Firibastat Versus Ramipril After Acute Mechanical Reperfusion of Anterior Myocardial Infarction: A Phase 2 Study.
Journal
American journal of cardiovascular drugs : drugs, devices, and other interventions
ISSN: 1179-187X
Titre abrégé: Am J Cardiovasc Drugs
Pays: New Zealand
ID NLM: 100967755
Informations de publication
Date de publication:
Mar 2023
Mar 2023
Historique:
accepted:
09
01
2023
pubmed:
10
2
2023
medline:
15
3
2023
entrez:
9
2
2023
Statut:
ppublish
Résumé
Preclinical data suggest that central renin-angiotensin system blockade by the brain aminopeptidase-A inhibitor firibastat can improve left ventricular ejection fraction (LVEF) after myocardial infarction (MI). This study aimed to compare the effect of firibastat versus ramipril on post-MI LVEF. In this phase 2, randomized, double-blind trial, patients selected within 24 h of first acute anterior MI treated by primary percutaneous coronary intervention were randomly assigned (1:1:1) to firibastat 100 mg, firibastat 500 mg or ramipril 5 mg, each twice daily for 12 weeks. The primary endpoint was change in LVEF on cardiac magnetic resonance imaging (cMRI) from baseline to day 84 in the modified intent-to-treat (mITT) population (at least one dose received and one follow-up cMRI available) for each treatment group. From June 4, 2019 to April 12, 2021, 294 patients were randomized and 229 were evaluable for the mITT analysis. After 12 weeks, mean ± standard deviation (SD) percent change in LVEF was 5.6 ± 1.2 with firibastat 100 mg, 5.3 ± 1.1 with firibastat 500 mg and 5.7 ± 1.1 with ramipril. The absolute ± SE adjusted difference in LVEF change from baseline between firibastat 500 mg and ramipril was - 0.36 ± 1.32% (p = 0.79). Occurrence of treatment-related adverse events was similar in the three groups. Firibastat was not superior to ramipril for prevention of left ventricular dysfunction after first acute anterior MI, and their safety profiles were similar. ClinicalTrials.gov identifier NCT03715998.
Sections du résumé
BACKGROUND
BACKGROUND
Preclinical data suggest that central renin-angiotensin system blockade by the brain aminopeptidase-A inhibitor firibastat can improve left ventricular ejection fraction (LVEF) after myocardial infarction (MI).
OBJECTIVES
OBJECTIVE
This study aimed to compare the effect of firibastat versus ramipril on post-MI LVEF.
METHODS
METHODS
In this phase 2, randomized, double-blind trial, patients selected within 24 h of first acute anterior MI treated by primary percutaneous coronary intervention were randomly assigned (1:1:1) to firibastat 100 mg, firibastat 500 mg or ramipril 5 mg, each twice daily for 12 weeks. The primary endpoint was change in LVEF on cardiac magnetic resonance imaging (cMRI) from baseline to day 84 in the modified intent-to-treat (mITT) population (at least one dose received and one follow-up cMRI available) for each treatment group.
RESULTS
RESULTS
From June 4, 2019 to April 12, 2021, 294 patients were randomized and 229 were evaluable for the mITT analysis. After 12 weeks, mean ± standard deviation (SD) percent change in LVEF was 5.6 ± 1.2 with firibastat 100 mg, 5.3 ± 1.1 with firibastat 500 mg and 5.7 ± 1.1 with ramipril. The absolute ± SE adjusted difference in LVEF change from baseline between firibastat 500 mg and ramipril was - 0.36 ± 1.32% (p = 0.79). Occurrence of treatment-related adverse events was similar in the three groups.
CONCLUSIONS
CONCLUSIONS
Firibastat was not superior to ramipril for prevention of left ventricular dysfunction after first acute anterior MI, and their safety profiles were similar.
REGISTRATION
BACKGROUND
ClinicalTrials.gov identifier NCT03715998.
Identifiants
pubmed: 36757536
doi: 10.1007/s40256-023-00567-8
pii: 10.1007/s40256-023-00567-8
doi:
Substances chimiques
Ramipril
L35JN3I7SJ
Banques de données
ClinicalTrials.gov
['NCT03715998']
Types de publication
Randomized Controlled Trial
Clinical Trial, Phase II
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
207-217Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
Références
Mahmood SS, Wang TJ. The epidemiology of congestive heart failure: the Framingham Heart Study perspective. Glob Heart [Internet]. 2013;8:77–82. Available at: https://globalheartjournal.com/articles/abstract/10.1016/j.gheart.2012.12.006/
Roger VL. Epidemiology of heart failure. Circ Res. 2013;113:646–59.
