Despite premature termination limiting the precision of mortality estimates, the REBOOT-PARADOX trial offers rare randomized, long-term patient-level data examining whether TAVR adds a survival benefit compared with optimal medical therapy (OMT) in symptomatic patients with paradoxical low-flow, low-gradient aortic stenosis (pLFLG).

The trial, presented at ESC Congress 2026 and simultaneously published in JACC, randomized a total of 120 patients (median age 82 years; 53% women) 2:1 to either TAVR or OMT. Of the OMT patients, 19 eventually crossed over to TAVR, primarily due to symptom progression.

The primary endpoint of all-cause death, assessed two years after enrollment of the last patient, occurred in 29% of those assigned to TAVR vs. 37% of those assigned to OMT. Five-year mortality was less in the TAVR group (~45%) compared with the OMT group (~57%). In addition, TAVR was associated with improved symptoms and fewer rehospitalizations. There were no differences in functional capacity or quality of life.

Enrollment in REBOOT-PARADOX stopped after only 120 of the planned 783 patients due to the COVID pandemic, leaving the study markedly underpowered. "As a result, findings did not demonstrate a mortality benefit with TAVR, but it also could not establish equivalence or exclude a clinically meaningful survival benefit," said Aakriti Gupta, MD, FACC, an executive associate editor of JACC.

According to REBOOT-PARADOX investigators, while early closure "left the effect of TAVR on mortality unresolved, the randomized treatment allocation, extended patient-level follow- up, and frequent crossover provide an unusual opportunity to characterize the clinical course following immediate TAVR vs. an initially conservative strategy."

"REBOOT-PARADOX provides the first randomized evidence in a difficult and understudied population, identifies a meaningful signal for reduced morbidity with earlier TAVR, and simultaneously demonstrates why correcting the valve alone may not normalize the prognosis," said Gupta. "It moves the field forward while leaving the survival question and optimal timing of intervention unresolved."

Clinical Topics: Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Valvular Heart Disease, Aortic Surgery, Cardiac Surgery and VHD, Interventions and Structural Heart Disease

Keywords: ESC Congress, ESC26, Transcatheter Aortic Valve Replacement, Aortic Valve Stenosis