Objective To quantify an association between acute kidney injury and use of high potency statins versus low potency statins.
Design Retrospective observational analysis of administrative databases, using nine population based cohort studies and meta-analysis. We performed as treated analyses in each database with a nested case-control design. Rate ratios for different durations of current and past statin exposure to high potency or low potency statins were estimated using conditional logistic regression. Ratios were adjusted for confounding by high dimensional propensity scores. Meta-analytic methods estimated overall effects across participating sites.
Setting Seven Canadian provinces and two databases in the United Kingdom and the United States.
Participants 2 067 639 patients aged 40 years or older and newly treated with statins between 1 January 1997 and 30 April 2008. Each person hospitalized for acute kidney injury was matched with ten controls.
Intervention A dispensing event was new if no cholesterol lowering drug or niacin prescription was dispensed in the previous year. High potency statin treatment was defined as ≥10 mg rosuvastatin, ≥20 mg atorvastatin, and ≥40 mg simvastatin; all other statin treatments were defined as low potency. Statin potency groups were further divided into cohorts with or without chronic kidney disease.
Main outcome measure Relative hospitalization rates for acute kidney injury.
Results Of more than two million statin users (2 008 003 with non-chronic kidney disease; 59 636 with chronic kidney disease), patients with similar propensity scores were comparable on measured characteristics. Within 120 days of current treatment, there were 4691 hospitalizations for acute kidney injury in patients with non-chronic kidney injury, and 1896 hospitalizations in those with chronic kidney injury. In patients with non-chronic kidney disease, current users of high potency statins were 34% more likely to be hospitalized with acute kidney injury within 120 days after starting treatment (fixed effect rate ratio 1.34, 95% confidence interval 1.25 to 1.43). Users of high potency statins with chronic kidney disease did not have as large an increase in admission rate (1.10, 0.99 to 1.23). χ2 tests for heterogeneity confirmed that the observed association was robust across participating sites.
Conclusions Use of high potency statins is associated with an increased rate of diagnosis for acute kidney injury in hospital admissions compared with low potency statins. The effect seems to be strongest in the first 120 days after initiation of statin treatment.
Comparison with existing evidence
According to data from the JUPITER trial, as published by the FDA,5 the maximum likelihood estimate of the relative risk was 1.11 for any renal event over a median follow-up duration of 1.9 years, and 1.19 for acute renal failure. Our rate ratio estimate was 1.15 for acute kidney injury for patients treated for one to two years. Over all treatment durations in our analysis, the average rate ratio was 1.17, or 1.20 if past treatment was excluded. The compatibility of these results with our hypothesis, their agreement with the maximum likelihood estimate observed in the large JUPITER trial, and the high degree of precision obtained from our study population, together lend meaningful support for this increased risk.
Similarity between our results and other epidemiologic studies is mixed. One multicenter study of statin use and acute kidney injury in patients with community acquired pneumonia (CAP) reported an odds ratio of 1.32 for acute kidney injury in patients with CAP who received statins compared with statin naive patients.23 By contrast, a meta-analysis of four observational studies of rosuvastatin, designed to study multiple outcomes but which included renal failure, reported no difference between rosuvatstain and other statins.24 This meta-analysis is impossible to interpret from a statin potency perspective, because the control patients received other statins of all different potencies.
It is also important to note that most statin treatment in randomized trials was of low potency. The JUPITER trial showed that about 450 patients needed to be treated with 20 mg rosuvastatin per day instead of placebo for two years to prevent one death from myocardial infarction, stroke, or cardiovascular disease (combined endpoint).4 It remains to be shown whether the number needed to treat to benefit with high potency statins instead of low potency statins (versus placebo) would outweigh the combined risk of acute kidney injury, rhabdomyolysis, and diabetes.
In this study of over two million patients newly treated with a statin, we found a significant relative increase of 34% in the rate of hospitalization for acute kidney injury within 120 days of initiation for patients receiving high potency statins versus low potency statins. Our as treated analysis was based on an expectation that less than perfect treatment persistence and a high tendency for subsequent switching to higher doses might cause a fixed cohort analysis to underestimate the risk while actually on treatment. Loss of some patients to follow-up and competing risks also could have contributed to an underestimation of the effect. The as treated analysis, which allowed quantification of risk from different durations of current exposure, indicated that risk remained elevated for at least two years.
Although we used multiplicative models to answer our study questions, it is the subsequent translation of relative risks into numbers needed to treat to harm that provides the most useful metric for prescribers, regulators, and decision makers. In this regard, we estimate that 1700 patients with non-chronic kidney disease need to be treated with a high potency statin instead of a low potency statin for 120 days to cause one additional hospitalization for acute kidney injury. A number of 1700 patients is sufficiently large for there not to be enough patients enrolled in randomized trials to find an association between acute kidney injury and statin use with high precision. However, our definition of acute kidney injury was chosen to be highly specific and thus probably excluded a number of patients with real but milder cases, which could have underestimated the absolute risk.
Further studies are necessary to determine the biological mechanism linking statins to kidney injury. The elevated risk in patients using high potency statins could be related to an increased risk of rhabdomyolysis. Another mechanism could be the statin induced suppression of coenzyme Q10, a fat soluble enzyme with antioxidant properties. Statins have been shown to block the production of coenzyme Q10,1920 and placebo controlled trials of coenzyme Q10 treatment in humans and animals with kidney disease have shown improvements in renal function within 28 days of use.20 21 Other studies have shown an association between statin treatment and proteinuria.5 22 Pleiotrophic statin effects should also be contemplated.