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Original Investigation |

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

Michelle L. O’Donoghue, MD, MPH1; Ruchira Glaser, MD, MSCE2; Matthew A. Cavender, MD1; Philip E. Aylward, BM, BCh, PhD3; Marc P. Bonaca, MD, MPH1; Andrzej Budaj, MD, PhD4; Richard Y. Davies, MS2; Mikael Dellborg, MD5; Keith A. A. Fox, MBChB6; Jorge Antonio T. Gutierrez, MD1; Christian Hamm, MD7; Robert G. Kiss, MD, PhD8; František Kovar, MD, PhD9; Julia F. Kuder, MA1; Kyung Ah Im, PhD1; John J. Lepore, MD2; Jose L. Lopez-Sendon, MD10; Ton Oude Ophuis, MD, PhD11; Alexandr Parkhomenko, MD12; Jennifer B. Shannon, MS13; Jindrich Spinar, MD14; Jean-Francois Tanguay, MD15; Mikhail Ruda, MD, PhD16; P. Gabriel Steg, MD17; Pierre Theroux, MD15; Stephen D. Wiviott, MD1; Ian Laws, PhD2; Marc S. Sabatine, MD, MPH1; David A. Morrow, MD, MPH1 ; for the LATITUDE-TIMI 60 Investigators
[+] 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.
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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

Figures in this Article

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Figure 1.
Participant Flow in the LATITUDE-TIMI 60 Trial

Database did not include the number of individuals screened for study participation or the number excluded before randomization.

aCompromise of data integrity at a single site led to exclusion of data in 14 participants.

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Figure 2.
Kaplan-Meier Curves for the Primary End Point

Cumulative incidence of the primary end point of cardiovascular death, myocardial infarction, or severe recurrent ischemia leading to urgent revascularization through 12 weeks with losmapimod vs placebo.

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Figure 3.
Hazard Ratios for the Primary End Point in Prespecified Subgroups of Interest at 12 Weeks After Randomization

Hazard ratios for the primary end point (cardiovascular death, myocardial infarction [MI], or severe recurrent ischemia leading to urgent revascularization) with losmapimod vs placebo in various subgroups at 12 weeks. Predictors of cardiovascular risk included age 60 years or older, prior MI, prior coronary artery bypass graft (CABG) surgery, non–ST elevation with ST-segment depression, diabetes mellitus requiring pharmacotherapy or coexistent arterial disease in at least 1 other peripheral territory. PCI indicates percutaneous coronary intervention. Data marker sizes are weighted based on number of individuals in each subgroup.

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Figure 4.
Serial Biomarker Concentrations

Concentration of high-sensitivity C-reactive protein (hs-CRP) and N-terminal pro–brain natriuretic peptide (NT-pro-BNP) over time with losmapimod vs placebo. The errors bars indicate the 95% confidence interval around the geometric mean. For hs-CRP, P<.001 for losmapimod vs placebo at 48 hours and at week 12; P=.004 at week 4. For NT-pro-BNP, P<.001 for losmapimod vs placebo at week 4 and at week 12.

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