LosmApimod To Inhibit p38 MAP Kinase as a TherapeUtic Target and moDify Outcomes After an Acute Coronary syndromE-TIMI 60 - LATITUDE-TIMI 60
The goal of the trial was to compare the efficacy of losmapimod on cardiovascular (CV) outcomes in patients hospitalized with acute myocardial infarction (AMI).
Contribution to the Literature: The LATITUDE-TIMI 60 trial suggests that losmapimod, a p38 MAP kinase inhibitor, is not superior to placebo in reducing adverse CV events at 12 weeks in patients hospitalized with an AMI and on optimal medical therapy.
Patients hospitalized with AMI on guideline-recommended therapy were randomized in a 1:1 fashion to either losmapimod 7.5 mg BID (n = 1,738) or placebo (n = 1,765).
- Total number of enrollees: 3,503
- Duration of follow-up: 12 weeks
- Mean patient age: 67 years
- Percentage female: 29%
- Percentage diabetics: 33%
Other salient features/characteristics:
- Prior MI: 24%
- High-sensitivity C-reactive protein (hs-CRP): 3.65 mg/L
- Cardiac catheterization for AMI: 96%
- Age ≥35 years
- Hospitalization for non–ST-elevation myocardial infarction (NSTEMI) or STEMI, with the following timing of symptoms: NSTEMI: Presence of ischemic symptoms (≥5 minutes) at rest within 24 hours prior to randomization (may include qualifying episode). STEMI: Onset of qualifying ischemic symptoms within 12 hours of randomization.
- At least one of the following:
- Age ≥60 years at randomization.
- MI prior to the qualifying acute coronary syndrome (ACS) event
- Coronary artery bypass grafting prior to qualifying ACS event
- NSTEMI with new ischemic ST-segment depression ≥0.1 mV in ≥2 contiguous leads
- Diabetes mellitus 2
- Coexistent clinically diagnosed arterial disease
- Current severe heart failure or shock
- Ongoing clinical instability
- History of chronic liver disease
- Known severe renal impairment
- Any condition, other than vascular disease, with life expectancy <1 year that might prevent the subject from completing the study
- Known active tuberculosis, human immunodeficiency virus, active opportunistic or life-threatening infections
- Vaccination with a live attenuated vaccine within 6 weeks of randomization
- Concomitant use of cytotoxic chemotherapy for cancer or known ongoing or anticipated use of chronic severe immunosuppressive agents
The trial was designed in two phases: phase A for initial safety and exploratory efficacy and a larger phase B if phase A was positive. The trial was terminated after phase A due to futility.
Primary outcome, CV death/MI/recurrent ischemia requiring revascularization at 12 weeks, for losmapimod vs. placebo: 8.1% vs. 7.0%, p = 0.24
- CV death: 2.1% vs. 2.5%
- MI: 5.3% vs. 4.3%
- Stroke: 0.8% vs. 0.9%
- Definite or probable stent thrombosis: 0.9% vs. 1.5%
- Serious adverse events: 16.0% vs. 14.2%
The results of this trial indicate that losmapimod is not superior to placebo in reducing adverse CV events at 12 weeks in patients hospitalized with an AMI and on optimal medical therapy. The trial had to be terminated early due to futility. Losmapimod is a selective and reversible p38 MAP kinase inhibitor, which was postulated to have salutary effects in AMI patients by reducing inflammation. In this trial, losmapimod reduced hs-CRP levels, but this did not translate into a clinical benefit at 12 weeks, highlighting the limitations of studies focusing on surrogate outcomes.
O’Donoghue ML, Glaser R, Cavender MA, et al., on behalf of the LATITUDE-TIMI 60 Investigators. Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction: A Randomized Clinical Trial. JAMA 2016;Apr 4:[Epub ahead of print].
Presented by Dr. Michelle L. O’Donoghue at the American College of Cardiology Annual Scientific Session, Chicago, IL, April 4, 2016.
Keywords: ACC Annual Scientific Session, Acute Coronary Syndrome, C-Reactive Protein, Cardiac Catheterization, Coronary Artery Bypass, Diabetes Mellitus, Mitogen-Activated Protein Kinase 14, Myocardial Infarction, Myocardial Ischemia, Myocardial Revascularization, Stents, Stroke, Thrombosis, p38 Mitogen-Activated Protein Kinases
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