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Association Between The Burden Of Cardiovascular-related Hospitalizations And All-cause Mortality In Transthyretin Amyloid Cardiomyopathy: Insights From ATTRibute-CM

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Author Block: Quan M. Bui1, Prem Soman2, Michele Emdin3,4, Justin L. Grodin5,6, Amrut Ambardekar7, Michel G. Khouri8, Kristoffer Grundtvig Skaarup9, Chris Chen10, Suresh Siddhanti10, Jean-François Tamby10, Hanna K. Gaggin11, Daniel P. Judge12, Kevin M. Alexander13, Ahmad Masri14. 1Division of Cardiovascular Medicine, University of California, La Jolla, San Diego, CA; 2Division of Cardiology, University of Pittsburgh Medical Center, Pittsburgh, PA; 3Interdisciplinary Center for Health Sciences, Scuola Superiore Sant’Anna, Pisa, Italy; 4Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy; 5Parkland Health and Hospital System, Dallas, TX; 6Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX; 7Division of Cardiology, Department of Medicine, University of Colorado,, Aurora, CO; 8Duke University School of Medicine, Durham, NC; 9Department of Cardiology, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark; 10BridgeBio Pharma, Inc., San Francisco, CA; 11Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA; 12Division of Cardiology, Medical University of South Carolina, Charleston, SC; 13Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA; 14Division of Cardiology, Oregon Health and Science University, Portland, OR
Disclosure Block: Q.M.Bui: Consultant; Bio-Medical Startup; Papillon Therapeutics, Myoventive, CureMetrix, Consultant; Pharmaceutical Company/Distributors; Bristol-Myers Squibb, Research Support; Pharmaceutical Company/Distributors; Ionis Pharmaceuticals. J.Tamby: n/a. H.K.Gaggin: n/a. D.P.Judge: Consultant; Pharmaceutical Company/Distributors; Alnylam Pharmaceuticals, Attralus, BridgeBio, LEXEO Therapeutics, Novo Nordisk, Rocket Pharmaceuticals, Bayer AG, Alexion Pharmaceuticals. K.M.Alexander: Advisory Panel; Pharmaceutical Company/Distributors; Alnylam Pharmaceuticals, Arbor Biotechnologies, Consultant; Pharmaceutical Company/Distributors; Eidos Therapeutics, Pfizer, Ionis Pharmaceuticals, Novo Nordisk, Bristol-Myers Squibb. A.Masri: Advisory Panel; Bio-Medical Startup; Haya, Consultant; Bio-Medical Startup; Tenaya Therapeutics, Intellia Therapeutics, Akros, Prothena, Edgewise, Consultant; Pharmaceutical Company/Distributors; AstraZeneca, Attralus, Bristol-Myers Squibb, Cytokinetics, Alnylam Pharmaceuticals, Pfizer, Ionis Pharmaceuticals, Eidos Therapeutics, BioMarin, Lexicon Pharmaceuticals, Alexion Pharmaceuticals, Research Support; Pharmaceutical Company/Distributors; Pfizer, Ionis Pharmaceuticals. P.Soman: Advisory Panel; Device Manufacturer/Distributor; Spectrum Dynamics, Ionetix, Advisory Panel; Pharmaceutical Company/Distributors; Alnylam Pharmaceuticals, Pfizer, Eidos Therapeutics, Pfizer. M.Emdin: n/a. J.L.Grodin: n/a. A.Ambardekar: None. M.G.Khouri: Advisory Panel; Pharmaceutical Company/Distributors; Alnylam Pharmaceuticals, Pfizer, Eidos Therapeutics, AstraZeneca, Research Support; Pharmaceutical Company/Distributors; Alnylam Pharmaceuticals, Eidos Therapeutics, Ionis Pharmaceuticals, Alexion Pharmaceuticals, Moleculin Biotech, Intellia Therapeutics, Speaker's Bureau; Pharmaceutical Company/Distributors; Alnylam Pharmaceuticals, Eidos Therapeutics. K.Grundtvig skaarup: n/a. C.Chen: n/a. S.Siddhanti: n/a.

Introduction: In the phase 3 ATTRibute-CM study (NCT03860935), treatment with acoramidis, a novel, oral transthyretin (TTR) stabilizer that achieves near‑complete (≥90%) TTR stabilization, led to a 50% risk reduction in cardiovascular-related hospitalization (CVH) through Month 30, compared with placebo, in participants with transthyretin amyloid cardiomyopathy (ATTR-CM). Efficacy on CVH was observed early, within the first 3 months. CVH, a known predictor of mortality in patients with general heart failure, is not well characterized in ATTR‑CM; the relationship between CVH burden and survival has not been fully evaluated.
Hypothesis: A higher burden of CVH is associated with an increased risk of all-cause mortality (ACM) in patients with ATTR-CM.
Methods: ATTRibute-CM participants were randomized 2:1 to receive acoramidis HCl 800 mg or placebo twice daily for 30 months. The modified intention-to-treat (mITT) population included all randomized participants who had a baseline estimated glomerular filtration rate ≥30 mL/min/1.73 m2. This post hoc analysis across pooled treatment groups in the mITT population evaluated the risk of subsequent ACM in participants who experienced 0, 1, and ≥2 CVH events during the study. CVH was defined as a nonelective admission to an acute care setting for cardiovascular-related morbidity (≥24 hours) or an urgent heart failure visit, defined as an outpatient visit to an emergency department or urgent care (<24 hours) for worsening heart failure requiring intravenous diuretics. Kaplan-Meier curves estimated survival within each group; a log-rank test was used to compare the curves. The timing of CVH events was not adjusted for.
Results: Of the 611 participants in the mITT population, 416 had no CVH events, 117 had 1 CVH event, and 78 had ≥2 CVH events. Participants with 0, 1, and ≥2 CVH events differed by proportion with variant ATTR-CM (7.5, 12.0, and 17.9%, respectively) and NT-proBNP at baseline (median: 2046.0, 2473.0, and 2881.0 pg/mL, respectively). Survival progressively decreased with increasing CVH burden over the 30-month follow-up period. The risk of ACM over 30 months significantly increased with increasing number of CVH events. Survival probability (95% CI) in participants with 0, 1, and ≥2 CVH events was 86.7% (82.9-89.7%), 68.4% (59.1-76.0%), and 47.7% (35.9-58.6%), respectively (log-rank p<0.0001), demonstrating an incremental increase in mortality risk across levels of CVH burden (Figure).
Conclusions: In ATTRibute-CM, a higher burden of CVH events was associated with a significantly higher subsequent risk of ACM over 30 months. The association between CVH reduction with effective therapies and improved survival warrants further study.