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

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.

Long-term mortality and quality of life after prolonged mechanical ventilation.

OBJECTIVE: To describe and identify factors associated with mortality rate and quality of life 1 yr after prolonged mechanical ventilation. DESIGN: Prospective, observational cohort study with patient recruitment over 26 months and follow-up for 1 yr. SETTING: Intensive care units at a tertiary care university hospital. PATIENTS: Adult patients receiving prolonged mechanical ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We measured mortality rate and functional status, defined as the inability to perform instrumental activities of daily living (IADLs) 1 yr following prolonged mechanical ventilation. The study enrolled 817 patients. Their median age was 65 yrs, 46% were women, and 44% were alive at 1 yr. Median ages at baseline of 1-yr survivors and nonsurvivors were 53 and 71 yrs, respectively. At the time of admission to the hospital, survivors had fewer comorbidities, lower severity of illness score, and less dependence compared with nonsurvivors. Severity of illness on admission to the intensive care unit and prehospitalization functional status had a significant association with short-term mortality rate, whereas age and comorbidities were related to long-term mortality. Fifty-seven percent of the surviving patients needed caregiver assistance at 1 yr of follow-up. The odds of having IADL dependence at 1-yr among survivors was greater in older patients (odds ratio 1.04 for 1-yr increase in age) and those with IADL dependence before hospitalization (odds ratio 2.27). CONCLUSIONS: Mortality rate after prolonged mechanical ventilation is high. Long-term mortality rate is associated with older age and poor prehospitalization functional status. Many survivors needed assistance after discharge from the hospital, and more than half still required caregiver assistance at 1 yr. Interventions providing support for caregivers and patients may improve the functional status and quality of life of both groups and thus need to be evaluated.