Rosuvastatin Has No Benefit, May Be Detrimental for Sepsis-Associated ARDS

Results of a large, multicenter, double-blind, randomized, placebo-controlled trial found that patients with sepsis-associated acute respiratory distress syndrome (ARDS) treated with rosuvastatin had no reduction in in-hospital mortality or improvements in other clinical outcomes compared to those treated with placebo [N Engl J Med. 2014;370(23):2191-2200]. Rosuvastatin may have also contributed to kidney and hepatic dysfunction, according to the study’s findings.

Prior data from observational studies suggested that the use of statins in patients with sepsis improves clinical outcomes. Based on this, the National Heart, Lung and Blood Institute ARDS Clinical Trial Network conducted this recent study to assess whether rosuvastatin therapy would improve clinical outcomes in critically-ill patients with sepsis-associated ARDS.

In the study, 745 patients with sepsis-associated ARDS were randomly assigned to receive rosuvastatin (n=379) or placebo (n=366) between March 2010 and September 2013. Rosuvastatin was administered within 4 hours of randomization at a 40 mg loading dose, followed by maintenance doses of 20 mg daily (or reduced to 10 mg in patients with morning serum creatinine level of 2.8 mg/dL) until the third day after discharge from the intensive care unit.

All patients received positive-pressure mechanical ventilation through an endotracheal tube, had a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of ≤300, and had pulmonary edema without evidence of left atrial hypertension, all during a single 24-hour period. All patients also had infection and met criteria for a systemic inflammatory response.

Exclusion criteria included the presence of ARDS for >48 hours; chronic conditions that could adversely affect survival, compromise adherence to the protocol, or impair weaning from the ventilator; ingestion of a statin 48 hours prior to randomization; and elevated serum levels of creatine kinase, aspartate aminotransferase, or alanine aminotransferase (ie, 5 times the upper limit of normal range).

The primary outcome of the study was mortality before hospital discharge or until day 60 of the study if the patient was still hospitalized. Secondary outcomes included the number of days off the ventilator to day 28 and organ failure-free days to day 14.

The study was stopped because of futility after 745 patients of an estimated 1000 were enrolled. The study found no significant differences in the primary outcome, with in-hospital mortality occurring in 28.5% and 24.9% of patients in the rosuvastatin and placebo groups, respectively (P=.21). Secondary outcomes also were not significant, with a mean ventilator-free days of 15.1 for both treatment groups (P=.96).

Along with no significant differences in clinical improvement, rosuvastatin was associated with fewer days free of renal failure to day 14 compared to placebo (10.1 vs 11, respectively; P=.01) and fewer days of free hepatic failure to day 14 (10.8 vs 11.8, respectively; P=.003).

According to the authors, these results challenge prior data from observational studies that showed a significant reduction in morbidity and mortality in patients with infection who receive statins prior to hospitalization.

The investigators also conducted a planned post-hoc analysis of outcomes in a subgroup of patients prescribed statins before the development of ARDS but who had not received a statin for at least 48 hours prior to randomization. Of the 109 patients in this group, 54 were randomized to receive rosuvastatin and 55 to receive placebo.

The study found no significant difference in mortality between the patients in the rosuvastatin and placebo groups, with 17 (31%) deaths in the rosuvastatin group and 11 (20%) in the placebo group (95% confidence interval, -4.8-27.8 percentage points; P=.14). In addition, no significant differences were seen in the number of ventilator-free days (14.7 for rosuvastain vs 15.3 for placebo; P=.80).

The investigators concluded, “these results, coupled with those of smaller randomized trials of other statins, do not provide support for initiating or continuing statin therapy for the treatment of sepsis-associated ARDS.”