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Statins for primary prevention of cardiovascular disease and the risk of acute kidney injury

Abstract Purpose To investigate the risk of acute kidney injury (AKI) in subjects initiating statin therapy for primary prevention of cardiovascular disease (CVD). Methods A nationwide cohort study using French hospital discharge and claims databases was performed, studying subjects from the general population aged 40 to 75 years in 2009, with no history of CVD and no lipid‐lowering drugs during the preceding 3‐year period, followed for up to 7 years. Exposure to statins (type, dose, and time since first use) and to other drugs for CVD risk was assessed. The primary outcome was hospital admission for AKI. Results The cohort included 8 236 279 subjects, 818 432 of whom initiated a statin for primary prevention. During 598 487 785 person‐months exposed to statins, 700 events were observed, corresponding to an incidence of AKI of 4.59 per 10 000 person‐years (7.01 in men, 3.01 in women). AKI mainly occurred in the context of organ failure, sepsis, and genitourinary disease. A 19% increased rate of AKI (hazard ratio = 1.19, 95%CI: 1.08‐1.31) was observed in men exposed to statins, whereas no increase in the overall risk of AKI was observed in women. However, exposure to high‐potency statins was associated with a 72% to 116% increased risk in both genders and a dose‐effect relationship observed for rosuvastatin and atorvastatin. No temporal pattern of occurrence nor interaction with drugs for CVD risk was observed. Conclusions Although the overall risk of AKI appears moderately increased, more attention should be paid to renal function in subjects taking statins for primary prevention both in clinical practice and from a research viewpoint.


| INTRODUCTION
Statins have become a cornerstone treatment in the primary and secondary prevention of atherosclerotic cardiovascular disease (CVD). 1,2 Statins are generally well tolerated, with only rare serious, lifethreatening adverse events (AE). 3 Most well-documented AEs associated with statins are related to muscle toxicity, including rhabdomyolysis. 4,5 Kidney diseases, notably acute kidney injury (AKI), have been reported to be associated with statins, independently of rhabdomyolysis. In early clinical trials involving high doses (>40 mg daily), rosuvastatin was suspected to cause proteinuria, hematuria, and AKI. 6,7 Several observational and real life studies have also demonstrated that other statins can be associated with some degree of kidney disease, usually in a dose-dependent manner. [8][9][10] However, in all but one of these studies, which considered the context of statin prescription (primary or secondary prevention), 10 their results may have been confounded by bias relative to statin indication and other factors related to the patients' pathological background, such as CVD, which increase the risk of AKI. Because the primary prevention population is of particular interest, given the relevance of safety issues in this population and because it can be used to study the relationships between statins and AEs with only limited confounding from multiple morbidities and comedications, we investigated the risk of AKI associated with statins in this context. We therefore conducted a large nationwide cohort study in France on subjects starting statins for primary prevention using the French population-based hospital discharge and claims databases, which cover all of the country's 66 million inhabitants. Particular attention was paid to the type of statin, dose, time since first use, interaction with other drugs for CVD risk, and the pathological context in which AKI occurs.

| Study design and data source
We carried out a nationwide cohort study in France using the comprehensive French national health insurance claims database (Système

| Study population
To study a presumably healthy population that may initiate statin therapy for primary prevention of CVD, in accordance with recent American College of Cardiology/American Heart Association guidelines, 1  subjects were considered to be exposed during this 30-day gap and nonexposed thereafter until the end of follow-up or censorship, or until treatment was resumed. Subjects who had never taken statins were considered to be nonexposed until the end of follow-up or censorship.
High-potency statin therapy was defined as at least 10-mg rosuvastatin, at least 20-mg atorvastatin, or at least 40-mg simvastatin. 13 Changes in dose and type of statin were defined by any difference between N and N + 1 dispensings considered on a daily time-scale.

| Outcomes
The primary endpoint was hospital admission for AKI. All discharge diagnoses (ICD-10 code: N17 "Acute kidney failure") were used to define the endpoint, and the event was considered to occur on the first day of admission to hospital. However, in a sensitivity analysis, the effect of using a narrower definition of AKI was explored, considering only severe cases requiring hemodialysis or hemofiltration (Supplementary Table 1).

| Follow-up
Patients were followed for up to 7 years from 1 January 2009 until predefined outcome, CVD, LTD, hospitalization for more than 8 days over a 1-year period, death from any cause, or 31 December 2015, whichever came first. In the presence of CVD, the subject would no longer correspond to the context of primary prevention and the presence of serious disease (LTD or hospitalization ≥8 days, eg, for cancer) would probably require review of the need for or the priority of primary prevention of CVD.

