Scott D Solomon1, David Adams2, Arnt Kristen3, Martha Grogan4, Alejandra González-Duarte5, Mathew S Maurer6, Giampaolo Merlini7, Thibaud Damy8, Michel S Slama9, Thomas H Brannagan10, Angela Dispenzieri11, John L Berk12, Amil M Shah1, Pushkal Garg13, Akshay Vaishnaw13, Verena Karsten13, Jihong Chen13, Jared Gollob13, John Vest13, Ole Suhr14. 1. Brigham and Women's Hospital, Harvard Medical School, Boston, MA (S.D.S., A.M.S.). 2. Assistance Publique - Hôpitaux de Paris, National Reference Center for FAP, CHU Bicêtre, INSERM U1195, Université Paris Sud, Le Kremlin-Bicêtre, France (D.A.). 3. Department of Cardiology, University of Heidelberg, Germany (A.K.). 4. Mayo Clinic, Rochester, MN (M.G.). 5. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, Mexico (A.G.-D.). 6. Department of Medicine/Cardiology, Columbia University Medical Center, New York, NY (M.S.M.). 7. Amyloidosis Research and Treatment Center, Foundation IRCCS Policlinico San Matteo and University of Pavia, Italy (G.M.). 8. French Referral Center for Cardiac Amyloidosis, Amyloidosis Mondor Network, GRC Amyloid Research Institute, Department of Cardiology, Assistance Publique - Hôpitaux de Paris, CHU Henri Mondor, and INSERM U955, Clinical Investigation Center, and DHU ATVB, Creteil, France (T.D.). 9. Hôpital Bichat, Cardiology Department, Université Paris Sud, Paris, France (M.S.S.). 10. Neurology Department, Columbia University, College of Physicians and Surgeons, New York, NY (T.H.B.). 11. Division of Hematology, Mayo Clinic, Rochester, MN (A.D.). 12. Amyloidosis Center, Boston Medical Center, MA (J.L.B.). 13. Alnylam Pharmaceuticals, Cambridge, MA (P.G., A.V., V.K., J.C., J.G., J.V.). 14. Department of Public Health and Clinical Medicine, Umeå University, Sweden (O.S.).
Abstract
BACKGROUND: Hereditary transthyretin-mediated (hATTR) amyloidosis is a rapidly progressive, multisystem disease that presents with cardiomyopathy or polyneuropathy. The APOLLO study assessed the efficacy and tolerability of patisiran in patients with hATTR amyloidosis. The effects of patisiran on cardiac structure and function in a prespecified subpopulation of patients with evidence of cardiac amyloid involvement at baseline were assessed. METHODS: APOLLO was an international, randomized, double-blind, placebo-controlled phase 3 trial in patients with hATTR amyloidosis. Patients were randomized 2:1 to receive 0.3 mg/kg patisiran or placebo via intravenous infusion once every 3 weeks for 18 months. The prespecified cardiac subpopulation comprised patients with a baseline left ventricular wall thickness ≥13 mm and no history of hypertension or aortic valve disease. Prespecified exploratory cardiac end points included mean left ventricular wall thickness, global longitudinal strain, and N-terminal prohormone of brain natriuretic peptide. Cardiac parameters in the overall APOLLO patient population were also evaluated. A composite end point of cardiac hospitalizations and all-cause mortality was assessed in a post hoc analysis. RESULTS: In the cardiac subpopulation (n=126; 56% of total population), patisiran reduced mean left ventricular wall thickness (least-squares mean difference ± SEM: -0.9±0.4 mm, P=0.017), interventricular septal wall thickness, posterior wall thickness, and relative wall thickness at month 18 compared with placebo. Patisiran also led to increased end-diastolic volume (8.3±3.9 mL, P=0.036), decreased global longitudinal strain (-1.4±0.6%, P=0.015), and increased cardiac output (0.38±0.19 L/min, P=0.044) compared with placebo at month 18. Patisiran lowered N-terminal prohormone of brain natriuretic peptide at 9 and 18 months (at 18 months, ratio of fold-change patisiran/placebo 0.45, P<0.001). A consistent effect on N-terminal prohormone of brain natriuretic peptide at 18 months was observed in the overall APOLLO patient population (n=225). Median follow-up duration was 18.7 months. The exposure-adjusted rates of cardiac hospitalizations and all-cause death were 18.7 and 10.1 per 100 patient-years in the placebo and patisiran groups, respectively (Andersen-Gill hazard ratio, 0.54; 95% CI, 0.28-1.01). CONCLUSIONS:Patisiran decreased mean left ventricular wall thickness, global longitudinal strain, N-terminal prohormone of brain natriuretic peptide, and adverse cardiac outcomes compared with placebo at month 18, suggesting that patisiran may halt or reverse the progression of the cardiac manifestations of hATTR amyloidosis. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01960348.
