Effect of losmapimod on cardiovascular outcomes in patients hospitalized with acute myocardial infarction: A randomized clinical trial

LATITUDE-TIMI 60 Investigators

Research output: Article

81 Citations (Scopus)

Abstract

Importance: p38 Mitogen-activated protein kinase (MAPK)-stimulated inflammation is implicated in atherogenesis, plaque destabilization, and maladaptive processes inmyocardial 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 acutemyocardial 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 (7.5mg; 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 pointwas 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.

Original languageEnglish
Pages (from-to)1591-1599
Number of pages9
JournalJAMA - Journal of the American Medical Association
Volume315
Issue number15
DOIs
Publication statusPublished - ápr. 19 2016

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

ASJC Scopus subject areas

  • Medicine(all)

Cite this

@article{ff157545c54d48c3a946d33af6eba092,
title = "Effect of losmapimod on cardiovascular outcomes in patients hospitalized with acute myocardial infarction: A randomized clinical trial",
abstract = "Importance: p38 Mitogen-activated protein kinase (MAPK)-stimulated inflammation is implicated in atherogenesis, plaque destabilization, and maladaptive processes inmyocardial 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 acutemyocardial 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 (7.5mg; 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 pointwas 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.",
author = "{LATITUDE-TIMI 60 Investigators} and O'Donoghue, {Michelle L.} and Ruchira Glaser and Cavender, {Matthew A.} and Aylward, {Philip E.} and Bonaca, {Marc P.} and Andrzej Budaj and Davies, {Richard Y.} and Mikael Dellborg and Fox, {Keith A A} and Gutierrez, {Jorge Antonio T} and Christian Hamm and R. Kiss and František Kovar and Kuder, {Julia F.} and Im, {Kyung Ah} and Lepore, {John J.} and Lopez-Sendon, {Jose L.} and Ophuis, {Ton Oude} and Alexandr Parkhomenko and Shannon, {Jennifer B.} and Jindrich Spinar and Tanguay, {Jean Francois} and Mikhail Ruda and Steg, {P. Gabriel} and Pierre Theroux and Wiviott, {Stephen D.} and Ian Laws and Sabatine, {Marc S.} and Morrow, {David A.}",
year = "2016",
month = "4",
day = "19",
doi = "10.1001/jama.2016.3609",
language = "English",
volume = "315",
pages = "1591--1599",
journal = "JAMA - Journal of the American Medical Association",
issn = "0002-9955",
publisher = "American Medical Association",
number = "15",

}

TY - JOUR

T1 - Effect of losmapimod on cardiovascular outcomes in patients hospitalized with acute myocardial infarction

T2 - A randomized clinical trial

AU - LATITUDE-TIMI 60 Investigators

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, R.

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.

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 inmyocardial 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 acutemyocardial 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 (7.5mg; 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 pointwas 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.

AB - Importance: p38 Mitogen-activated protein kinase (MAPK)-stimulated inflammation is implicated in atherogenesis, plaque destabilization, and maladaptive processes inmyocardial 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 acutemyocardial 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 (7.5mg; 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 pointwas 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.

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U2 - 10.1001/jama.2016.3609

DO - 10.1001/jama.2016.3609

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SP - 1591

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JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0002-9955

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