A recent study has shown an association between high-potency statins and risk of acute kidney injury. However, these data are from observational studies, and it is not clear if similar signal is seen from randomized controlled trials. We evaluated the risk of renal-associated serious adverse events (SAEs) using statins versus placebo trials and the high-dose versus low-dose statin trials that were available to us. The outcome of interest was renal-related SAEs. The incidence of adverse events relating to kidney injury was determined through review of the adverse event database. The following outcomes were evaluated: (1) renal-related SAEs within 120 days of randomization (primary outcome), (2) renal-related SAEs after 120 days of randomization (secondary), and (3) drug discontinuation due to renal-related SAEs (secondary). There was no difference in the incidence of renal-related SAEs at 120 days (0.04% vs 0.10%, p = 0.162) between atorvastatin and placebo in the 24 placebo-controlled trials (10,345 patients on atorvastatin (10 to 80 mg/day) versus 8,945 patients on placebo) or in the high-dose versus low-dose statin trials including the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study (0.05% vs 0.02%, p = 0.625) or the Treating to New Targets (TNT) trial (0.0% vs 0.04%, p = 0.500) trial. Results were similar for renal-related SAEs after 120 days (placebo controlled trials [0.38% vs 0.36%, p = 0.905], IDEAL trial [0.56% vs 0.65%, p = 0.683], or the TNT trial [0.76% vs 1.04%, p = 0.168]) and for drug withdrawal due to renal-related SAE (placebo controlled trials [0.05% vs 0.04%, p = 1.00], IDEAL trial [0.02% vs 0.0%, p = 0.499], or the TNT trial [0.08% vs 0.12%, p = 0.754]). In conclusion, the results from clinical trials with data from 149,882 patient-years of follow-up fail to show any increase in renal-related SAEs with statins compared with controls.
A recent observational study of >2 million statin users using an analysis of administrative databases concluded that the use of high-potency statins was associated with an increased rate of diagnosis for acute kidney injury (AKI), especially within the first 120 days after statin initiation, compared with low-potency statins. Although no robust biologic mechanism linking statins to kidney injury was put forth, some of the proposed mechanisms included increased risk of rhabdomyolysis, suppression of coenzyme Q10, and other “pleiotropic” effects. The question is important as the recently published 2013 American College of Cardiology/American Heart Association blood cholesterol guidelines recommend moderate- to high-intensity statins for secondary and primary prevention, thus potentially exposing a vast group of patients to this AKI risk. However, observational studies have a number of limitations including selection and ascertainment bias. In addition, administrative data sets have misclassification bias, inability to account for many known and unknown cofounders, and, most importantly, do not provide a causal inference. We therefore assessed the incidence of renal-associated serious adverse events (SAEs) with statin use from randomized controlled trials that were available to us.
Methods
Evaluation for renal-associated SAEs was performed using statins versus placebo trials and the high-dose versus low-dose statin trials. The statins versus placebo cohort was a pooled analysis of 24 placebo-controlled atorvastatin trials ( Supplementary Appendix ; 10,345 patients taking atorvastatin [10 to 80 mg/day] vs 8,945 patients taking placebo) including the Collaborative Atorvastatin Diabetes Study (CARDS), Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN), Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL), and Deutsche Diabetes Dialyse Studie (4D) trials, which were long-term cardiovascular outcomes trials with median follow-up of 48 months. The remaining placebo studies were primarily short-term studies with the shortest study of 2 weeks duration and median follow-up of 4 months. For the high-dose versus low-dose statin trials, we used the Treating to New Targets (TNT) trial (atorvastatin 80 mg vs 10 mg in 10,001 patients with coronary artery disease) and the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) trial (atorvastatin 80 mg vs simvastatin 20 mg in 8,888 patients after myocardial infarction). The outcome of interest was renal-related SAEs. The incidence of adverse events (AE) relating to kidney injury was determined through review of the AE database. The following outcomes were evaluated: (1) renal-related SAEs within 120 days of randomization (primary outcome), (2) renal-related SAEs after 120 days of randomization (secondary), and (3) drug discontinuation due to renal-related SAEs (secondary). We used broad AE terms to evaluate for these outcomes including “Renal impairment,” “Renal disorder,” “Renal failure,” “Renal failure acute,” “Nephritis,” “Nephropathy,” “Renal tubular disorder,” or “Renal tubular necrosis.”
Results
There was no difference in the incidence of renal-related SAEs at 120 days between atorvastatin and placebo in the 24 placebo-controlled trials (0.04% vs 0.10%, p = 0.162) or in the high-dose versus low-dose statin trials including the IDEAL (0.05% vs 0.02%, p = 0.625) or the TNT (0.0% vs 0.04%, p = 0.500) trial. Results were similar for renal-related SAEs after 120 days (placebo-controlled trials [0.38% vs 0.36%, p = 0.905], IDEAL trial [0.56% vs 0.65%, p = 0.683], or the TNT trial [0.76% vs 1.04%, p = 0.168]) and for drug withdrawal due to renal-related SAEs (placebo-controlled trials [0.05% vs 0.04%, p = 1.00], IDEAL trial [0.02% vs 0.0%, p = 0.499], or the TNT trial [0.08% vs 0.12%, p = 0.754]).
Results
There was no difference in the incidence of renal-related SAEs at 120 days between atorvastatin and placebo in the 24 placebo-controlled trials (0.04% vs 0.10%, p = 0.162) or in the high-dose versus low-dose statin trials including the IDEAL (0.05% vs 0.02%, p = 0.625) or the TNT (0.0% vs 0.04%, p = 0.500) trial. Results were similar for renal-related SAEs after 120 days (placebo-controlled trials [0.38% vs 0.36%, p = 0.905], IDEAL trial [0.56% vs 0.65%, p = 0.683], or the TNT trial [0.76% vs 1.04%, p = 0.168]) and for drug withdrawal due to renal-related SAEs (placebo-controlled trials [0.05% vs 0.04%, p = 1.00], IDEAL trial [0.02% vs 0.0%, p = 0.499], or the TNT trial [0.08% vs 0.12%, p = 0.754]).
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