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Clinical Nephrology |
* Department of Vascular Biochemistry, University of Glasgow, Glasgow, United Kingdom; Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands; Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama; Cardiology Division, VA Central California Healthcare System and UCSF School of Medicine, Fresno, California; || Global Research and Development; ** Pfizer Global Pharmaceuticals, Pfizer Inc., New York, New York; ¶ Scientific Solutions, Envision Pharma Ltd., Horsham, United Kingdom; and Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia
Correspondence: Dr. James Shepherd, Department of Biochemistry, Macewen Building Glasgow Royal Infirmary, 8 Alexandra Parade, Glasgow, G31 2ER, UK. Phone: +44-141-5520689; Fax: +44-141-5531703; E-mail: jshepherd{at}gri-biochem.org.uk
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Abstract |
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Design, setting, participants, & measurements: A total of 10,001 patients with coronary heart disease and LDL cholesterol levels of <130 mg/dl were randomly assigned to double-blind therapy with 10 or 80 mg/d atorvastatin. Estimated GFR using the Modification of Diet in Renal Disease equation was compared at baseline and at the end of follow-up in 9656 participants with complete renal data.
Results: Mean estimated GFR at baseline was 65.6 ± 11.4 ml/min per 1.73 m2 in the 10-mg group and 65.0 ± 11.2 ml/min per 1.73 m2 in the 80-mg group. At the end of follow-up (median time to final creatinine measurement 59.5 months), mean change in estimated GFR showed an increase of 3.5 ± 0.14 ml/min per 1.73 m2 with 10 mg and 5.2 ± 0.14 ml/min per 1.73 m2 with 80 mg (P < 0.0001 for treatment difference). In the 80-mg arm, estimated GFR improved to 
60 ml/min per 1.73 m2 in significantly more patients and declined to <60 ml/min per 1.73 m2 in significantly fewer patients than in the 10-mg arm.
Conclusions: The expected 5-yr decline in renal function was not observed. Estimated GFR improved in both treatment groups but was significantly greater with 80 mg than with 10 mg, suggesting this benefit may be dosage related.
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Introduction |
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Post hoc analyses of randomized, controlled trials have suggested that statins may have a protective effect on renal function (9). In 15,696 patients with coronary disease, other occlusive arterial disease, or diabetes in the Heart Protection Study, allocation to 40 mg/d simvastatin was associated with a smaller fall in the estimated GFR (eGFR) compared with placebo after an average follow-up of 4.6 yr. This difference was small (0.8 ml/min) but significant (10). In patients with hyperlipidemia and previous myocardial infarction in the Cholesterol And Recurrent Events trial, 40 mg of pravastatin significantly reduced the rate of eGFR decline in individuals with more severe chronic renal insufficiency (eGFR of <40 or <50 ml/min per 1.73 m2) compared with placebo; however, these findings did not extend overall to patients with eGFR of <60 or 60 ml/min per 1.73 m2 (11). Data suggest that atorvastatin may also have nephroprotective effects (12–14). In the Aggressive Lipid-Lowering Initiation Abates New Cardiac Events (ALLIANCE) study, aggressive atorvastatin therapy prevented the anticipated decline in renal function during the 4 yr of the trial and modified the progression of CKD when compared with usual care (14).
Atorvastatin in both primary and secondary cardiovascular prevention studies has been shown to reduce the risk for cardiovascular events in a broad range of patients, without any safety concerns (15–20). The Treating to New Targets (TNT) study prospectively investigated the effects of lowering LDL cholesterol to a target of 75 mg/dl with 80 mg/d atorvastatin compared with an LDL cholesterol target of 100 mg/dl with 10 mg/d atorvastatin in approximately 10,000 patients with stable coronary heart disease (CHD) (19). After 5 yr of follow-up, treatment with 80 mg of atorvastatin resulted in a significant reduction in major cardiovascular events compared with 10 mg/d atorvastatin. We conducted the current post hoc analysis of the TNT study to investigate further the initial indication from the ALLIANCE study of a renoprotective effect with more intensive atorvastatin treatment. In addition, this is the first study to evaluate whether such an effect could be dosage dependent.
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Concise Methods |
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Patient Population
Patients who were eligible for inclusion were men and women who were aged 35 to 75 yr and had clinically evident CHD, defined as previous myocardial infarction, previous or present angina with objective evidence of atherosclerotic CHD, or previous coronary revascularization procedure. Major exclusion criteria were statin hypersensitivity, current liver disease, nephrotic syndrome, pregnancy or uncontrolled CHD risk factors, CHD event or revascularization within the previous month, congestive heart failure, creatine phosphokinase levels more than six times the upper limit of normal (ULN), life-threatening malignancy, or immunosuppressive or lipid-lowering drug treatment. There were no exclusions based on serum creatinine concentration at baseline.
