By Arzo Hamidi, PharmD, BCCCP
Clinical Pharmacy Specialist, Adult Critical Care, Rush University Medical Center, Chicago
SYNOPSIS: Based on this randomized, placebo-controlled Phase II trial, further research still is required to determine if aspirin therapy is beneficial for the treatment of acute respiratory distress syndrome, since aspirin did not improve oxygenation index or other respiratory physiologic markers.
SOURCE: Toner P, Boyle AJ, McNamee JJ, et al. Aspirin as a treatment for ARDS: A randomized, placebo-controlled clinical trial. Chest 2022;161:1275-1284.
Acute respiratory distress syndrome (ARDS) is a diffuse, inflammatory lung injury that is associated with significant morbidity and mortality. Few interventions have been shown to decrease the risk of mortality with ARDS. Previous research has proposed beneficial effects of aspirin on hemostatic and inflammatory processes. The lungs are a site for platelet maturation. Animal studies have shown that antiplatelets may modulate the immune function and influence the onset and progression of ARDS and acute lung injury.1,2
The Aspirin as a Treatment for ARDS (STAR) trial presented here recruited patients from five intensive care units (ICUs) in Northern Ireland. The study was a randomized, double-blind, allocation-concealed, multicenter, placebo-controlled Phase II trial. The study question was to determine if aspirin improved surrogate clinical outcomes and if it was safe in patients with ARDS. Patients requiring mechanical ventilation were eligible within 72 hours of ARDS onset. ARDS was defined using the Berlin definition with PaO2/FIO2 ratio ≤ 40 kPa with positive end-expiratory pressure of 5 cm H2O with bilateral infiltrates on radiography. Excluded patients were patients on concurrent therapy with aspirin within the past four weeks, platelet count < 50 × 109/L, hemophilia, concurrent anticoagulant therapy, active or history of recurrent peptic ulcer or gastric hemorrhage, traumatic brain injury, severe chronic liver disease, and other relevant contraindications to aspirin.
Patients were assigned to receive either aspirin 75 mg or placebo daily continued until day 14. The primary outcome was oxygenation index (OI) on day 7. OI was calculated as [mean airway pressure (cm H2O) × FiO2 × 100]/PaO2 (kPa). Secondary outcomes were OI on days 4 and 14; respiratory compliance; PaO2/FiO2 on days 4, 7, and 14; and change in Sequential Organ Failure Assessment (SOFA) score on days 4, 7, and 14. Twenty-four patients were assigned to the aspirin group and 25 patients were assigned to the placebo group. There was no significant difference between the mean observed OI on day 7 between the two groups. In addition, there were no significant differences in any of the secondary outcomes between groups. Total adverse events (AE) were not different between the two groups; the most common AE was a drop in hemoglobin, although the mean hemoglobin was not different between the two groups on day 14. Measured thromboxane B2 levels were lower in the aspirin group, but were not statistically different between the two groups.
COMMENTARY
The broad, yet appropriate, exclusion criteria resulted in less than 10% of originally recruited patients being enrolled. The authors of this study did not meet their sample size needed to reach the calculated power despite increasing the number of the enrollment centers. Overall, no statistical difference was seen in the primary outcome or secondary outcomes.
There are several challenges to note when considering aspirin use in patients with ARDS. Oral aspirin may have variable bioavailability and absorption in critically ill patients, especially given that almost 60% of patients required vasopressors in this study. Additionally, there are myriad reasons for thrombocytopenia in ICU patients, which may complicate the use of antiplatelets. Lastly, concomitant use of other anti-inflammatory interventions, including steroids, statins, and/or non-steroidal anti-inflammatory drugs (NSAIDs), may confound interpretation of these results. The use of these agents was not reported in this study. Other non-pharmacological interventions for the treatment of ARDS, such as proning, were not described in detail. Of note, the mean tidal volume (mL/kg of predicted body weight) was about 7 mL/kg, which is within the recommended range but slightly higher than the recommended 6 mL/kg for a lung protective ventilation strategy. Ventilation strategies among these two groups could have affected the results, and the frequency of such interventions in each group is unknown.
Although the population included was small, it was heterogeneous, with various etiologies for ARDS and an overall mortality rate on par with previous studies. Although this study fails to show significant improvement with aspirin in the treatment of ARDS with significant limitations as discussed, it does raise future questions to study regarding the use of antiplatelets in a wide population of critically ill patients with ARDS.
REFERENCES
- Toner P, McAuley DF, Shyamsundar M. Aspirin as a potential treatment in sepsis or acute respiratory distress syndrome. Crit Care 2005;19:1-9.
- Yu H, Ni YN, Liang ZA, et al. The effect of aspirin in preventing the acute respiratory distress syndrome/acute lung injury: A meta-analysis. Am J Emer Med 2018;36:1486-1491.
