of 43% based on natural history data. Far lower than predicted by baseline characteristics, only 21% had died at 1 year and only 30% had been hospitalized, leaving 60.4% free of either event and far exceeding the prespecified performance goal of 43% (P = .0002).

All patients had severe mitral regurgitation at baseline, but none had significant regurgitation at discharge from the hospital. At 1 year, 6% had 1+ regurgitation and 3% had 2+. The remaining 91% had no regurgitation, according to the investigators.

Both NYHA functional heart class and quality of life as measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ) improved immediately after device implantation and then progressively over follow up. Relative to the 74% in class III or IV heart failure at baseline, the proportions at 1, 6, and 12 months fell to 31%, 15%, and 13%, respectively. The KCCQ score climbed progressively from 49.2 at baseline to 69.8 at 12 months.

Mortality Rates Lower than Expected

The valve was successfully deployed in 99% of cases, and the procedure was considered a technical success in 94%, the researchers said. Nearly 7% of patients died in the first 30 days, but this figure was lower than that predicted by the baseline risk calculator from the Society of Thoracic Surgeons. The most common adverse event was bleeding of which 10% was fatal or considered life-threatening. 

Like SUMMIT-MAC, which was a pivotal multicenter trial to evaluate the Tendyne platform in MAC, ENCIRCLE was a pivotal multicenter trial to evaluate the SAPIEN M3 transseptal device in severe regurgitation. The study, which was published in The Lancet, involved 56 participating centers in North America, Europe, Asia, and Australia.

The 287 patients enrolled had grade 3+ or higher mitral regurgitation and were considered unsuitable for surgery or other transcatheter devices due to comorbidities or anatomical criteria, according to David D. Daniels, MD, an interventional cardiologist at the California Pacific Medical Center, San Francisco, who presented the results.

ENCIRCLE used the same primary composite endpoint of all-cause death or heart failure rehospitalization as SUMMIT-MAC, but it was expressed as events occurred rather than events avoided. The 25.2% of patients who experienced either event was nearly 50% lower than the prespecified performance goal of 45% (P < .0001).

From baseline, when 52.2% of patients had mitral regurgitation of grade 3+ and 47.7% had 4+, none had grade above 2+ at 30 days or 1 year. The proportion with no or trace regurgitation was 78.2% at 30 days and 79.3% at 1 year, Daniels’ group reported. 

Relative to the more than 70% of patients who were in NYHA class 3 or higher heart failure at baseline, only 20.8% had heart failure symptoms that severe at 30 days, and 35.1% had no symptoms. At 1 year, the figures were 12% and 40.3%, respectively. The KCCQ score climbed from 57 at baseline to 75 at 1 year.

By risk calculator, the expected 30-day mortality for mitral valve replacement in this population was 6.6% at baseline, according to Daniels. As a result, the observed 0.7% rate of 30-day mortality was approximately one-tenth of the predicted figure.

By 1 year, rates of stroke (9.3%) and device thrombosis (6.7%) were substantial, but Daniels noted that 18% of patients had already had a stroke when entering the trial. Inadequate anticoagulation was a factor, he noted, and when stratified by this variable, rates of stroke climbed from 7.1% to 12.5%. Rates of device thrombosis limbed from 5.2% to 8.7% in cases of inadequate anticoagulation.

Reflecting the effort to enroll patient with severe mitral disease with the greatest likelihood of benefit from these new devices, screen failure rates were high in both trials. Of 474 patients screened for SUMMITT-MAC, only 120 were deemed eligible and only 103 were treated. For ENCIRCLE, 1174 were screened, 299 were selected, and 287 received a device.

Still for eligible patients, these are “landmark studies,” according to Martin B. Leon, MD, director of the Center for Interventional Vascular Therapy at New York Presbyterian/Columbia University Irving Medical Center. Leon, who moderated the session during which both studies were presented, agreed each device addresses indications for which “there are really no other options.”

Mayra E. Guerrero, MD, a professor of cardiology at Mayo Clinic in Rochester, Minnesota, was the principal investigator of ENCIRCLE, and served on a panel of experts discussing both trials. Like many others, she called them practice changing.

“This is a historical moment,” she said. These trials represent “a remarkable milestone that will transform practice and the lives of patients.”

The SUMMIT-MAC trial received funding from Abbott Structural, with which Sorajja has a financial relationship. He also has financial relationships with Adona, AMX Technologies, Arcos, Boston Scientific, ConKay, Coramaze, CroiValve, Cultiv8, Edwards Lifesciences, Egg Medical, Evolution Med, Foldax, 4C Medical, GE Medical Haemonetics, InQ8, LAZA, Medtronic, Mirus, Philips, Polares, Tricares, vDyne, Unorthodox Ventures, Valcarem and xDot. The ECLIPSE trial received funding from Edwards Lifesciences with which Daniels has a financial relationship. He also has a financial relationship with Solo Pace. Mehran reported financial relationships with Abbott, Affluent Medical, Alleviant, Amgen, AstraZeneca, Boston Scientific, Bristol-Myers Squibb, CardiaWave, Chiesi, Concept Medical, Daiichi Sankyo, Elexir, Janssen, MedAlliance, Novartis, Novo Nordisk. Leon reported financial relationships with Abbott, Boston Scientific, Edwards Lifesciences, and Medtronic. Guerrero reported a financial relationship with Edwards Lifesciences.