title: Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction: A Randomized Clinical Trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT02145468.
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: O'Donoghue
authors.affiliation: Metabolic Pathways and Cardiovascular Unit, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Ruchira
authors.initials: R
authors.lastname: Glaser
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cavender
authors.affiliation: South Australian Health and Medical Research Institute, Flinders University Medical Centre, Adelaide, South Australia, Australia.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Aylward
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Bonaca
authors.affiliation: Postgraduate Medical School, Grochowski Hospital, Warsaw, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Budaj
authors.affiliation: Metabolic Pathways and Cardiovascular Unit, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Richard Y
authors.initials: RY
authors.lastname: Davies
authors.affiliation: Sahlgrenska University Hospital/Ostra and Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Dellborg
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, Scotland.
authors.forename: Keith A A
authors.initials: KA
authors.lastname: Fox
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Jorge Antonio T
authors.initials: JA
authors.lastname: Gutierrez
authors.affiliation: Kerckhoff Heart Center, Bad Nauheim, University of Giessen, Giessen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hamm
authors.affiliation: Department of Cardiology, Military Hospital, Budapest, Hungary.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Kiss
authors.affiliation: Department of Internal Medicine I, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovak Republic.
authors.forename: František
authors.initials: F
authors.lastname: Kovar
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Julia F
authors.initials: JF
authors.lastname: Kuder
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Kyung Ah
authors.initials: KA
authors.lastname: Im
authors.affiliation: Metabolic Pathways and Cardiovascular Unit, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: John J
authors.initials: JJ
authors.lastname: Lepore
authors.affiliation: Cardiovascular Division, University Hospital La Paz, Madrid, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Lopez-Sendon
authors.affiliation: Canisius-Wilhelmina Hospital, Nijmegen, the Netherlands.
authors.forename: Ton Oude
authors.initials: TO
authors.lastname: Ophuis
authors.affiliation: Ukranian Strazhesko Institute of Cardiology, Kiev, Ukraine.
authors.forename: Alexandr
authors.initials: A
authors.lastname: Parkhomenko
authors.affiliation: PAREXEL International, Durham, North Carolina.
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Shannon
authors.affiliation: University Hospital, Jihlavska, Brno, Czech Republic.
authors.forename: Jindrich
authors.initials: J
authors.lastname: Spinar
authors.affiliation: Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Tanguay
authors.affiliation: Cardiology Research Center, Moscow, Russia.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Ruda
authors.affiliation: Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, and Université Paris-Diderot, Paris, France.
authors.forename: P Gabriel
authors.initials: PG
authors.lastname: Steg
authors.affiliation: Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Theroux
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Wiviott
authors.affiliation: Metabolic Pathways and Cardiovascular Unit, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Ian
authors.initials: I
authors.lastname: Laws
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Sabatine
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: David A
authors.initials: DA
authors.lastname: Morrow
mesh_terms: D000368:Aged; D000465:Algorithms; D002097:C-Reactive Protein / Q000032:analysis; D003521:Cyclopropanes / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality; D017202:Myocardial Ischemia / Q000517:prevention & control / Q000601:surgery; D009204:Myocardial Revascularization; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D012008:Recurrence; D055502:Secondary Prevention; D017211:Treatment Failure; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: C543534:6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide; D003521:Cyclopropanes; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D002097:C-Reactive Protein; D048051:p38 Mitogen-Activated Protein Kinases