RCT Entities:
BACKGROUND: Hereditary transthyretin-mediated (hATTR) amyloidosis is a rapidly progressive, multisystem disease that presents with cardiomyopathy or polyneuropathy. The APOLLO study assessed the efficacy and tolerability of patisiran in patients with hATTRamyloidosis. The effects of patisiran on cardiac structure and function in a prespecified subpopulation of patients with evidence of cardiac amyloid involvement at baseline were assessed. METHODS: APOLLO was an international, randomized, double-blind, placebo-controlled phase 3 trial in patients with hATTRamyloidosis. Patients were randomized 2:1 to receive 0.3 mg/kg patisiran or placebo via intravenous infusion once every 3 weeks for 18 months. The prespecified cardiac subpopulation comprised patients with a baseline left ventricular wall thickness ≥13 mm and no history of hypertension or aortic valve disease. Prespecified exploratory cardiac end points included mean left ventricular wall thickness, global longitudinal strain, and N-terminal prohormone of brain natriuretic peptide. Cardiac parameters in the overall APOLLO patient population were also evaluated. A composite end point of cardiac hospitalizations and all-cause mortality was assessed in a post hoc analysis. RESULTS: In the cardiac subpopulation (n=126; 56% of total population), patisiran reduced mean left ventricular wall thickness (least-squares mean difference ± SEM: -0.9±0.4 mm, P=0.017), interventricular septal wall thickness, posterior wall thickness, and relative wall thickness at month 18 compared with placebo. Patisiran also led to increased end-diastolic volume (8.3±3.9 mL, P=0.036), decreased global longitudinal strain (-1.4±0.6%, P=0.015), and increased cardiac output (0.38±0.19 L/min, P=0.044) compared with placebo at month 18. Patisiran lowered N-terminal prohormone of brain natriuretic peptide at 9 and 18 months (at 18 months, ratio of fold-change patisiran/placebo 0.45, P<0.001). A consistent effect on N-terminal prohormone of brain natriuretic peptide at 18 months was observed in the overall APOLLO patient population (n=225). Median follow-up duration was 18.7 months. The exposure-adjusted rates of cardiac hospitalizations and all-cause death were 18.7 and 10.1 per 100 patient-years in the placebo and patisiran groups, respectively (Andersen-Gill hazard ratio, 0.54; 95% CI, 0.28-1.01). CONCLUSIONS:Patisiran decreased mean left ventricular wall thickness, global longitudinal strain, N-terminal prohormone of brain natriuretic peptide, and adverse cardiac outcomes compared with placebo at month 18, suggesting that patisiran may halt or reverse the progression of the cardiac manifestations of hATTRamyloidosis. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01960348.
Authors: Frederick L Ruberg; Martha Grogan; Mazen Hanna; Jeffery W Kelly; Mathew S Maurer Journal: J Am Coll Cardiol Date: 2019-06-11 Impact factor: 24.094
Authors: Riemer H J A Slart; Andor W J M Glaudemans; Walter Noordzij; Johan Bijzet; Bouke P C Hazenberg; Hans L A Nienhuis Journal: Eur J Nucl Med Mol Imaging Date: 2019-04-23 Impact factor: 9.236
Authors: Luca Gentile; Massimo Russo; Marco Luigetti; Giulia Bisogni; Andrea Di Paolantonio; Angela Romano; Valeria Guglielmino; Ilenia Arimatea; Mario Sabatelli; Antonio Toscano; Giuseppe Vita; Anna Mazzeo Journal: Brain Sci Date: 2021-04-19