ORLANDO – Statins administered perioperatively offered no protection against acute kidney injury following cardiac surgery, according to new results of a 5-year randomized clinical trial.
The findings held true whether or not patients were naive to statins; serum creatinine levels actually increased significantly more for statin-naive patients given atorvastatin than those given placebo.
The study was stopped early for patients naive to statins because increased acute kidney injury was seen in those patients who had chronic kidney disease (eGFR less than 60 mL/min/1.73 m2), and was subsequently stopped early for futility for all patients.
Dr. Frederic Tremaine Billings
“De novo initiation of daily perioperative atorvastatin treatment did not reduce the incidence of AKI or reduce the increase in serum creatinine concentration associated with cardiac surgery,” wrote Dr. Frederic T. Billings IV, professor of medicine at Vanderbilt University, Nashville, Tenn., and his collaborators. The findings (JAMA 2016 Feb 23. doi: 10.1001/jama.2016.0548) were published concurrently with his presentation at the Critical Care Congress, sponsored by the Society for Critical Care Medicine.
In what Dr. Phil B. Fontanarosa, executive editor of JAMA and comoderator of the late-breaking trials session at the meeting, described as “really an elegant clinical trial,” Dr. Billings and his collaborators enrolled 615 patients over 5 years at Vanderbilt University Medical Center.
Patients undergoing elective coronary artery bypass grafting, valvular heart surgery, or ascending aortic surgery were eligible. Patients were excluded if they had prior statin intolerance, acute coronary syndrome, or liver dysfunction; were taking potent CYP3A4 inhibitors or cyclosporine; were receiving renal replacement therapy or had a kidney transplant; or were pregnant.
Both patients currently on a statin and patients naive to statins were recruited. Statin-naive patients received 80 mg atorvastatin the day before surgery, and then 40 mg of atorvastatin on the day of surgery and daily following surgery, or a matched placebo regimen.
Patients who were already on a statin received the study drug only on days that they would not have received a statin if treated according to the current standard of care. It was deemed unethical to allow those patients to receive placebo during and after surgery, since observational studies suggested that doing so might increase their potential for AKI.
For those patients already on a statin, this meant that they stayed on their usual regimen until the day of surgery, and then were randomized to receive either 80 mg of atorvastatin on the day of surgery and 40 mg of atorvastatin the day after surgery, or a matching placebo regimen.
For both groups, the study drug was given at least 3 hours before surgery on the day of surgery.
Randomization was stratified for prior statin use, for chronic kidney disease, and by history of diabetes. The 199 patients naive to statins and the 416 already on a statin were similar in demographic and health characteristics. Median age was 67 years, 188 (30.6%) were women; 202 participants (32.8%) had diabetes.
The primary outcome measure was diagnosis of AKI, defined as an increase of 0.3 mg/dL in serum creatinine, or beginning renal replacement therapy within 48 hours of surgery. Baseline serum creatinine was measured no more than 7 days prior to surgery.
AKI occurred in 64 of 308 patients (20.8%) in the atorvastatin group, and in 60 of 307 patients (19.5%) receiving placebo overall (P = .75). For those naive to statins, 21.6% of the atorvastatin group and 13.4% of the placebo group developed AKI (P = .15). Overall, 179 enrolled patients had CKD, and the incidence of AKI did not significantly differ in the atorvastatin and the placebo arms of this subgroup.
The subpopulation of participants with CKD who were statin naive (n = 36), however, saw an increased incidence of AKI with atorvastatin compared to placebo. AKI occurred in 9 of 17 patients (52.9%) given atorvastatin, and in 3 of 19 (15.8%) given placebo group (RR, 3.35[95% confidence interval 0.12 to 10.05]; P = .03). “It should be noted that the number of patients in this subgroup was particularly small, leading to a wide confidence interval and an increased chance of type 1 error,” said Dr. Billings.
Secondary outcome measures were maximum increase in creatinine concentration from baseline through postop day 2, delirium in the ICU, degree of myocardial injury, and incidence of postoperative pneumonia, atrial fibrillation, or stroke. Perioperative atorvastatin administration did not affect any of these endpoints.
The safety analysis showed no indications of increased risk of skeletal muscle or liver injury with perioperative atorvastatin use.
In the real world, “Most patients presenting for cardiac surgery … are already taking statins, and in the current study there was little evidence that continuation or withdrawal from statin treatment on the day of surgery and postoperative day 1 affects AKI,” wrote Dr. Billings and his coauthors.