High-Dose Perioperative Atorvastatin and Acute Kidney Injury Following Cardiac Surgery: A Randomized Clinical Trial

Abstract

Importance: Statins affect several mechanisms underlying acute kidney injury (AKI).

Objective: To test the hypothesis that short-term high-dose perioperative atorvastatin would reduce AKI following cardiac surgery.

Design, setting, and participants: Double-blinded, placebo-controlled, randomized clinical trial of adult cardiac surgery patients conducted from November 2009 to October 2014 at Vanderbilt University Medical Center.

Interventions: Patients naive to statin treatment (n = 199) were randomly assigned 80 mg of atorvastatin the day before surgery, 40 mg of atorvastatin the morning of surgery, and 40 mg of atorvastatin daily following surgery (n = 102) or matching placebo (n = 97). Patients already taking a statin prior to study enrollment (n = 416) continued taking the preenrollment statin until the day of surgery, were randomly assigned 80 mg of atorvastatin the morning of surgery and 40 mg of atorvastatin the morning after (n = 206) or matching placebo (n = 210), and resumed taking the previously prescribed statin on postoperative day 2.

Main outcomes and measures: Acute kidney injury defined as an increase of 0.3 mg/dL in serum creatinine concentration within 48 hours of surgery (Acute Kidney Injury Network criteria).

Results: The data and safety monitoring board recommended stopping the group naive to statin treatment due to increased AKI among these participants with chronic kidney disease (estimated glomerular filtration rate <60 mL/min/1.73 m2) receiving atorvastatin. The board later recommended stopping for futility after 615 participants (median age, 67 years; 188 [30.6%] were women; 202 [32.8%] had diabetes) completed the study. Among all participants (n = 615), AKI occurred in 64 of 308 (20.8%) in the atorvastatin group vs 60 of 307 (19.5%) in the placebo group (relative risk [RR], 1.06 [95% CI, 0.78 to 1.46]; P = .75). Among patients naive to statin treatment (n = 199), AKI occurred in 22 of 102 (21.6%) in the atorvastatin group vs 13 of 97 (13.4%) in the placebo group (RR, 1.61 [0.86 to 3.01]; P = .15) and serum creatinine concentration increased by a median of 0.11 mg/dL (10th-90th percentile, -0.11 to 0.56 mg/dL) in the atorvastatin group vs by a median of 0.05 mg/dL (10th-90th percentile, -0.12 to 0.33 mg/dL) in the placebo group (mean difference, 0.08 mg/dL [95% CI, 0.01 to 0.15 mg/dL]; P = .007). Among patients already taking a statin (n = 416), AKI occurred in 42 of 206 (20.4%) in the atorvastatin group vs 47 of 210 (22.4%) in the placebo group (RR, 0.91 [0.63 to 1.32]; P = .63).

Conclusions and relevance: Among patients undergoing cardiac surgery, high-dose perioperative atorvastatin treatment compared with placebo did not reduce the risk of AKI overall, among patients naive to treatment with statins, or in patients already taking a statin. These results do not support the initiation of statin therapy to prevent AKI following cardiac surgery.

Trial registration: clinicaltrials.gov Identifier: NCT00791648.

Figure 1. Recruitment, randomization, and follow-up

We sought to study three patients each week in order to maximize recruitment but ensure each subject was studied per protocol with the research staff available. We were unable to recruit all eligible patients. Approximately (~) 1753 were not approached, and ~280 did not provide consent.

Figure 2. Efficacy of treatment to prevent Acute Kidney Injury in all patients and prespecified subgroups

Absolute differences are the estimated differences in proportions between statin and placebo groups derived from model transformations. Quasi-Poisson, log-linear regression was used to calculate estimates and confidence intervals (CI) and should be interpreted as risk ratios or the relative risk (RR) of treatment for the primary end point, acute kidney injury. P-values correspond to the Pearson chi-square test.