Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction

A Randomized Clinical Trial

Michelle L O'Donoghue, Ruchira Glaser, Matthew A. Cavender, Philip E. Aylward, Marc P. Bonaca, Andrzej Budaj, Richard Y Davies, Mikael Dellborg, Keith A A Fox, Jorge Antonio T Gutierrez, Christian Hamm, Robert Gabor Kiss, František Kovar, Julia F Kuder, Kyung Ah Im, John J Lepore, Jose L Lopez-Sendon, Ton Oude Ophuis, Alexandr Parkhomenko, Jennifer B Shannon & 11 others Jindrich Spinar, Jean Francois Tanguay, Mikhail Ruda, P. Gabriel Steg, Pierre Theroux, Stephen D. Wiviott, Ian Laws, Marc S. Sabatine, David A. Morrow, LATITUDE-TIMI 60 Investigators, Alessandro Salvioni

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1591-9
Number of pages9
JournalJAMA - Journal of the American Medical Association
Volume315
Issue number15
DOIs
Publication statusPublished - Apr 19 2016

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Randomized Controlled Trials
Myocardial Infarction
Placebos
p38 Mitogen-Activated Protein Kinases
6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide
Inflammation
Safety
Protein Kinase Inhibitors
Atherosclerosis
Ischemia
Guidelines
Therapeutics
Population

Keywords

  • Aged
  • Algorithms
  • C-Reactive Protein
  • Cyclopropanes
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • Hospitalization
  • Humans
  • Male
  • Middle Aged
  • Myocardial Infarction
  • Myocardial Ischemia
  • Myocardial Revascularization
  • Protein Kinase Inhibitors
  • Pyridines
  • Recurrence
  • Secondary Prevention
  • Treatment Failure
  • p38 Mitogen-Activated Protein Kinases
  • Journal Article
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

Cite this

Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction : A Randomized Clinical Trial. / O'Donoghue, Michelle L; Glaser, Ruchira; Cavender, Matthew A.; Aylward, Philip E.; Bonaca, Marc P.; Budaj, Andrzej; Davies, Richard Y; Dellborg, Mikael; Fox, Keith A A; Gutierrez, Jorge Antonio T; Hamm, Christian; Kiss, Robert Gabor; Kovar, František; Kuder, Julia F; Im, Kyung Ah; Lepore, John J; Lopez-Sendon, Jose L; Ophuis, Ton Oude; Parkhomenko, Alexandr; Shannon, Jennifer B; Spinar, Jindrich; Tanguay, Jean Francois; Ruda, Mikhail; Steg, P. Gabriel; Theroux, Pierre; Wiviott, Stephen D.; Laws, Ian; Sabatine, Marc S.; Morrow, David A.; LATITUDE-TIMI 60 Investigators ; Salvioni, Alessandro.

In: JAMA - Journal of the American Medical Association, Vol. 315, No. 15, 19.04.2016, p. 1591-9.

Research output: Contribution to journalArticle

O'Donoghue, ML, Glaser, R, Cavender, MA, Aylward, PE, Bonaca, MP, Budaj, A, Davies, RY, Dellborg, M, Fox, KAA, Gutierrez, JAT, Hamm, C, Kiss, RG, Kovar, F, Kuder, JF, Im, KA, Lepore, JJ, Lopez-Sendon, JL, Ophuis, TO, Parkhomenko, A, Shannon, JB, Spinar, J, Tanguay, JF, Ruda, M, Steg, PG, Theroux, P, Wiviott, SD, Laws, I, Sabatine, MS, Morrow, DA, LATITUDE-TIMI 60 Investigators & Salvioni, A 2016, 'Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction: A Randomized Clinical Trial', JAMA - Journal of the American Medical Association, vol. 315, no. 15, pp. 1591-9. https://doi.org/10.1001/jama.2016.3609
O'Donoghue, Michelle L ; Glaser, Ruchira ; Cavender, Matthew A. ; Aylward, Philip E. ; Bonaca, Marc P. ; Budaj, Andrzej ; Davies, Richard Y ; Dellborg, Mikael ; Fox, Keith A A ; Gutierrez, Jorge Antonio T ; Hamm, Christian ; Kiss, Robert Gabor ; Kovar, František ; Kuder, Julia F ; Im, Kyung Ah ; Lepore, John J ; Lopez-Sendon, Jose L ; Ophuis, Ton Oude ; Parkhomenko, Alexandr ; Shannon, Jennifer B ; Spinar, Jindrich ; Tanguay, Jean Francois ; Ruda, Mikhail ; Steg, P. Gabriel ; Theroux, Pierre ; Wiviott, Stephen D. ; Laws, Ian ; Sabatine, Marc S. ; Morrow, David A. ; LATITUDE-TIMI 60 Investigators ; Salvioni, Alessandro. / Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction : A Randomized Clinical Trial. In: JAMA - Journal of the American Medical Association. 2016 ; Vol. 315, No. 15. pp. 1591-9.
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TY - JOUR

T1 - Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction

T2 - A Randomized Clinical Trial

AU - O'Donoghue, Michelle L

AU - Glaser, Ruchira

AU - Cavender, Matthew A.

AU - Aylward, Philip E.

AU - Bonaca, Marc P.

AU - Budaj, Andrzej

AU - Davies, Richard Y

AU - Dellborg, Mikael

AU - Fox, Keith A A

AU - Gutierrez, Jorge Antonio T

AU - Hamm, Christian

AU - Kiss, Robert Gabor

AU - Kovar, František

AU - Kuder, Julia F

AU - Im, Kyung Ah

AU - Lepore, John J

AU - Lopez-Sendon, Jose L

AU - Ophuis, Ton Oude

AU - Parkhomenko, Alexandr

AU - Shannon, Jennifer B

AU - Spinar, Jindrich

AU - Tanguay, Jean Francois

AU - Ruda, Mikhail

AU - Steg, P. Gabriel

AU - Theroux, Pierre

AU - Wiviott, Stephen D.

AU - Laws, Ian

AU - Sabatine, Marc S.

AU - Morrow, David A.

AU - LATITUDE-TIMI 60 Investigators

AU - Salvioni, Alessandro

PY - 2016/4/19

Y1 - 2016/4/19

N2 - 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.

AB - 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.

KW - Aged

KW - Algorithms

KW - C-Reactive Protein

KW - Cyclopropanes

KW - Double-Blind Method

KW - Drug Administration Schedule

KW - Female

KW - Hospitalization

KW - Humans

KW - Male

KW - Middle Aged

KW - Myocardial Infarction

KW - Myocardial Ischemia

KW - Myocardial Revascularization

KW - Protein Kinase Inhibitors

KW - Pyridines

KW - Recurrence

KW - Secondary Prevention

KW - Treatment Failure

KW - p38 Mitogen-Activated Protein Kinases

KW - Journal Article

KW - Multicenter Study

KW - Randomized Controlled Trial

KW - Research Support, Non-U.S. Gov't

U2 - 10.1001/jama.2016.3609

DO - 10.1001/jama.2016.3609

M3 - Article

VL - 315

SP - 1591

EP - 1599

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0002-9955

IS - 15

ER -