| Statistical analysis
Cox proportional hazards models were used to estimate the hazard ratios of AKI for statins. Time-varying definitions for drug exposures were employed, allowing patients to fluctuate between exposure statuses (nonexposed, exposed at dose X 1 of statin Y 1 , at dose X 2 of statin Y 2 , etc.) and to simultaneously contribute time to multiple exposure categories. As recommended, 14 a discrete time dataset was formed, in which follow-up time was segmented into 84 one-month intervals. The type and dose of specific statin regimens were studied only for the first sequence of statin prescribed (ie, before the first treatment was stopped or changed). Hazard ratios and 95% confidence intervals (CI) were adjusted for all measured factors found to be associated with both statin prescription and AKI: age, CMUc, and the deprivation index of the patient's municipality of residence among baseline covariates, and antihypertensive, antidiabetic, and nonsteroidal anti-inflammatory drugs, aminoglycosides, imaging procedures with administration of iodinated contrast media among timedependent exposures (Supplementary Table 1). Due to large differences in exposures and incidence of AKI, all analyses were conducted separately by gender.

| RESULTS
The cohort included 8 236 279 subjects, 3 230 868 men and 5 005 411 women, followed for an average of 72.7 months, among whom 325 815 men and 492 617 women initiated a statin for CVD primary prevention. Atorvastatin and rosuvastatin were the most commonly prescribed statins, followed by simvastatin and pravastatin (Table 1).
No major difference in terms of the main sociodemographic characteristics, exposure to statins, and main drugs for CVD risk (antidiabetics and antihypertensives) was observed according to gender.
The incidence of AKI was much higher in men than in women either exposed to statins (422 cases, 7.01 per 10 000 person-years, 95% CI: 6.37-7.71 per 10 000 person-years in men, vs 278 cases, 3.01 per 10 000 person-years, 95% CI: 2.68-3.39 per 10 000 person-years in women) or not exposed to statins (4.69 per 10 000 person years, Baseline characteristics and short-term outcome of cases of AKI are presented in Table 2 (primary definition) and Supplementary Table 2 (cases treated by hemodialysis only). Cases treated by hemodialysis (N = 3112, 21%) were similar in terms of sociodemographic characteristics and statin exposure, but obviously presented more severe outcome, with a hospital mortality rate more than twofold higher than that observed in the overall cohort (55% vs 25%). There were 144 fatal cases among the 700 AKI events occurring on statin therapy (mean age: 61 years, case fatality rate: 21%), mostly concerning men (90/144). Twenty-seven deaths occurred on highpotency statin therapy (out of the 119 AKI events occurring on high-  Table 3). No major differences in the distribution of comorbidities and associated conditions were observed between cases occurring with or without statin therapy; in particular, rhabdomyolysis was reported equally  (10) Exposure to high-potency statins b , c 58 769 (18)  71 853 (15) Person-months exposed to statins 7 227 419 11 082 906 Person-months exposed to high-potency statins c 878 970 1 013 273 Exposure to antidiabetic drugs during follow-up (cumulative incidence) 134 284 (4)  189 084 (4) Exposure to antihypertensive drugs during follow-up (cumulative incidence) 1 058 166 (33)  1 781 532 (36) First sequence of statins: type and initial dose of specific statin given b Percentages among those exposed to statins. c High-potency statin treatment was defined as at least 10-mg rosuvastatin, at least 20-mg atorvastatin, and at least 40-mg simvastatin; all other statin treatments were defined as low-potency.
d Percentages among those exposed to the specific statin.
infrequently in combination with AKI occurring in patients receiving statin therapy (5%) and those not receiving statin therapy (5%).
After stratification for age and adjustment for baseline and timedependent covariates, a 19% increase in the AKI rate (hazard ratio = 1.19, 95% CI: 1.08-1.31) was observed in men exposed to statins (  Type and dose of specific statin given (only cases exposed to statins during first sequence) Exposed to atorvastatin 70 41 Exposed to fluvastatin 1 5 Exposed to pravastatin 25 26 Exposed to rosuvastatin 95 42 Exposed to simvastatin 38 20 Exposed to simvastatin/ezetimibe combination 3 1 Duration of treatment at the time of the event (all cases exposed to statins) b High-potency statin treatment was defined as at least 10-mg rosuvastatin, at least 20-mg atorvastatin, and at least 40-mg simvastatin; all other statin treatments were defined as low-potency (percentages among those exposed to statins). c Percentages among those exposed to statins.  Table 4). No marked difference of risk according to duration of treatment was observed, but most cases of AKI occurred more than 90 days after initiation of statin therapy (Tables 2   and 3).
The results concerning the first sequence of statin therapy showed marked differences between statin types: exposures to rosuvastatin and atorvastatin were clearly associated with an increased risk of AKI, with generally linear dose-effect relationships in both genders for these two molecules.
The results using the narrower definition of severe AKI (requiring hemodialysis or hemofiltration) are presented in Supplementary   Table 5. Associations between this event and statin exposure were very similar to those observed using the standard definition of AKI.