Study Design
All previously prescribed lipid-regulating drugs were discontinued at screening, and all participants required a washout period of 1 to 8 wk (8 wk for those who had previously received lipid-regulating drugs and 1 wk for those who had not). To ensure that all participants at baseline achieved LDL cholesterol levels consistent with current guidelines for the treatment of stable CHD, those with LDL cholesterol levels between 130 and 250 mg/dl (3.4 to 6.5 mmol/L) and triglyceride levels 
600 mg/dl (6.8 mmol/L) entered an 8-wk open-label treatment period with 10 mg/d atorvastatin. At the end of the run-in phase (baseline), participants with a mean LDL cholesterol <130 mg/dl (3.4 mmol/L) were randomly assigned to double-blind therapy with either 10 or 80 mg/d atorvastatin. Cholesterol inclusion/exclusion criteria were selected to achieve an average LDL cholesterol level of 100 mg/dl (2.6 mmol/L) in the 10-mg/d treatment arm. For reaching an average LDL cholesterol level in the comparator group of approximately 75 mg/dl (1.9 mmol/L), 80 mg/d atorvastatin was chosen. During the double-blind period, follow-up visits occurred at week 12 and at months 6, 9, and 12 in the first year and every 6 mo thereafter.
Efficacy and Safety Outcomes
In line with a recent American Heart Association Science Advisory (22), renal function was assessed using the Modification of Diet in Renal Disease (MDRD) equation (23), a serum creatinine–based estimate of GFR. The Cockcroft-Gault equation (24), another creatinine-based estimate of GFR, incorporating patient weight, was also used. Serum creatinine measurements using a modified alkaline picrate method of Jaffé (25,26) were taken at baseline and after 12, 24, 36, 48, 60, and 72 mo of treatment by individuals at a central study laboratory who were blinded to treatment assignment. Creatinine measurements were made using the Hitachi 747 analyzer (Roche Diagnostics, Indianapolis). Quality control samples were analyzed every 40 samples. The coefficients of variation for a monthly average creatinine concentration of 0.6 mg/dl were 4.5 to 9.0% and for a monthly average creatinine concentration of 4.7 mg/dl were 1.3 to 1.7%. Internal quality assurance and College of American Pathologists external quality assurance showed the measurement of creatinine to be stable and acceptably calibrated throughout the study. Final availability for each participant was used for the analysis of eGFR change. For the baseline Cockcroft-Gault GFR estimate, weight at baseline or the visit 2 wk earlier (if baseline weight was not available) was used.
Safety was assessed by monitoring vital signs, clinical end points, adverse events (both clinical and laboratory based), and concurrent medication information at each visit. Physical examinations and electrocardiograms were performed and laboratory specimens were collected at alternate visits. Elevations in liver function enzymes (alanine aminotransferase and aspartate aminotransferase) were reported by the central laboratory as levels more than three times the ULN and creatine phosphokinase as a level >10 times the ULN.
Statistical Analyses
eGFR values at baseline were compared between the two atorvastatin treatment groups using an ANOVA model with items for treatment, center, race, age, and gender. eGFR at the end of follow-up was assessed using a last observation carried forward analysis. Fisher exact test was used for treatment arm comparisons of the proportions of participants who experienced decline or improvement of renal function. Mean changes from baseline eGFR during the course of the study and at the end of the study in the two treatment groups were compared using an analysis of covariance model with items for treatment, center, race, age, gender, and baseline eGFR.
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Results |
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Serum Lipid Levels
Baseline lipid levels (after 8 wk of open-label 10 mg of atorvastatin) in participants with complete renal data were well matched between treatment groups for LDL cholesterol, HDL cholesterol, total cholesterol, and triglycerides (Table 2). The difference between the 10- and 80-mg groups at the end of the study was statistically significant for LDL cholesterol, total cholesterol, and triglycerides, in favor of 80 mg of atorvastatin (Table 2). There was no difference between the treatment groups in HDL cholesterol.
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Renal Function
Mean (±SD) eGFR at baseline as assessed by the MDRD was 65.6 ± 11.4 ml/min per 1.73 m2 in the 10-mg group and 65.0 ± 11.2 ml/min per 1.73 m2 in the 80-mg group (Table 1). Mean change from baseline eGFR showed a progressive increase during the course of the study in both treatment groups. At the end of follow-up, mean change from baseline eGFR (±SE) showed an increase of 3.5 ± 0.14 ml/min per 1.73 m2 in the 10-mg group and 5.2 ± 0.14 ml/min per 1.73 m2 in the 80-mg group, which represented increases of 5.6 and 8.3%, respectively (Figure 2). The difference between treatment groups in mean change from baseline eGFR was highly significant (1.68 ± 0.20 ml/min per 1.73 m2; P < 0.0001). In 9644 participants with data available for assessment using the Cockcroft-Gault equation, renal outcomes were consistent with those observed with the MDRD equation (mean changes from baseline 1.1 ± 0.17 ml/min for 10 mg of atorvastatin and 2.6 ± 0.17 ml/min for 80 mg of atorvastatin; P < 0.0001).
