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Transcatheter aortic valve implantation (TAVI) has transformed the treatment of aortic stenosis, with hundreds of thousands of patients worldwide receiving the minimally invasive therapy since it entered practice nearly two decades ago. However, for patients with aortic regurgitation, treatment options remain more limited.
Untreated, severe, symptomatic aortic regurgitation is associated with high mortality, and surgery is recommended for patients with native severe aortic regurgitation. However, there are a number of patients who are high-risk for surgery and are not offered the treatment.
“The most recent data from prevalence studies, largely related to patient populations over the age of 65, indicate about a 2–4% prevalence of significant aortic regurgitation,” Martin Leon (Columbia University, New York, USA) tells Cardiovascular News, relating to patients with moderate-to-severe, or severe, often symptomatic, aortic regurgitation. “That is larger than people would predict, and in some studies it exceeds the prevalence of symptomatic, significant aortic stenosis.”
Leon describes the criteria for making an accurate diagnosis of aortic regurgitation severity as “frustratingly burdensome”, contributing to what he sees as a large number of eligible patients not receiving treatment. “There are estimates that in a population of significant aortic regurgitation patients, who by most guideline criteria would be operable candidates, only as many as 25% actually get treated within the first few years of diagnosis,” he explains. “So, aortic regurgitation is underdiagnosed, it is undertreated, it is more prevalent, and guidelines have been very static over a period of two decades in terms of suggesting which patients should be treated.”
Anatomical features make current-generation TAVI devices, which have been engineered for use in the treatment of aortic stenosis, largely inappropriate in the setting of aortic regurgitation. “The predicate understanding of using a transcatheter valve in the aortic position is that you have a platform, which is a high friction, calcified aortic valve complex, that will allow the metallic frame to adhere to it so that it is stable,” explains Leon. “All of those predicate anatomic assumptions are invalid if you are dealing with aortic regurgitation. You have a compliant, almost elastic, annulus. You have very little in the way of calcification. The valves are somewhat larger, and none of the presently approved transcatheter valves take that into consideration.”
The availability of a dedicated transcatheter device for the treatment of aortic regurgitation with proven performance is likely to change the outlook, and results from the ALIGN-AR pivotal trial, presented at the 2023 TCT meeting (23–26 October, San Francisco, USA), have raised hope that this is a realistic prospect. ALIGN-AR studied the use of the Trilogy (JenaValve) transcatheter system in high-risk patients with symptomatic, severe aortic regurgitation. The device currently has a CE mark, but is yet to be approved for use outside of clinical trials in the USA.
The Trilogy valve features locators that clip onto native leaflets and enable secure anchoring in the absence of calcium, as well as large-open cells that are designed to facilitate future coronary access. “The fixation of the valve is both at the annular zone, with a self-expanding frame, but also it clips onto the three leaflets so that that creates stability and fixation in a non-calcified structure,” Leon says of the device. “That is why it is so ideally suited for the aortic regurgitation patients.”
The landmark, prospective, single-arm investigation device exemption (IDE) ALIGN AR study enrolled a total of 180 patients at 20 US sites, assessing the safety and efficacy of the Trilogy system within high-risk patients with symptomatic aortic regurgitation. The study is intended to support a premarket approval submission to the US Food and Drug Administration (FDA), with clinical evaluation, echocardiography, functional and quality of life assessments scheduled at 30 days, six months, one year and annually up to five years.
The results reported at TCT 2023 measured favourably on the efficacy of the device, determined by the rate of all-cause mortality at one year, with a rate of 7.8% reported by investigators compared against a 25% prespecified historical control. “That is dramatically lower than what you would expect to see in an untreated aortic regurgitation patient population,” comments Leon.
Trilogy was also shown to perform favourably in terms of safety, which was assessed against a composite of 30-day all-cause mortality, stroke, life-threatening or major bleeding, major vascular complications, acute kidney injury (AKI), valve intervention, new permanent pacemaker or moderate or greater paravalvular regurgitation (PVR), with the device meeting the non-inferiority criteria needed to achieve its primary endpoint, with a rate of 26.7% recorded against a prespecified non-inferiority margin of 40.5%.
Leon also notes that patients saw an improvement in symptoms as a result of the therapy, demonstrated by increased Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, as well as a low rate of PVR and improvement in left ventricular (LV) remodelling. “From all parameters from ALIGN-AR we should be enthusiastic that this is an effective therapy for managing patients with aortic regurgitation,” he comments.
Plans for a randomised study assessing the therapy in patients eligible for surgery are “progressing rapidly”, according to Leon, who explains that this will be the next stage for research in this arena.
“When we first started TAVI we were doing only what we called inoperable, not just high-risk, but extreme- or prohibitive-risk patients.” he comments. “Everybody said that this was a small population. The reality is that it was not a small population, especially in a globally ageing population, there are more and more of these patients. So, certainly I think we have underestimated the clinical significance of this group of patients for aortic regurgitation as well.”
Leon describes himself as “bullish” for the prospects of advancing TAVI among patients with aortic regurgitation, telling Cardiovascular News that he believes this to be a “seminal turning point” in the management of the disease.
“We have been static with this disease for decades and now we have an opportunity to make some very significant impacts on patient care both with managing the patients by guideline-appropriate candidates that are not being treated, and also to look at earlier stage treatment, which we call pre-emptive treatment in severe aortic regurgitation, thinking that we can alter the natural history effectively, now that we have what we believe is a safe and effective device,” he says.
Though TAVI in the aortic stenosis population has taken years to reach maturity, Leon believes that experience from this process could speed up the advance of TAVI for those with aortic regurgitation. “It took us 15 years to go through all of the different patient population scenarios in aortic stenosis, now that we have a better understanding of what to expect, the operators are much more mature, well trained, [and] have great experience,” he proffers. “I think we can extrapolate those positive experiences from the aortic stenosis side and we can accelerate the development of the aortic regurgitation platform.”