| DISCUSSION
This large-scale population-based study conducted in a healthy, primary prevention population showed a moderately increased risk of AKI associated with statin exposure, with marked differences according to gender, potency, and type of statins. Men were at slightly greater risk of AKI overall (+19% increased risk vs +8% for women) as were users of high-potency statins (+72% for men and +116% for women), particularly rosuvastatin and atorvastatin users in whom a dose-effect relationship was observed. No clear temporal pattern nor interaction with antihypertensive drugs and antidiabetic drugs was observed, suggesting that AKI may arise from direct dose-related toxicity, independently of a possible microangiopathic or macroangiopathic background. In addition, rhabdomyolysis was rarely reported in association with AKI in this setting, suggesting that this well-known mechanism plays only a very minor role in AKI risk.
Our results significantly contribute to the scant literature concerning the risk of AKI in statin users. Clinical trials on the kidney safety of statins have generally been short-term and most of them addressed low-potency statins in the context of secondary prevention. 15 However, in the Jupiter trial, rosuvastatin, administered at a dose of 20 mg, was associated with a 19% increased risk of AKI. 16 Apart from two studies reporting discordant results on the risk of AKI in patients concurrently taking a statin and a macrolide antibi- The second study 9 only considered patients exposed to statins between 1997 and 2008, with no distinction between primary and secondary prevention: a 34% increased risk of AKI was observed with high-potency versus low-potency statins, with no interaction with macrolide antibiotics, calcium channel blockers, and fibrates. The last study 10 studied the risk of AKI separately in patients receiving statins between 2003 and 2012 in the context of primary prevention: the authors found an overall increased risk of 25%, lower than in the entire cohort including secondary prevention patients (30%), but did not investigate the time pattern or the type and potency of statins.
The mechanisms underlying the potential nephrotoxicity of statins remain uncertain. An increased risk of statin-induced rhabdomyolysis is well known, 19 but this condition has been reported in only 5% of patients with AKI in our study. However, this complication may have been underreported. 5 Early studies had shown that high doses of rosuvastatin may induce direct nephrotoxicity, with an increased incidence of dose-dependent tubular proteinuria. 20,21 This tubular toxicity has been reported in rare case reports, 22 sometimes associated with tubulointerstitial nephritis. 23  In any event, it should be noted that the renal risk of statins, which appears to be quite low in our study, should be compared with the potential benefit of these drugs in terms of global cardiovascular risk.
The JUPITER study has shown that the prescription of rosuvastatin was associated with a reduction of the incidence of major cardiovascular events (HR: 0.56), when given to apparently healthy subjects with LDL-cholesterol levels <1.3 g/L and CRP levels higher than 2 mg/L. 30 A particularly marked benefit of primary prevention with statins has been observed in high-risk populations 31 and even in patients with CKD. 32,33 Although CVD and CKD patients are considered to be at high risk for AKI, 34 the risk-benefit ratio of statin therapy is certainly positive in terms of overall morbidity and mortality.
This study presents several limitations, mainly due to the use of administrative and claims data. First, there is a potential for misclassification of exposures and outcomes. Poor medication adherence may have interfered with measurement of statin exposure. Outcome misclassification is also a potential limitation, as the validity of the three-character code used for AKI (N17) has not been extensively assessed. 35 However, the mortality rate in our cases, close to that expected, 36,37 does not indicate inconsistent coding, and the consistency of the results obtained using a broad, natural, and unconstrained definition of AKI and those obtained using a narrower definition, only including cases requiring hemodialysis or hemofiltration, is reassuring.
Moreover, since exposure and outcome were determined independently, this misclassification is nondifferential and hence produces bias toward the null.
Second, despite careful adjustment for sociodemographic factors associated with both statin prescription (age, CMUc, and deprivation index) and AKI, and time-dependent exposures, notably antihypertensive, antidiabetic, and other drugs classically associated with AKI, residual unmeasured confounding therefore remains a concern.
Exclusion from the cohort, at baseline and during follow-up, of subjects with "LTD" status (with 100% reimbursement for costs associ- Third, we selected a healthy population of subjects, free of any significant disease (at baseline and during follow-up) that might interfere with the decision to prescribe or to regularly take statins for primary prevention. This selection made the cohort more homogeneous and minimized confounding biases but presented a certain disadvantage in terms of external validity. In addition, censorship at the time of intercurrent LTD (or death) and especially censorship at the date of hospitalization for any disease other than AKI may have led to the exclusion of future cases of AKI. All these methodological choices could only lead to underestimation of the strength of the association and could probably explain the apparent protective effect observed in women.
Fourth, although this study was conducted according to an "explicative" approach, in that the study design allowed the construc-