Introduction
Aortic regurgitation (AR) is a valvular heart disease characterized by the backflow of blood from the aorta into the left ventricle during diastole, resulting in volume overload and progressive cardiac remodeling. Severe symptomatic native AR often requires intervention to improve survival and quality of life. Traditionally, surgical aortic valve replacement has been the mainstay treatment, but many patients, especially those at high surgical risk due to age or comorbidities, face significant morbidity and mortality risks from surgery.
Transcatheter aortic valve implantation (TAVI) has revolutionized treatment for calcific aortic stenosis, yet devices developed for stenosis often are not optimized for native AR due to the absence of calcification, which complicates valve anchoring. There remains limited data on devices specifically designed for treating native AR.
The ALIGN-AR Program Overview
The ALIGN-AR program comprised two pivotal prospective, multicenter, single-arm studies evaluating the safety and effectiveness of the Trilogy transcatheter heart valve, a device purpose-built to treat symptomatic moderate-to-severe or severe native aortic regurgitation in patients at high risk for surgical intervention. Conducted across multiple US centers, these studies aimed to address critical gaps in treatment options for patients otherwise unsuitable for surgery.
Study Designs and Patient Populations
Extended ALIGN-AR Pivotal Study
Between June 2018 and July 2025, this study enrolled a total of 700 patients (180 in the pivotal cohort and 520 in a continued-access cohort) with symptomatic native AR. The median age was 79 years, and patients were predominantly White (76%), with balanced gender distribution. Inclusion criteria focused on high surgical risk patients with moderate-to-severe or severe symptomatic AR.
Initial ALIGN-AR Study
Conducted from June 2018 to August 2022, this study screened 346 patients and enrolled 180. The mean age was 75.5 years, with a similar demographic profile. Patients were carefully selected by multidisciplinary heart teams and independent screening committees to ensure high risk for mortality or complications post-surgical valve replacement.
Methods and Outcome Measures
Both studies employed rigorous prospective protocols, using the Trilogy valve designed specifically for AR. Primary endpoints included a safety composite of major adverse events within 30 days—encompassing all-cause mortality, stroke, life-threatening bleeding, acute kidney injury, vascular complications, need for additional interventions, new pacemaker implantation, and residual moderate or worse AR—and all-cause mortality at one year. Safety endpoints were tested for non-inferiority against established performance goals derived from literature, while mortality endpoints were assessed for superiority or non-inferiority per study design.
Key Findings
Technical Success and Immediate Outcomes
Technical success, defined as effective valve deployment without procedural mortality, was high at approximately 95% across studies. Complication rates within 30 days remained within acceptable ranges, meeting or exceeding prespecified performance goals.
Safety Profile
In the extended pivotal study, the 30-day composite safety endpoint occurred in 24% of patients, significantly below the 40.5% performance goal, demonstrating non-inferiority (p < 0.0001). Mortality within 30 days was low (1.6%), with stroke observed in 1.7%. Pacemaker implantation occurred in roughly 21-24% of patients, reflecting conduction disturbances associated with valve implantation, a recognized procedural risk. Importantly, moderate or severe residual AR was rare (0.5% to none), indicating effective valve competence.
Long-term Mortality and Clinical Outcomes
One-year all-cause mortality was 7.7% in the extended cohort and 7.8% in the initial study, both substantially lower than the 25% benchmark, demonstrating treatment efficacy. Two-year mortality in the extended study cohort was 13.3%, supporting sustained benefits. Patients experienced marked reductions in AR severity, improved valve haemodynamics, and evidence of favorable left ventricular remodeling. Functional status and quality of life metrics showed significant improvements lasting up to two years after implantation.
Interpretation and Clinical Implications
The ALIGN-AR studies establish that TAVI with the Trilogy valve is a feasible, safe, and effective treatment modality for high-risk patients suffering from symptomatic native moderate-to-severe or severe AR who are unsuitable candidates for surgical valve replacement. The dedicated design of the Trilogy valve addresses challenges unique to native AR, such as lack of calcification for secure anchoring, achieving excellent valve function and minimizing residual regurgitation.
This therapy expands the treatment landscape by offering a less invasive alternative with favorable safety profiles and improved clinical outcomes, including enhanced survival and quality of life. The early evidence of myocardial remodeling and sustained functional gains further underscore the potential long-term benefits.
While short- and mid-term data are promising, ongoing long-term follow-up from these prospective studies will be critical to fully understand durability, late complications, and sustained patient outcomes.
Conclusion
The ALIGN-AR program confirms that transcatheter aortic valve implantation using a purpose-built device for native AR can safely and effectively treat patients at high surgical risk. The Trilogy valve delivers excellent valve competence, low complication rates, and meaningful survival benefits up to two years post-procedure. These findings support adoption of TAVI as an important treatment option for selected patients with symptomatic native AR who cannot undergo surgery.
Funding and Disclosure
Both ALIGN-AR studies were funded by JenaValve Technology. The study designs, analyses, and reporting were conducted with rigorous scientific oversight to ensure validity and reliability of outcomes.
References
Makkar RR et al. (2025). Transcatheter aortic valve implantation with the Trilogy valve for symptomatic native aortic regurgitation (ALIGN-AR): a pivotal, multicentre, single-arm, investigational device exemption study. Lancet. DOI: 10.1016/S0140-6736(25)02215-9.
Vahl TP et al. (2024). Transcatheter aortic valve implantation in patients with high-risk symptomatic native aortic regurgitation (ALIGN-AR): a prospective, multicentre, single-arm study. Lancet. DOI: 10.1016/S0140-6736(23)02806-4.
