First 500 patients in Align-AR trial using TAVR for pure aortic regurgitation show strong outcomes
Highly encouraging results were seen in the first 500 pure aortic regurgitation (AR) patients treated in the Align-AR trial using the JenaValve transcatheter aortic valve replacement (TAVR) system, presented as a late-breaking study at the American College of Cardiology (ACC) 2025 annual meeting.
This late-breaking clinical trial marks a significant step forward for a population long underserved by current transcatheter options. Unlike aortic stenosis, pure AR presents unique challenges due to the absence of valve calcification, making standard TAVR devices more likely to embolize. The JenaValve, was designed specifically for non-calcified anatomy and has received FDA Breakthrough Device designation.
"The prognosis in patients who have symptomatic aortic regurgitation, especially when they have NYHA Class III or IV heart failure symptoms is pretty dismal. Almost half the patients may be dead at the end of five years. The only approved treatment is surgery, but a lot of patients are not treated because they're high-risk surgical candidates, explained Raj Makkar, MD, director, interventional cardiology, director, Interventional Cardiology Research Program and professor of medicine, Smidt Heart Institute, Cedars-Sinai Hospital, who presented the data at ACC and spoke to cardiovascular Business in a video interview.
He said operators have used a lot of off-label commercially available TAVR devices, but these are designed for use in patients with a aortic stenosis (AS) with a heavily calcified aortic annulus to anchor the valve. The results in AR patients without calcium is less than ideal, Makkar said.
"We tend to have a high risk of complications, specifically valve migration or embolization, which can be about 10-15%. There also is a significant incidence of paravalvular leakage, which contributes to poor long-term outcomes," Makkar explained.
The JenaValve system is a self-expanding valve and features three leaflet-locating clips that anchor the valve securely by clipping the valve leaflets and without relying on calcification. This design provides a stable fit and significantly reduces the risk of valve migration or embolization—challenges common when using off-label devices for AR.
The Align-AR trial is looking at safety and efficacy. Data from the first 180 patients presented at TCT 2023 was submitted to the U.S. Food and Drug Administration (FDA) for review.
Key clinical findings from the Align-AR trial
"We were able to meet our primary endpoint at 30 days, and this safety endpoint was a composite of number of clinical outcomes such as death, stroke, reinterventions and bleeding complications, but also included pacemaker implantation, and moderate or more paravalvular leak. So we met our primary endpoint in terms of primary efficacy endpoint, which was death rates at one year," Makkar said.
Makkar said the latest data showed numerous positive outcomes:
• Zero intraprocedural deaths among the 500 patients treated.
• 30-day mortality rate of 1.6%, significantly lower than the expected 4% based on Society of Thoracic Surgeons (STS) risk scores.
• One-year mortality was just 8%, far outperforming the pre-specified performance goal of 25%.
• Stroke rates were low, with disabling strokes in only 0.8% of patients at 30 days.
• Paravalvular leak was rare, with moderate or greater leakage observed in just 0.3% of patients.
• Dramatic improvement in symptoms: Over 90% of patients improved to NYHA Class I or II by 30 days.
• Sustained improvement in valve function and patient quality of life up to two years post-procedure.
• Heart remodeling was favorable, with reductions in left ventricular volume and mass.
• Kansas City Cardiomyopathy Questionnaire (KCCQ) score improved by a solid 20 points from baseline to one year and also at two years.
Pacemaker rate was high in the ALIGN AR trial
One issue seen in the trial was a relatively high new pacemaker implantation rate of 23% of patients. This is similar to rates seen in early Corevalve AS TAVR patients from a decade ago. Makkar said this is a point of ongoing study and refinement. He said the pacemaker rate may be due in part to operator setting a low threshold for pacemaker implants and operator inexperience with the valve. Like Corevalve, he expects the rate will decrease over time as operators gain more experience with the valve.
Makkar said the larger the valve size, the more pacemakers were implanted. The pacemaker rate with the smallest 23 mm valve was 16.8%, but rose to 28.9% with the largest 27mm size.
They also created a list of predictors for new pacemakers, including history of heart failure, baseline severe AR, an annular perimeter of more than 85 mm and baseline right bundle branch block (RBBB).
Regulatory path and future directions
The FDA submission for premarket approval is already underway, and Makkar said alongside two-year follow-up data from more than 200 patients is expected to further support regulatory approval.
The Align-AR trial’s success is paving the way for a new randomized trial—the ARtist Trial, which will include over 1,000 patients who are not high-risk surgical candidates, comparing TAVR with traditional surgery in a head-to-head design. Patients will be followed for up to 10 years.
Dave Fornell has covered healthcare for more than 17 years, with a focus in cardiology and radiology. Fornell is a 5-time winner of a Jesse H. Neal Award, the most prestigious editorial honors in the field of specialized journalism. The wins included best technical content, best use of social media and best COVID-19 coverage. Fornell was also a three-time Neal finalist for best range of work by a single author. He produces more than 100 editorial videos each year, most of them interviews with key opinion leaders in medicine. He also writes technical articles, covers key trends, conducts video hospital site visits, and is very involved with social media. E-mail: [email protected]