Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction: A Randomized Clinical Trial | Acute Coronary Syndromes | JAMA | JAMA Network
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Original Investigation
April 19, 2016

Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction: A Randomized Clinical Trial

Author Affiliations
  • 1TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts
  • 2Metabolic Pathways and Cardiovascular Unit, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania
  • 3South Australian Health and Medical Research Institute, Flinders University Medical Centre, Adelaide, South Australia, Australia
  • 4Postgraduate Medical School, Grochowski Hospital, Warsaw, Poland
  • 5Sahlgrenska University Hospital/Ostra and Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  • 6Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, Scotland
  • 7Kerckhoff Heart Center, Bad Nauheim, University of Giessen, Giessen, Germany
  • 8Department of Cardiology, Military Hospital, Budapest, Hungary
  • 9Department of Internal Medicine I, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovak Republic
  • 10Cardiovascular Division, University Hospital La Paz, Madrid, Spain
  • 11Canisius-Wilhelmina Hospital, Nijmegen, the Netherlands
  • 12Ukranian Strazhesko Institute of Cardiology, Kiev, Ukraine
  • 13PAREXEL International, Durham, North Carolina
  • 14University Hospital, Jihlavska, Brno, Czech Republic
  • 15Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada
  • 16Cardiology Research Center, Moscow, Russia
  • 17Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, and Université Paris-Diderot, Paris, France
JAMA. 2016;315(15):1591-1599. doi:10.1001/jama.2016.3609
Abstract

Importance  p38 Mitogen-activated protein kinase (MAPK)–stimulated inflammation is implicated in atherogenesis, plaque destabilization, and maladaptive processes in myocardial infarction (MI). Pilot data in a phase 2 trial in non–ST elevation MI indicated that the p38 MAPK inhibitor losmapimod attenuates inflammation and may improve outcomes.

Objective  To evaluate the efficacy and safety of losmapimod on cardiovascular outcomes in patients hospitalized with an acute myocardial infarction.

Design, Setting, and Patients  LATITUDE-TIMI 60, a randomized, placebo-controlled, double-blind, parallel-group trial conducted at 322 sites in 34 countries from June 3, 2014, until December 8, 2015. Part A consisted of a leading cohort (n = 3503) to provide an initial assessment of safety and exploratory efficacy before considering progression to part B (approximately 22 000 patients). Patients were considered potentially eligible for enrollment if they had been hospitalized with an acute MI and had at least 1 additional predictor of cardiovascular risk.

Interventions  Patients were randomized to either twice-daily losmapimod (7.5 mg; n = 1738) or matching placebo (n = 1765) on a background of guideline-recommended therapy. Patients were treated for 12 weeks and followed up for an additional 12 weeks.

Main Outcomes and Measures  The primary end point was the composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization with the principal analysis specified at week 12.

Results  In part A, among the 3503 patients randomized (median age, 66 years; 1036 [29.6%] were women), 99.1% had complete ascertainment for the primary outcome. The primary end point occurred by 12 weeks in 123 patients treated with placebo (7.0%) and 139 patients treated with losmapimod (8.1%; hazard ratio, 1.16; 95% CI, 0.91-1.47; P = .24). The on-treatment rates of serious adverse events were 16.0% with losmapimod and 14.2% with placebo.

Conclusions and Relevance  Among patients with acute MI, use of losmapimod compared with placebo did not reduce the risk of major ischemic cardiovascular events. The results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population.

Trial Registration  clinicaltrials.gov Identifier: NCT02145468

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