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Randomized Controlled Trial
. 2025 Jan 21;333(3):213-221.
doi: 10.1001/jama.2024.22730.

Early Intervention in Patients With Asymptomatic Severe Aortic Stenosis and Myocardial Fibrosis: The EVOLVED Randomized Clinical Trial

Krithika Loganath  1 , Neil J Craig  1   2 , Russell J Everett  2 , Rong Bing  2 , Vasiliki Tsampasian  3   4 , Patrycja Molek  5 , Simona Botezatu  6 , Saadia Aslam  7 , Steff Lewis  8 , Catriona Graham  9 , Audrey C White  1   2 , Tom MacGillivray  10 , Christopher E Tuck  1 , Phillip Rayson  8 , Denise Cranley  8 , Sian Irvine  8 , Ruth Armstrong  8 , Lynsey Milne  8 , Calvin W L Chin  11   12 , Graham S Hillis  13   14 , Timothy Fairbairn  15 , John P Greenwood  16   17 , Richard Steeds  18 , Stephen J Leslie  19 , Chim C Lang  20   21 , Chiara Bucciarelli-Ducci  22   23 , Nikhil V Joshi  22 , Vijay Kunadian  24   25 , Vassilios S Vassiliou  3   4 , Jason N Dungu  26   27 , Sandeep S Hothi  28 , Nicholas Boon  29 , Sanjay K Prasad  23 , Niall G Keenan  30   31 , Dana Dawson  32 , Thomas A Treibel  33 , Mani Motwani  34 , Christopher A Miller  35 , Nicholas L Mills  1   2   36 , Ronak Rajani  37 , David P Ripley  38 , Gerry P McCann  7 , Bernard Prendergast  39 , Anvesha Singh  7 , David E Newby  1   2 , Marc R Dweck  1   2 ; EVOLVED investigators
Collaborators, Affiliations
Randomized Controlled Trial

Early Intervention in Patients With Asymptomatic Severe Aortic Stenosis and Myocardial Fibrosis: The EVOLVED Randomized Clinical Trial

Krithika Loganath et al. JAMA. .

Abstract

Importance: Development of myocardial fibrosis in patients with aortic stenosis precedes left ventricular decompensation and is associated with an adverse long-term prognosis.

Objective: To investigate whether early valve intervention reduced the incidence of all-cause death or unplanned aortic stenosis-related hospitalization in asymptomatic patients with severe aortic stenosis and myocardial fibrosis.

Design, setting, and participants: This prospective, randomized, open-label, masked end point trial was conducted between August 2017 and October 2022 at 24 cardiac centers across the UK and Australia. Asymptomatic patients with severe aortic stenosis and myocardial fibrosis were included. The final date of follow-up was July 26, 2024.

Intervention: Early valve intervention with transcatheter or surgical aortic valve replacement or guideline-directed conservative management.

Main outcomes and measures: The primary outcome was a composite of all-cause death or unplanned aortic stenosis-related hospitalization in a time-to-first-event intention-to-treat analysis. There were 9 secondary outcomes, including the components of the primary outcome and symptom status at 12 months.

Results: The trial enrolled 224 eligible patients (mean [SD] age, 73 [9] years; 63 women [28%]; mean [SD] aortic valve peak velocity of 4.3 [0.5] m/s) of the originally planned sample size of 356 patients. The primary end point occurred in 20 of 113 patients (18%) in the early intervention group and 25 of 111 patients (23%) in the guideline-directed conservative management group (hazard ratio, 0.79 [95% CI, 0.44-1.43]; P = .44; between-group difference, -4.82% [95% CI, -15.31% to 5.66%]). Of 9 prespecified secondary end points, 7 showed no significant difference. All-cause death occurred in 16 of 113 patients (14%) in the early intervention group and 14 of 111 (13%) in the guideline-directed group (hazard ratio, 1.22 [95% CI, 0.59-2.51]) and unplanned aortic stenosis hospitalization occurred in 7 of 113 patients (6%) and 19 of 111 patients (17%), respectively (hazard ratio, 0.37 [95% CI, 0.16-0.88]). Early intervention was associated with a lower 12-month rate of New York Heart Association class II-IV symptoms than guideline-directed conservative management (21 [19.7%] vs 39 [37.9%]; odds ratio, 0.37 [95% CI, 0.20-0.70]).

Conclusions and relevance: In asymptomatic patients with severe aortic stenosis and myocardial fibrosis, early aortic valve intervention had no demonstrable effect on all-cause death or unplanned aortic stenosis-related hospitalization. The trial had a wide 95% CI around the primary end point, with further research needed to confirm these findings.

Trial registration: ClinicalTrials.gov Identifier: NCT03094143.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Lang reported receiving grants from Novo Nordisk, Boehringer Ingelheim, AstraZeneca, Moderna, and Roche Diagnostics outside the submitted work. Dr Bucciarelli-Ducci reported receiving personal fees from Siemens Healthineers, GE HealthCare, Philips, and Bayer outside the submitted work and serving as chief executive officer (part-time contractor) for the Society for Cardiovascular Magnetic Resonance. Dr Keenan reported shareholding and nonfinancial support from MyCardium AI outside the submitted work. Dr Treibel reported receiving personal fees from AstraZeneca outside the submitted work. Dr Miller reported receiving nonfinancial support from Univar Solutions and grants from National Institute for Health and Care Research, Amicus Therapeutics, Guerbet Laboratories Limited, and AstraZeneca and personal fees from AstraZeneca, PureTech Health, Novo Nordisk, Boehringer Ingelheim, HAYA Therapeutics, and Eli Lilly outside the submitted work. Dr McCann reported receiving grants from University of Edinburgh during the conduct of the study and grants from British Heart Foundation for another trial of intervention in aortic stenosis outside the submitted work. Dr Prendergast reported receiving personal fees from Edwards Lifesciences, Valvosoft, and Medtronic outside the submitted work. Dr Dweck reported receiving personal fees from Edwards outside the submitted work and receiving speaker fees from Novartis and consultancy fees from Novartis, Jupiter Bioventures, AstraZeneca, Beren Therapeutics, and Silence Therapeutics. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Recruitment, Randomization, and Follow-Up in the EVOLVED Trial
aThree participants who did not proceed to cardiac magnetic resonance imaging had no clear reason recorded on the trial database. bRandomization used minimization with stratification for age, sex, aortic valve peak velocity, ischemic heart disease, and screening method. cTwo participants were excluded because they were randomized after already being referred for surgery (see eMethods in Supplement 1 for details).
Figure 2.
Figure 2.. Cumulative Incidence of Aortic Valve Intervention
At 12 months, 86% of patients in the early intervention group received aortic valve intervention compared with 28% of patients in the guideline-directed conservative management group.
Figure 3.
Figure 3.. Cumulative Incidence of the Primary Composite End Point and Its Components
Time-to-first-event Kaplan-Meier analysis. The median (IQR) observation times were (A) 48.2 (12.6-52.1) months for early intervention and 36.5 (13.8-49.6) months for conservative management; (B) 48.5 (15.9-52.9) months for early intervention and 48.1 (23.7-55.3) months for conservative management; and (C) 48.2 (12.6-52.1) months for early intervention and 36.5 (13.8-49.6) months for conservative management.
See this image and copyright information in PMC

Comment on

References

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