Initiating aspirin therapy to emergency room patients at risk of lung injury does not influence the chance that these patients will experience acute respiratory distress syndrome(ARDS), researchers reported here.
The development of ARDS occurred within 7 days in 20 of 195 patients (10.3%) assigned to aspirin and in 17 of 195 patients (8.7%) presenting in the emergency room (P=0.53), reported Daryl Kor, MD, of the Mayo Clinic in Rochester, Minn.
n presenting their research at the annual meeting of the American Thoracic Society, additionally, Kor and colleagues reported no statistically significant differences in ventilator-free days, in length of stay in the intensive care unit, in hospital length of stay, in 28-day survival, or in bleeding events. The study was published online in the Journal of American Medical Association simultaneously with its presentation here.
“Among at-risk patients presenting to the emergency department, the use of aspirin compared with placebo did not reduce the risk of ARDS at 7 days,” Kor reported. “The findings of this Phase 2b trial do not support continuation to a larger Phase 3 trial.”
Patients who were included in the trial received a loading dose of aspirin 325 mg, followed by daily 81 mg doses within 24 hours of emergency department presentation and continued to hospital day 7, discharge, or death. The median age of the patients was 57 years, and 48% of the patients included in the study were women. Patients were evaluated on the basis of the Lung Injury Prediction Score — with a score of 4 or greater the threshold for the aspirin therapy.
The researchers suggested that aspirin might make a difference in outcomes “based on the body of existing experimental data demonstrating alterations in platelet function during the development of ARDS. Platelet activation, aggregation, and sequestration, as well as modulation of anti-inflammatory lipid mediators, including leukotrienes, thromboxane, and prostaglandins,have all been implicated as important mediators of ARDS progression and severity. Aspirin directly modifies these mechanistic pathways, making it a plausible preventive and therapeutic measure in this setting.”
But in the clinical trial, treatment with aspirin didn’t improve outcomes.
Ventilator-free days through day 28 were 24.9 among the patients on aspirin; 25.2 among those on placebo (P=0.72).
Intensive care unit length of stay was 5.2 days among patients treated with aspirin; 5.4 days among patients who received placebo (P=0.87).
Hospital length of stay was 8.8 days among the aspirin-treated patients; 9.0 days among those on placebo (P=0.79).
Survival at 28 days was 90% for both cohorts (P=0.92).
One-year estimated survival was 73% among the patients on aspirin and 75% among the placebo patients (P=0.79).
No statistically significant differences were found in measures of safety. Eleven patients or 5.6% of those on aspirin experienced bleeding events compared with 5 patients or 2.6% of patients on placebo (P=0.13).
Kor reported that the trial results were likely shaped by a less than expected rate of ARDS in the population. The rate of 9.5% was far lower than the predicted 18% rate, he reported. “In addition to the lower than expected rate of ARDS, low rates of mechanical ventilation, acute kidney injury, and mortality suggest that the enrolled study population may have had a more modest overall severity of illness than what was anticipated at study onset,” the researchers stated. “As a result, the external validity of our findings in a cohort of critically ill patients with greater severity of illness remains unclear. Still, the results of this trial appear robust and consistent between the clinical and biomarker outcome measures.”
In an editorial that accompanied the study in JAMA, John Reilly, MD, instructor in medicine, and Jason Christie, MD, professor of medicine at the University of Pennsylvania, wrote:
“The attributable mortality associated with ARDS in the setting of critical illness is controversial, but ARDS is associated with increased length of intensive care unit stay, duration of ventilatory support, and poor long-term function and neurocognitive outcomes.
“Preventing ARDS is a worthy goal; however, ARDS is not a patient-centered outcome, nor a validated surrogate outcome for patient-centered outcomes,” they suggested. “Additionally, preventing ARDS does not ensure either improved survival or post-hospitalization quality of life. It is possible that an intervention may decrease ARDS risk but actually increase mortality.
“For example, if aspirin reduced ARDS incidence but resulted in significant bleeding complications or other unforeseen effects, the therapy should be avoided. Alternatively, an immunomodulatory therapy that reduces ARDS risk also may reduce pathogen clearance in patients with sepsis, resulting in overall negative effects.
“Conventional ARDS trials have chosen mortality as a primary outcome. In an ARDS prevention trial with mortality of 9%, as seen in the LIPS-A study, conducting a larger trial with sufficient power to detect mortality effects would be excessively expensive and likely infeasible.
“Ideally, future trials would both aim to prevent ARDS but also focus on mortality, functional status, or hospital costs in a population selected to be at highest risk and most likely to respond to a specific therapy,” they suggested.