Ongoing clinical trials looking at transcatheter aortic valve implantation (TAVI) for patients with moderate aortic stenosis could lead to an expansion of indications for current TAVI platforms to include many patients currently outside of the scope of the therapy.
Presently, guidelines limit TAVI to encompass severe aortic stenosis, but continued advances in TAVI device technology have led to a growing interest into whether patients at a less advanced disease state—including those with symptomatic, moderate aortic stenosis—may benefit from early intervention to relieve symptoms and halt disease progression.
New research presented at TVT 2022 (The Structural Heart Summit, 8–10 June, Chicago, USA), points towards a growing interest in the long-term outcomes in patients with moderate aortic stenosis, against the backdrop of ongoing trials to assess the efficacy of TAVI as a treatment option in these patients.
“The impact of this disease on long-term clinical outcomes has not been fully described,” Augustin Coisne (Cardiovascular Research Foundation, New York, USA) told delegates at the TVT meeting where he put moderate aortic in the spotlight in a late-breaking, featured clinical research session.
Coisne presented findings of a soon-to-be-published systematic review and meta-analysis looking at the impact of moderate aortic stenosis on long-term clinical outcomes, which included data from 25 previous studies. The primary endpoint of the analysis was all-cause death, with secondary endpoints including cardiac death, heart failure, sudden death, and aortic valve replacement.
Coisne detailed that the study included over 12,143 patients, with around 3.7 years of follow-up. The mean age of the study population was 74 years, 41% of patients were women, 38% had coronary artery disease, 30% were diabetic, and 72% had hypertension. Of these patients, 7% were classified as having New York Heart Association (NYHA) class III-IV functional classification, the mean aortic valve area was 1.22cm2, and mean left ventricular ejection fraction (LVEF) was 58%.
Detailing the rates of adverse events, pooled per 100 patients per year, Coisne reported that there were nine deaths per 100 patients, with cardiac death occurring in 4.9, heart failure in 3.9, sudden death in 1.1, and aortic valve replacement required in 7.2. The study team also carried out an alternative analysis, excluding the studies that used a definition of moderate aortic stenosis no longer supported by current guidelines, which Coisne said yielded similar results.
“Looking at the meta-regression analysis of all-cause mortality, we can see that diabetes, coronary artery disease, presence of symptoms and left ventricular function were all associated with a significant impact on the overall estimate of all-cause death,” Coisne told the TVT meeting.
Investigators also carried out a sub-group analysis according to left ventricular function, in which they found that all-cause mortality was higher in patients with reduced LVEF (<50%) than with normal LVEF respectively 16.5 (95% CI:5.2-52.3) and 4.2 (95% CI: 1.4-12.8) per 100 patients per year.
Finally, the study team produced a meta-analysis comparing moderate aortic stenosis including those with no/mild or severe disease. Coisne reported at TVT that the incidence rate difference of all-cause mortality was -3.9 per 100 patients per year for patients with no/mild AS compared to +2.2 per 100 patients per year for patients with severe stenosis.
Coisne and colleagues drew several conclusions from the study. “We observed a progressive increase in mortality with each higher grade of aortic stenosis severity—a gradual increase in risk of death from mild to moderate to severe aortic stenosis,” he told TVT attendees.
Randomised trials are ongoing
Randomised clinical trials are eagerly anticipated to help to determine whether moderate aortic stenosis patients may benefit from early intervention with a reasonable risk benefit ratio in specific population subsets, Coisne commented, namechecking several ongoing trials that may shape thinking in this regard—TAVR UNLOAD, PROGRESS and EXPAND TAVR II—all of which are presently recruiting.
Of these three trials, the Medtronic-sponsored EXPAND TAVR II is the most recent entrant to the field, having commenced in spring 2022. The multicentre, international, prospective trial is being conducted in USA, Canada, Japan, EMEA regions, Australia, and New Zealand and will evaluate the safety and effectiveness of TAVI using the Evolut Pro+ system (Medtronic) with guideline-directed management and therapy (GDMT), compared to GDMT alone in moderate, symptomatic aortic stenosis patients. Findings may be used to support future regulatory submissions to expand the current indications for the TAVI platform, according to Medtronic.
The EXPAND TAVR II pivotal trial will enrol up to 650 patients and will include two co-primary endpoints with follow-up out to 10 years. The primary safety endpoint is a composite of all-cause mortality, all-stroke, life threatening or fatal bleeding, acute kidney injury, hospitalisation due to device or procedure-related complication, or valve dysfunction (requiring reintervention) at 30 days. The primary effectiveness endpoint is the composite rate of all-cause mortality, heart failure event, or aortic valve replacement or reintervention at two years.
“Historically, we have known about the need to redefine thresholds for intervention in valvular heart disease as our treatments continue to improve in terms of safety with the potential for positively impacting survival,” EXPAND TAVR II principal investigator Paul Sorajja (Minneapolis Heart Institute Foundation, Minneapolis, USA) tells Cardiovascular News.
Commenting that aortic stenosis is a “progressive” disease, Sorajja adds that there are numerous single centre and national registry studies documenting impaired survival for patients with moderate aortic stenosis. “Annual mortality for these patients is 7‒10%, with rates of heart failure hospitalisation twice that,” he says. “Determining the benefit of aortic valve for relief of ‘moderate’ aortic stenosis in these patients with evidence of heart failure is needed.”
As moderate aortic stenosis is not a current indication for intervention unless there is another concomitant reason for CABG, “one may say it is undertreated due to a lack of clinical evidence informing treatment guidelines,” Sorajja adds. Currently, he notes, the recommended management of patients with moderate aortic stenosis includes periodic monitoring with transthoracic echocardiography every one-to-two years—or with any change in symptoms or findings. “As clinicians, we think we can do better and improve patient outcomes to help millions live longer, healthier lives,” he says.
Commenting on the importance of having an interventional option for the treatment of moderate aortic stenosis, Sorajja says that early intervention—if and when clinically indicated—means prevention of severe disease. “This patient population, while outside of current TAVI indications, represents more than two times the population of patients with severe aortic stenosis,” he comments. “Such insight into the potential benefit is needed, and may change thresholds for intervention in order to improve survival and long-term prognosis, including lower likelihood of heart failure and hospitalisation.”
Furthermore, Sorajja comments, TAVI is a “safe, minimally invasive method for relief of aortic stenosis, and thus, describes it as “ideal” for testing the impact of moderate aortic stenosis relief in patients with evidence of heart failure.