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The progressive increase in eGFR for both dosages of atorvastatin was consistent in participants with CKD at baseline and in participants with normal eGFR at baseline, with a mean change from baseline of 3.5 ml/min per 1.73 m2 with 10 mg of atorvastatin and 5.2 ml/min per 1.73 m2 with 80 mg of atorvastatin in both eGFR categories (Figure 3); however, this represented a greater mean percentage increase from baseline for participants with CKD (9.9% with 80 mg of atorvastatin and 6.6% with 10 mg of atorvastatin) than those with normal eGFR (7.6% with 80 mg of atorvastatin and 5.2% with 10 mg of atorvastatin; Figure 3).
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60 ml/min per 1.73 m2, significantly fewer in the 80-mg group declined to <60 ml/min per 1.73 m2 at the end of the study than in the 10-mg group (6.6 versus 9.2%; P < 0.0001; Figure 4). Among participants with a baseline eGFR <60 ml/min per 1.73 m2, significantly more in the 80-mg group improved to 60 ml/min per 1.73 m2 at the end of the study than in the 10-mg group (45.6 versus 37.8%; P = 0.0001; Figure 4). Among participants with CKD at baseline (eGFR <60 ml/min per 1.73 m2), 80 (5.3%) who were assigned to 10 mg of atorvastatin and 54 (3.4%) who were assigned to 80 mg of atorvastatin experienced a decline in eGFR of 25% (P = 0.0077).
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Discussion |
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The expected decline in renal function that was seen in other cardiovascular treatment trials (10,11,28) was not observed during the 5 yr of the TNT study in either the 10- or 80-mg treatment group; however, the absence of an untreated control arm is a recognized limitation of this study, because the actual age-related decline in renal function was not measured in the TNT population and can only be estimated from similar clinical trials. The age-related decline in renal function has been well documented in studies (10) of patients with CHD, with reported eGFR declines in control groups of up to 6.7 ml/min per 1.73 m2 during 5 yr of follow-up. Thus, although the 5-yr improvements in eGFR were numerically small, drug-related improvements in renal function or significant modification of the anticipated renal decline should be considered clinically relevant. Such renoprotective effects would be of particular importance in patients who have GFR 60 ml/min per 1.73 m2, who, with additional loss of renal function, are at significantly greater risk for future cardiovascular events (7,8). The observation that eGFR showed an improvement in the TNT study may have been related to the intensity of statin therapy. Previous studies with moderate dosages of pravastatin (11,29) and simvastatin (10) demonstrated a slowing in the decline of eGFR, whereas improvements have been repeatedly observed with atorvastatin (13,14) and more recently in short-term studies of rosuvastatin (30). Although improvement in eGFR occurred with 10 mg of atorvastatin, by the end of the trial, 80 mg of atorvastatin had demonstrated significantly greater improvement in eGFR than that achieved by low-dosage atorvastatin. This not only suggests that atorvastatin improves renal function but also indicates that there may be a dosage-dependent renoprotective effect.
These data are consistent with two previous studies that demonstrated significant renal benefit of a titrate-to-goal regimen of atorvastatin (10 to 80 mg) over a regimen of "usual care" in patients with established CHD (13,14); however, when compared with the TNT study, patients in both of these trials had substantially higher LDL cholesterol at baseline, and follow-up LDL cholesterol levels in the titrate-to-goal treatment groups were similar to that achieved by the 10-mg atorvastatin arm of TNT. Furthermore, fewer than half of the patients in the ALLIANCE study (18) and only 3% in the Greek Atorvastatin and Coronary Heart Disease Prevention (GREACE) study (13) received 80 mg/d atorvastatin. These factors could possibly reduce the potential for improvement. Observations from ALLIANCE and GREACE tend to reinforce the importance of the TNT findings of the potential dosage-related effect of atorvastatin on eGFR in patients with CHD and the greater renal benefit that is associated with intensive therapy with 80 mg of atorvastatin.
The mechanisms that are involved in this observed nephroprotective effect of atorvastatin have yet to be determined. Such an effect could be linked to the cardiovascular benefits of LDL cholesterol reduction, because on-treatment LDL cholesterol proved to be a significant predictor of change in eGFR. Other cholesterol-independent statin pleiotropic effects could also account for or contribute to the observed clinical findings. In vivo studies (31–35) suggested a variety of mechanisms whereby statins may have an impact on renal endothelial function. In one such study, upregulation of vascular endothelial nitric oxide synthase and inhibition of oxidative stress were observed with atorvastatin treatment and were thought to protect against the development of end-organ injury (31). The gradual improvement of eGFR over time and differential response between patients with CKD and patients with normal eGFR observed in the TNT study may indicate such an effect on the vasculature that increases over time, rather than a direct effect on increased creatinine excretion or reduction in muscle mass.