doi: 10.1161/CIRCRESAHA.113.300268
pubmed: 23989710
pmcid: 3806290
Tokmakova MP, Skali H, Kenchaiah S, et al. Chronic kidney disease, cardiovascular risk, and response to angiotensin-converting enzyme inhibition after myocardial infarction: the Survival And Ventricular Enlargement (SAVE) study. Circulation. 2004;110:3667–73.
doi: 10.1161/01.CIR.0000149806.01354.BF
pubmed: 15569840
Køber L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med. 1995;333:1670–6.
doi: 10.1056/NEJM199512213332503
pubmed: 7477219
Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Lancet. 1993;342:821–8.
Dickstein K, Kjekshus J. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Lancet. 2002;360:752–60.
doi: 10.1016/S0140-6736(02)09895-1
pubmed: 12241832
Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:1893–906.
doi: 10.1056/NEJMoa032292
pubmed: 14610160
Ibanez B, James S, Agewall S, et al. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;39:119–77.
doi: 10.1093/eurheartj/ehx393
pubmed: 28886621
O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;127:e362-425.
doi: 10.1161/CIR.0b013e3182742c84
pubmed: 23247304
Marc Y, Boitard SE, Balavoine F, Azizi M, Llorens-Cortes C. Targeting brain aminopeptidase A: a new strategy for the treatment of hypertension and heart failure. Can J Cardiol. 2020;36:721–31.
doi: 10.1016/j.cjca.2020.03.005
pubmed: 32389345
Huang BS, Ahmad M, White RA, Marc Y, Llorens-Cortes C, Leenen FHH. Inhibition of brain angiotensin III attenuates sympathetic hyperactivity and cardiac dysfunction in rats post-myocardial infarction. Cardiovasc Res. 2013;97:424–31.
doi: 10.1093/cvr/cvs420
pubmed: 23257024
Leenen FHH, Ahmad M, Marc Y, Llorens-Cortes C. Specific inhibition of brain angiotensin III formation as a new strategy for prevention of heart failure after myocardial infarction. J Cardiovasc Pharmacol. 2019;73:82–91.
doi: 10.1097/FJC.0000000000000638
pubmed: 30531435
Boitard SE, Marc Y, Keck M, et al. Brain renin-angiotensin system blockade with orally active aminopeptidase A inhibitor prevents cardiac dysfunction after myocardial infarction in mice. J Mol Cell Cardiol. 2019;127:215–22.
doi: 10.1016/j.yjmcc.2018.12.008
pubmed: 30599150
Boitard SE, Keck M, Deloux R, et al. QGC606, a best-in-class orally active centrally acting aminopeptidase A inhibitor prodrug, for treating heart failure following myocardial infarction. Can J Cardiol. 2022;38:815–27.
doi: 10.1016/j.cjca.2022.01.019
pubmed: 35091008
Azizi M, Courand PY, Denolle T, et al. A pilot double-blind randomised placebo controlled crossover pharmacodynamic study of the centrally active aminopeptidase A inhibitor, firibastat, in hypertension. J Hypertens. 2019;37:1722–8.
doi: 10.1097/HJH.0000000000002092
pubmed: 30882604
Ferdinand KC, Balavoine F, Besse B, et al. Efficacy and safety of firibastat, a first-in-class brain aminopeptidase A inhibitor, in hypertensive overweight patients of multiple ethnic origins. Circulation. 2019;140:138–46.
doi: 10.1161/CIRCULATIONAHA.119.040070
pubmed: 31014072
Balavoine F, Azizi M, Bergerot D, et al. Randomised, double-blind, placebo-controlled, dose-escalating phase I study of QGC001, a centrally acting aminopeptidase A inhibitor prodrug. Clin Pharmacokinet. 2014;53:385–95.
doi: 10.1007/s40262-013-0125-y
pubmed: 24337978
FRESH Study: https://www.clinicaltrials.gov/ct2/show/NCT04277884 .
REFRESH Study: https://www.clinicaltrials.gov/ct2/show/NCT04857840 .
GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Gruppo Italiano per lo Studio della Sopravvivenza nell'infarto Miocardico. Lancet. 1994;343:1115–22.
ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. Lancet. 1995;345:669–85.
Pfeffer MA, Claggett B, Lewis EF, et al. Angiotensin receptor–neprilysin inhibition in acute myocardial infarction. N Engl J Med. 2021;385:1845–55.
doi: 10.1056/NEJMoa2104508
pubmed: 34758252
Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309–21.
doi: 10.1056/NEJMoa030207
pubmed: 12668699