Twelve-months safety of valvosoft non-invasive ultrasound therapy (NIUT) in patients with severe symptomatic aortic valve stenosis: a first-in-human study
Authors: Messas E , Goudot G , Ijsselmuiden A , Den Heijer P , Trifunovic D , Petrovic O , Puymirat E , Cholley B , Velinovic M , Karan R , Remond M C , Penot R , Pernot M , Tanter M , Spaargaren R ,   Valvosoft First in Human trial
Published: October 2021

Abstract

Background
Despite overall favourable outcome of surgical and transcatheter aortic valve replacement (SAVR/TAVR) in patients with severe calcific aortic stenosis (CAS), not all patients are eligible for an invasive treatment1 because of too high predicted mortality and complications.
Cardiawave© has developed a novel non-invasive ultrasound therapy (NIUT) device called Valvosoft to treat calcific aortic stenosis (CAS). Based on preclinical results2,3, a prospective first-in-human study was conducted in two centres in 10 patients in 2019 and a second one in 4 patients in 2020. All patients had symptomatic severe CAS and were not eligible for aortic valve replacement according to local heart teams.

Methods
Fourteen patients with severe symptomatic CAS not eligible for valve replacement were enrolled. Transthoracic therapeutic ultrasound was delivered by the Valvosoft transducer coupled with an echocardiographic phased-array probe for real-time monitoring. Clinical and echocardiographic evaluation were performed at baseline, discharge, 1-, 3-, 6- and 12-months follow-up. Additionally, the 4 patients of the second study had a brain-MRI performed before and after treatment to rule out silent cerebrovascular events.

Results
Patients were advanced in age (82.4±5.3 years) with severe comorbidities (57% with heart failure and 50% with coronary heart disease) and severe CAS. No adverse events occurred during the procedure other than isolated ventricular extrasystoles. No device- or procedure-related SAEs were reported at 1-month follow-up as adjudicated by the Clinical Event Committee (CEC). No death, stroke or TIAs or deterioration of neurological status were observed at 1-month follow-up for all 14 patients.
During 12-months follow-up, 5 out of the 14 patients died (from 2 to 7 months after the procedure). All deaths were adjudicated as non-procedure related. The survival rate was higher (100%, 93%, 79%, 64% at 1-, 3-, 6- and 12-months) comparing to the natural evolution of the disease on an equivalent studied population4 (94%, 73%, 73%, 54% at 1, 3, 6 and 12-months). No abnormality was detected in any of the 4 patients who had a brain-MRI before and after treatment.

Conclusions
NIUT seemed feasible and safe and in a small first cohort of very frail patients with severe comorbidities suffering from severe symptomatic CAS. Brain-MRIs performed before and after treatment ruled out silent cerebrovascular events. The survival comparison of the studied population contrasted to the natural evolution of the disease suggests that NIUT is beneficial for these patients with no other medical option.

Funding Acknowledgement
Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This study has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement 829492 and is supported by the French Government, managed by the National Research Agency (ANR) under the program “Investissements d'avenir” with the reference ANR-16-RHUS-0003 and ANR VALVOSOFT-17-CE19-0019-02.