Mammalian Target of Rapamycin Inhibition in Patients With ST-Segment Elevation Myocardial Infarction.

BACKGROUND

Early inflammation following acute ST-segment elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (PCI) affects myocardial infarct (MI) size and left ventricular remodeling. The mammalian target of rapamycin (mTOR) is involved in the enhanced inflammatory response and its inhibition has exerted beneficial effects on MI size in preclinical models of acute MI.

OBJECTIVES

The CLEVER-ACS (Controlled Level Everolimus in Acute Coronary Syndromes) trial evaluated the effects of targeting inflammation by mTOR inhibition in patients with STEMI undergoing PCI.

METHODS

CLEVER-ACS was a randomized, multicenter, international, double-blind, placebo-controlled trial. A total of 150 patients with STEMI undergoing PCI were randomly assigned to oral everolimus (days 1-3: 7.5 mg daily; days 4-5: 5.0 mg daily) or placebo for 5 days. The primary endpoint was the change in MI size. The secondary endpoint was the change in microvascular obstruction (MVO) from baseline (12 hours to 5 days after PCI) to 30 days as assessed by cardiac magnetic resonance imaging.

RESULTS

The changes in MI size from baseline to 30 days, the primary endpoint, were -14.2 g (95% CI: -17.4 to -11.1 g) and -12.3 g (95% CI: -16.0 to -8.7 g) in the everolimus and placebo groups (P = 0.99). Corresponding changes in MVO were -4.8 g (95% CI: -6.7 to -2.9 g) and -6.3 g (95% CI: -8.7 to -4.0 g) in the everolimus and placebo groups (P = 0.14). Adverse events did not differ between the study groups.

CONCLUSIONS

Among STEMI patients undergoing PCI, early mTOR inhibition with everolimus did not reduce MI size or MVO at 30 days. (CLEVER-ACS [Controlled Level Everolimus in Acute Coronary Syndromes; NCT01529554).

Informations de copyright

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Funding Support and Author Disclosures This Investigator-Initiated Trial (IIT) was supported by the Swiss National Science Foundation (33IC30_166872; Swiss Clinical Trials Programme). Verum and placebo were provided by Novartis (Basel, Switzerland), including funding to cover the manufacturing and provision of everolimus (Votubia) tablets and the corresponding placebo tablets, the packaging of medications into blister packs according to the randomization list and shipment by the Institute of Hospital Pharmacy, University Hospital Bern, Bern, Switzerland. Dr Stähli has been supported by the H.H. Sheikh Khalifa bin Hamad Al-Thani Research Programme; has received grants to the institution from the OPO Foundation, the Iten-Kohaut Foundation, the German Center for Cardiovascular Research (DZHK), the German Heart Research Foundation, the B. Braun Foundation, Boston Scientific, and Edwards Lifesciences; and has received consulting and speaker fees from Boston Scientific, Abbott Vascular, and MedAlliance. Drs Jung and Kelm have received funds from CRC 1116 of the German Research Foundation. Dr Räber has received research grants to the institution by Abbott, Biotronik, Boston Scientific, Heartflow, Sanofi, and Regeneron; and has received speaker/advisory board fees from Abbott, Amgen, AstraZeneca, Canon, Medtronic, NovoNordisk, Occlutech, and Sanofi. Dr Windecker has received grants to the institution from Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardinal Health, CardioValve, Corflow Therapeutics, CSL Behring, Daiichi-Sankyo, Edwards Lifesciences, Guerbet, InfraRedx, Janssen-Cilag, Johnson & Johnson, Medicure, Medtronic, Merck Sharp & Dohme, Miracor Medical, Novartis, Novo Nordisk, Organon, OrPha Suisse, Pfizer, Polares, Regeneron, Sanofi, Servier, Sinomed, Terumo, Vifor, and V-Wave; has served as unpaid advisory board member and/or unpaid member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Boston Scientific, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, Janssen, MedAlliance, Medtronic, Novartis, Polares, Recardio, Sinomed, Terumo, V-Wave and Xeltis; and has been a member of the steering/executive committee group of several investigator-initiated trials that receive funding by industry without impact on his personal remuneration. Dr Lüscher has received grants from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim Daichi-Sankyo, Novartis, Sanofi, Servier, and Vifor to his institution outside the scope of this work. Dr Landmesser has received grant support to his institution from Novartis, Bayer, and Amgen; and has been speaker or honorary advisory for Novartis, Bayer, Amgen, Pfizer, and Sanofi. Dr Ruschitzka has not received personal payments by pharmaceutical companies or device manufacturers in the last 3 years (remuneration for the time spent in activities, such as participation as steering committee member of clinical trials and member of the Pfizer Research Award selection committee in Switzerland, were made directly to the University of Zurich); the Department of Cardiology (University Hospital of Zurich/University of Zurich) reports research grants, educational grants, and/or travel grants from Abbott, Amgen, AstraZeneca, Bayer, Berlin Heart, B. Braun, Biosense Webster, Biosensors Europe AG, Biotronik, Bristol Myers Squibb, Boehringer Ingelheim, Boston Scientific, Bracco, Cardinal Health Switzerland, Corteria, Daiichi, Diatools AG, Edwards Lifesciences, Guidant Europe NV (BS), Hamilton Health Sciences, Kaneka Corporation, Kantar, Labormedizinisches Zentrum, Medtronic, Merck Sharp & Dohme, Mundipharma Medical Company, Novartis, Novo Nordisk, Orion, Pfizer, Quintiles Switzerland Sarl, Roche Diagnostics, Sahajanand IN, Sanofi, Sarstedt AG, Servier, SIS Medical, SSS International Clinical Research, Terumo Deutschland, Trama Solutions, V-Wave, Vascular Medical, Vifor, Wissens Plus, and ZOLL. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.