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Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction: A
Michelle L O'Donoghue1, Ruchira Glaser2, Matthew A Cavender1
1TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
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.
Insights
Losmapimod did not reduce major ischemic cardiovascular events in acute myocardial infarction patients. This p38 MAPK inhibitor did not demonstrate sufficient efficacy to warrant further large-scale trials.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Inflammation Research
Background:
- p38 Mitogen-activated protein kinase (MAPK)-stimulated inflammation is linked to atherosclerosis and myocardial infarction (MI).
- Pilot studies suggested losmapimod, a p38 MAPK inhibitor, may reduce inflammation and improve outcomes in non-ST elevation MI.
- LATITUDE-TIMI 60 aimed to assess losmapimod's efficacy and safety in acute MI patients.
Purpose of the Study:
- To evaluate the efficacy and safety of losmapimod in reducing cardiovascular events in patients hospitalized with acute myocardial infarction.
- To determine if losmapimod, as an adjunct to guideline-recommended therapy, improves cardiovascular outcomes compared to placebo.
Main Methods:
- LATITUDE-TIMI 60 was a randomized, placebo-controlled, double-blind trial involving 3503 patients with acute MI and cardiovascular risk factors.
- Patients received either losmapimod (7.5 mg twice daily) or placebo for 12 weeks, with follow-up for an additional 12 weeks.
- The primary endpoint was a composite of cardiovascular death, MI, or urgent revascularization at 12 weeks.
Main Results:
- The primary endpoint occurred in 7.0% of placebo patients and 8.1% of losmapimod patients (HR, 1.16; 95% CI, 0.91-1.47; P=.24) at 12 weeks.
- No significant reduction in major ischemic cardiovascular events was observed with losmapimod compared to placebo.
- On-treatment rates of serious adverse events were comparable: 16.0% for losmapimod and 14.2% for placebo.
Conclusions:
- Losmapimod did not demonstrate efficacy in reducing major ischemic cardiovascular events in patients with acute myocardial infarction.
- The exploratory findings did not support progression to a larger efficacy trial in this patient population.
- Further research may be needed to explore potential benefits in specific subgroups or different inflammatory pathways.
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