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JAMA. 2016 Apr 19;315(15):1591-9. doi: 10.1001/jama.2016.3609.

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

Collaborators (352)

Ardissino D, Atar D, Budaj A, Corbalán R, Dalby AJ, Dellborg M, Diaz R, Dorobantu M, Goudev AR, Hamm C, Huo Y, Kiss R, Kovar F, Lewis B, Merlini P, Nicolau JC, Ophuis TO, Parkhomenko A, Ruda M, Seung KB, Sinnaeve P, Jensen JS, Ŝpinar J, Sritara P, Tanguay JF, Tziakas D, Uren N, White H, O'Donoghue M, Alves de Lima A, Gomez Vilamajo O, Hrabar A, Licheri A, Macin S, Zapata G, Amerena J, Hammett C, Lehman S, Muhlmann M, Nguyen M, Poulter R, Raffel C, Roberts-Thomson P, Stramer G, Van Gaal W, Charlier F, Cools F, Dangoisse V, De Raedt H, Hermans K, Hoffer E, Missault L, Sinnaeve P, Verhaert D, Vervoort G, Atzev B, Draganov T, Gelev V, Goudev A, Lazov P, Mihov A, Petrov I, Billingsley I, Cheung S, Costa Vitali A, Della Siega A, Kassam S, Nguyen M, Pearce M, Tanguay JF, Wong G, Pérez Pino L, Pincetti C, Rodriguez Venegas M, Verdejo H, Coufal Z, Gregor P, Homza M, Horak D, Matejka J, Sedlon P, Smid O, Spacek R, Spinar J, Stasek J, Tousek F, Brønnum-Schou J, Nielsen H, Rasmussen SL, Skov Jensen J, Hedman A, Reinmets J, Soopold U, Agraou B, Cottin Y, De Labriolle A, Decoulx E, Delarche N, Elbaz M, Ohlmann P, Probst V, Schiele F, Steg G, Appel KF, Bavendiek U, Butter C, Fuisting J, Ghanem A, Groenefeld G, Hamm C, Hoffman U, Kadel C, Karakas M, Leschke M, Mangner N, Moellmann H, Olbrich HG, Reith S, Schwimmbeck P, Sechtem U, Smettan J, Stellbrink C, vom Dahl J, Vorpahl M, Werner N, Zeh W, Zirlik A, Kanakakis I, Kyriakides Z, Mantas I, Styliadis I, Tziakas D, Zarifis I, Chan KK, Wong CY, Yan PY, Benczúr B, Faluközy J, Kiss RG, Lupkovics G, Merkely B, Atar S, Banai S, Katz A, Meisel S, Mosseri M, Ardissino D, Cavallini C, Maria De Biase A, Morocutti G, Musumeci G, Pirelli S, Salvioni A, Hong BK, Jeong JO, Jeong M, Kim CJ, Kim HS, Rha S, Seung KB, Yoon J, Carrillo-Calvillo J, Esturau-Santalo RM, Dirksen M, Gosselink A, Hamer BJ, Magro M, Nierop P, Oude Ophuis, Perik PJ, Prins FJ, Rensing BJ, Ronner E, Slagboom T, Troquay R, van Daele M, van der Heijden R, Devlin G, Elliott J, Harding S, Scott D, Stewart R, Ternouth I, Atar D, Høgalmen G, Hysing J, Larsen A, Trovik T, Añonuevo J, Hay ET, Marañon D, Miranda A, Bujaj A, Gessek J, Jaworska K, Kubica J, Miekus P, Mysiak A, Przewlocki T, Raczak G, Serafin R, Trebacz J, Tyllo M, Wlodarczak A, Wojcik J, Cinteza M, Dorobantu M, Musetescu R, Aksentyev S, Apartsin K, Barbarash O, Berns S, Bessonova N, Duda A, Duplyakov D, Ermoshkina L, Gordeev I, Kobalava Z, Kostenko V, Lapin O, Markov V, Orlikova O, Rebrov A, Ruda M, Shalaev S, Tsyba L, Vishnevsky A, Yakushin S, Hranai M, Hricak V, Juhas S, Kovar F, Abelson M, Basson M, Cyster HP, Dalby A, Dawood S, Horak A, Saaiman J, Barrabes Riu JA, Cequier Fillat A, Delia MA, Fernández-Avilés Díaz F, Genover XB, González Juanatey JR, Lekuona Goya I, López de Sa E, Macaya C, Navarro MJ, Ortega Marcos J, Zamorano JL, Bandh S, Boberg G, Christensen K, Holmgren C, Hornestam B, Mooe T, Råmunddal T, Wagner H, Chiang CE, Hou JY, Hsia CH, Huang WC, Wang JH, Chotinaiwattarakul, Suithichaiyakul T, Yamwong S, Chunhakasem, Kuanprasert S, Kraiz I, Malynovsky Y, Parkhomenko O, Pavlyk S, Rishko M, Vakaliuk I, Zhurba S, Glover J, Irving R, Levy T, Purcell I, Pye M, Uren N, Albirini A, Aycock G Jr, Bach R, Banerjee S, Barr L, Bernstein M, Brechtken J, Burchenal J, Burke M, Chan M, Chandler B, Chandna H, Chane M, Conn E, Dodds A, Duffy B, Eaton G, Ferrier L, French W, Gammon R, Gessler C Jr, Ginete W, Graham B, Gray R, Gruberg L, Guidera S, Henderson DA, Hill R, Hoang K, Jackson C, Jaffrani N, Katopodis J, Kavanaugh K, Kazziha S, Klugherz B, Kraft P, Laddu A, Lambert C Jr, Larrain G, Lee K, Lotun K, Loussararain A, Mansouri V, McCullum K, McLaurin B, Mulkay A, Nahhas G, Othman I, Pap J, Pasquini J, Perlman R, Prashad R, Rao V, Rosenberg M, Ruff C, Sane D, Secaira R, Sharma S, Siegel C, Stuckey T, Tahirkheli N, Tang A, Uretsky B, Warden B, Webber J, Weiss R, Wickemeyer W, Zahr F, Zenni M, Zidar D.

Author information

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

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.

PMID:
27043082
DOI:
10.1001/jama.2016.3609
[Indexed for MEDLINE]

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