CHICAGO — A transcatheter aortic valve implantation (TAVI) device developed specifically for the treatment for aortic regurgitation has met all the prespecified safety and efficacy goals, so far, in an expansion cohort of the ALIGN-AR trial, paving the way for a randomized trial in lower-risk patients.
In patients who received the Trilogy System (JenaValve) and who have been followed out to 2 years, 90% have remained in New York Heart Association (NYHA) functional class I or II heart failure, which means marked improvements in hemodynamics and substantial reductions in markers of left ventricular dysfunction, said Raj R. Makkar, MD, associate director of the Smidt Heart Institute at Cedars-Sinai in Los Angeles.
In an expansion of the 180-patient ALIGN-AR trial, published last year, Makkar presented data on 500 patients during a late-breaker session at the American College of Cardiology (ACC) Scientific Session 2025.
The larger number of patients and longer follow-up in the expansion cohort have raised hope for regulatory approval that could fill a major gap in current care. Surgery is currently the only guideline-approved treatment for aortic regurgitation.
New Device Granted Breakthrough Status by the US Food and Drug Administration (FDA)
Because of the unmet need, the Trilogy System — which clips onto native aortic leaflets and is meant for noncalcified valves — has been granted breakthrough status by the FDA, Makkar reported.
The 500 patients who received the device had aortic regurgitation of grade 3 or higher, assessed by a core laboratory, had NYHA functional class II or higher heart failure, and were at a high risk for surgery. All patients have been followed for at least 30 days, so the study’s 30-day safety endpoint is based on complete data. The efficacy endpoint is based on data from 389 (77.8%) of the 500 patients followed for at least 1 year.
The nonblinded, single-group design of both the multicenter ALIGN-AR study and its expansion cohort had prespecified performance goals for safety. The study population was relatively sick. At baseline, 61% of patients were in NYHA class III or higher heart failure, 39% had atrial fibrillation, 29% had renal insufficiency, and the average Society of Thoracic Surgeons risk score was 3.9.
At 30 days, approximately 26% of patients had experienced at least one of the safety events, which included all-cause death, cardiovascular mortality, stroke, major bleeding, and vascular complications; the need for pacemaker implantation (23.3%) was the most common.
Device Easily Meets Safety and Performance Goals
The most serious adverse events, such as death (1.4%), cardiovascular death (1.2%), disabling stroke (1.2%), and acute kidney injury (0.6%), occurred at relatively low rates. All of these were lower than would be expected in the absence of treatment, and most were lower than the serious adverse events associated with TAVI) devices not designed to treat aortic regurgitation. The rate of valve embolization, for example, was 1.6%, whereas rates with off-label devices range from 10% to 15%.
The 30-day safety performance goal easily met the 40.5% prespecified safety margin (P < .0001).
At 1 year, the rate of all-cause mortality was 8.1%, a performance goal well within the prespecified efficacy margin of 25% (P < .0001). Rates of stroke overall (3.1%) and disabling stroke (1.5%) were considered acceptable.
“These stroke rates are quite reasonable, considering the age of patients and that nearly 40% had atrial fibrillation,” Makkar said.
The hemodynamics, which had improved markedly in 30 days, were “excellent” at 1 year, and the improvement has remained stable for those who have been followed for longer than that. This has been accompanied by improvements in left ventricular function, with steady declines from 30 days to 1 year in left ventricular mass, left ventricular end-diastolic diameter, and left ventricular end-systolic volume.
At 30 days, 82.6% of patients had no or only trace paravalvular regurgitation, and only 0.4% had moderate regurgitation. At 1 year, 93.4% of patients had no or only trace regurgitation, 6.3% had mild regurgitation, and 0.3% had moderate regurgitation. For patients followed to 2 years, there was an additional bump in the proportion with no regurgitation.
A similar improvement was seen in NYHA class. Whereas 62% of patients entered the trial in class III or IV heart failure, at 30 days, 53% were in class I and 39% were in class II. At 1 year, 62% were in class I, 31% in class II, and only 8% were in class III.
This was reflected in steep improvements in the Kansas City Cardiomyopathy Questionnaire (KCCQ) score. At 1 year, 84.0% of study patients were alive and well (KCCQ score ≥ 60).
They have been so favorable that a randomized trial in lower-risk patients has recently been approved by the FDA, Makkar reported. That trial will commence once 1-year follow-up data from the ALIGN-AR expansion cohort are complete.
Is Trial in Low-Risk Patients Justified?
An effective TAVI device for aortic regurgitation “is an important breakthrough indeed,” said Roxana Mehran, MD, director of Interventional Cardiovascular Research at the Icahn School of Medicine at Mount Sinai in New York City, who praised the effort to show efficacy in the “very high–risk population.”
However, she was not as enthusiastic about moving to a randomized trial in low-risk patients without first performing a controlled trial in high-risk patients or, at the very least, after substantially longer follow-up than in the ALIGN-AR expansion cohort.
Although rates of valve embolization and aortic dissection were low, they were not zero, said Mehran, who expressed concern about the “price to pay” with the high pacemaker rates, and wondered whether there will be efforts to mitigate these risks.
Pacemaker rates were approximately 25% when TAVI devices for aortic stenosis were first introduced, Makkar pointed out. Refinements already underway, such as better anchoring strategies, are expected to improve situation of the valve, which will likely reduce valve embolization and the need for pacemakers, he added.
In addition, a large annulus size (P = .005) and the presence of a right bundle branch block (P < .0001) are among the predictors of a need for a pacemaker, Makkar’s team has already shown, which provides a focus for seeking strategies to reduce the risk for this complication.
Given the benefits of controlling regurgitation, the results are “very reassuring,” even at the current rate of complications. The sustained control of regurgitation and the favorable effects on clinical echographic, functional, and quality-of-life measures are consistent, Makkar emphasized.
Rather than conduct a randomized trial in high-risk patients, a study population already complicated by the off-label use of existing TAVI devices, a controlled study in a lower-risk population will provide more information about how this device will fit with treatments for a condition that is often inadequately managed with current options, he added.
Makkar reported having financial relationships with Abbott, Boston Scientific, Edwards LifeSciences, Medtronic, and JenaValve, which provided funding for the ALIGN-AR trial. Mehran reported having financial relationships with Abbott Vascular, AstraZeneca, Bayer, Bristol Myers Squibb, Claret Medical, CSL Behring, Daiichi Sankyo, Elixir Medical, Janssen, Medtronic, Roivant Sciences, Siemens, and Sanofi.