Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction: A Randomized Clinical Trial

TY - JOUR

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

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 - Karakas, Mahir

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/analysis

KW - Cyclopropanes/adverse effects

KW - Double-Blind Method

KW - Drug Administration Schedule

KW - Female

KW - Hospitalization

KW - Humans

KW - Male

KW - Middle Aged

KW - Myocardial Infarction/drug therapy

KW - Myocardial Ischemia/prevention & control

KW - Myocardial Revascularization

KW - Protein Kinase Inhibitors/adverse effects

KW - Pyridines/adverse effects

KW - Recurrence

KW - Secondary Prevention

KW - Treatment Failure

KW - p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors

U2 - 10.1001/jama.2016.3609

DO - 10.1001/jama.2016.3609

M3 - SCORING: Journal article

C2 - 27043082

VL - 315

SP - 1591

EP - 1599

JO - JAMA-J AM MED ASSOC

JF - JAMA-J AM MED ASSOC

SN - 0098-7484

IS - 15

ER -