By Jeffrey Zimmet, MD, PhD
In this multicenter randomized trial of early transcatheter aortic valve replacement (TAVR) in patients with moderate aortic stenosis, TAVR was not superior to medical surveillance, with TAVR triggered by progression to severe aortic stenosis.
Van Mieghem NM, Elmariah S, Spitzer E, et al. Transcatheter aortic valve replacement in patients with systolic heart failure and moderate aortic stenosis: TAVR UNLOAD. J Am Coll Cardiol. 2024; Oct 28. doi: 10.1016/j.jacc.2024.10.070. [Online ahead of print].
The timing of aortic valve replacement in aortic stenosis (AS) has been a topic of intense debate in recent years, with much of the controversy centered around whether patients with severe AS do better with earlier intervention. Among patients with AS and heart failure with reduced ejection fraction (HFrEF), a common question in clinical practice has been whether these patients would benefit from transcatheter aortic valve replacement (TAVR) when the stenosis remains in the moderate range.
The theory behind this concept rests on the observation that a cornerstone of medical therapy for HFrEF reduces afterload on the failing ventricle. Also, the hypertrophy and fibrosis that come as a consequence of worsening AS might be especially deleterious in HFrEF.
Because AS produces a medically nonmodifiable increase in afterload, the question here is whether TAVR, in addition to optimal heart failure therapy, would improve clinical outcomes. Retrospective studies previously had reported benefits to early intervention in this population, but the limitations of such observational data are clear.
TAVR UNLOAD, therefore, was conceived as an international, multicenter randomized trial that would enroll patients with reduced EF and AS with mean gradients between 20 mmHg and 40 mmHg and calculated valve areas between 1.0 cm2 and 1.5 cm2. The rationale and design paper was published nearly eight years ago and proposed enrolling 600 patients who would be randomly assigned in a 1:1 fashion to TAVR with a balloon-expandable valve or to medical therapy and close observation, with TAVR to be performed upon progression to severe AS.
Because of slow enrollment and issues with funding, the study was modified after initiation and ultimately enrolled 178 patients from a total of 66 institutions. Included patients had an average age of 77 years, 79% were male, and a majority were New York Heart Association class III or IV. The mean Society of Thoracic Surgeons Risk Score predicted risk of mortality was 4.4%.
At 12 months after enrollment, the TAVR group showed an advantage in terms of Kansas City Cardiomyopathy Questionnaire (KCCQ)-reported symptoms, which drove a positive interim result in the hierarchical endpoint that included all-cause death, disabling stroke, heart failure hospitalization, and change in KCCQ score. None of the other components were significantly different. By 23 months (the time point at which the primary endpoint was reported), even the symptom advantage had dissipated such that the win ratio showed no significant difference (win ratio, 1.31; 95% confidence interval, 0.91-1.88).
Unsurprisingly, the TAVR procedures themselves had few complications, with one case each of disabling stroke, severe bleeding, acute heart failure hospitalization, acute kidney injury, and repeat procedure for early bioprosthetic valve-related dysfunction. The post-TAVR pacemaker rate was low. There were no procedural deaths or major vascular complications.
In the control arm, 38 (43%) patients underwent TAVR at a median of 12 months from enrollment, most as the result of progression to severe AS.
The authors concluded that a strategy of early TAVR was not superior to active surveillance for the primary composite endpoint in patients with HFrEF and moderate aortic stenosis. However, they emphasized the safety of what they termed preemptive TAVR in this population and reported early quality-of-life benefits.
Commentary
TAVR UNLOAD is the first randomized trial of TAVR in moderate AS patients, and its results were highly anticipated. On the face of it, these results confirm that we are not doing harm to our HFrEF patients by following current guidelines and waiting until AS is severe before proceeding to TAVR. Thus, guidelines are unlikely to change for this population based on this report.
That said, given the relative safety of the procedure, there certainly is room for individualized management, with earlier TAVR in a limited subset of patients who continue to have recurrent heart failure symptoms despite optimal guideline-directed medical therapy. The paper’s claims about short-term improvements in quality of life should be taken with a grain of salt, of course, in this open-label trial that was done without a placebo control.
The results here emphasize the need to meticulously review the studies on each patient to confirm the severity of AS in low-flow state patients, where transvalvular gradients often are lower and confirmatory tests, such as dobutamine echocardiography, sometimes are required.
The finding that nearly 40% of patients progressed to severe AS at a median of 12 months after enrollment suggests that some included patients may have been closer to the severe range. It also underscores the importance of close clinical and imaging follow-up in HFrEF patients with moderate AS to ensure that the appropriate window for aortic valve replacement is recognized.
Jeffrey Zimmet is Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center.
