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.
Objective
ACE Insertion/deletion (I/D) polymorphism has been reported to be associated with various cardiovascular conditions, however its impact in patients with AHF remains controversial.
This study aimed to analyze ACE I/D distribution, rate of acute heart failure (AHF) and survival in ST segment elevation myocardial infarction (STEMI) patients.
Methods
Genomic DNA from 245 STEMI patients and 87 healthy control subjects were analyzed by single polymerase chain reaction method. Based on the ACE I/D genotype STEMI patients were divided with AHF/no AHF, and then - for preserved/reduced ≤40% left ventricle (LV) ejection fraction (EF) to investigate the frequency of the mutant allele D.
Results
ACE gene polymorphism analyses revealed that D allele had been found more often in STEMI patients than in controls (84.1 vs. 72.4%). The frequency of II, ID, and DD genotypes in STEMI patients was 27.6%, 52.9% and 19.5% compared to 15.9%, 54.3% and 29.8%, respectively in controls with a significant difference in mutant homozygous genotype. Distribution of I/D ACE gene variants among AHF cases vs no AHF, showed similar frequency of II allele (15.8 vs 13.5%), ID allele (54.9 vs 52.8%) and DD allele (29.3 vs 33.7% respectively). In patients with preserved EF there was not statistical significance among different alleles with and without AHF. However, ACE DD polymorphism has been found in AHF patients with reduced EF significantly more often (50.0 vs 30.5%; p<0.05) in compare to AHF patients with preserved EF. Finally, cardiovascular death among all STEMI patients during 3-year follow up was more frequent in patients with DD allele (17.7% vs 5.7% with II and vs 9.9% with ID allele).
Conclusion
Presented results confirmed ACE DD polymorphism to be associated with higher rate of cardiovascular death and presence of AHF with reduced LV EF in STEMI patients. Future studies are needed to evaluate importance of ACE DD polymorphism in order to find optimal treatment strategies and to prevent negative outcomes in those patients.
Funding Acknowledgement
Type of funding sources: None.
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