A number of different methods are used to estimate GFR, based on serum creatinine. Because creatinine generation may be influenced by dietary protein intake, muscle mass, and activity, GFR estimates attempt to allow for this by using other variables, such as age, gender, race, and body size. The MDRD estimate of GFR used in this analysis has been evaluated for accuracy in clinical studies and is recommended by the National Kidney Foundation Clinical Practice Guidelines (3) and a recent American Heart Association Science Advisory (22) to detect, evaluate, and manage CKD. The MDRD equation corrects for body surface area and is less accurate in populations without CKD. The Cockcroft-Gault equation calculates creatinine clearance rather than GFR. Because creatinine clearance is higher than GFR (as a result of tubular secretion of creatinine), the Cockcroft-Gault equation often underestimates changes in GFR. Despite imperfections with each of these approaches, the results from this analysis were consistent across both measures.
The prevalence of CKD in the TNT study was approximately 32% (based on eGFR <60 ml/min per 1.73 m2), consistent with previous studies of CHD populations (11,29,34,36), illustrating that this is an important and potentially underrecognized condition in patients with CHD. By the end of the study, renal function in participants who had CKD and were treated with 80 mg of atorvastatin had improved by almost 10%, compared with 6.6% in participants who had CKD and were treated with 10 mg of atorvastatin. Furthermore, 46% of participants who had CKD and were treated with 80 mg of atorvastatin and 38% participants who had CKD and were treated with 10 mg of atorvastatin improved from an eGFR <60 to an eGFR 60 ml/min per 1.73 m2. Taking into account the accelerated increase in risk for cardiovascular events in patients with GFR <60 ml/min per 1.73 m2 (3,4,7,8) and the increased mortality after a coronary event in patients with mild to moderate renal impairment (37–40), these patients therefore represent those for whom delay in progression of renal disease has the greatest clinical relevance. It is also of note that the MDRD estimates of GFR are likely to be more accurate representations of actual GFR in these patients. The renoprotective effects that were demonstrated in this and other studies highlight a clinically relevant slowing of progression to CKD. These data also reinforce the current trend in guidelines advocating the use of high-dosage statin therapy to achieve lower target LDL cholesterol levels for optimal prevention of cardiovascular events (41).
The heightened renal benefit of 80 mg/d atorvastatin was achieved without additional safety concerns or increased risk to the patients and was consistent with other data that have shown high-dosage atorvastatin to be safe and well tolerated (17,18,20,42,43). Specifically, there was no increase in serious renal adverse events or those with potential for renal complications, and there was no increased risk with high-dosage atorvastatin to participants with CKD at baseline, compared with those with normal eGFR. Excretion of atorvastatin is mainly hepatic, and previous data (44–46) showed that renal disease has no influence on the achieved plasma concentrations of LDL cholesterol produced by atorvastatin.
As a post hoc analysis, using estimates of renal function, there are some limitations to the interpretation of these data. Generalizations should be made with caution, because the cause of renal disease in the TNT population is unknown. In addition, conclusions that can be made regarding patients with severe renal deficiency are limited given the small proportion of patients who had advanced CKD and were included in this analysis. The influence of nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs could not be assessed because the study was not designed to monitor actively the use of these drugs; however, we expect that the percentage of participants who were prescribed such drugs would have been similar between the treatment groups in this randomized trial.
These data demonstrating renal benefits with 80 mg/d atorvastatin over those achieved with 10 mg/d atorvastatin add to the growing evidence base for noncardiac benefits of statins. Although the absolute changes in eGFR with atorvastatin may seem small, the observation that there was an apparent improvement in GFR during the 5 yr of the TNT study rather than a steady decline demonstrates the clinical importance by preventing progression to CKD and ESRD. Although the mechanisms that are responsible for renoprotection with statins have yet to be determined, lowering LDL cholesterol levels to well below 100 mg/dl with high-dosage atorvastatin seems to maximize renal benefits in high-risk patients with CHD and should not be contraindicated in moderate CKD. The findings from this TNT study subanalysis are intriguing and, when taken in concert with previous statin clinical trials (10,11,13,14), may have significant clinical and therapeutic implications for the clinical treatment of patients who have CHD with CKD.
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Disclosures |
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Acknowledgments |
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We acknowledge the assistance of David DeMicco, PharmD, and Attila Kursun, MD (both employees of Pfizer Inc.), for contributions to the development of this article.
Data in this article were presented in abstract format at the American College of Cardiology 55th Annual Scientific Session; Atlanta, GA, March 11 to 14, 2006; 88th Annual Meeting of the Endocrine Society; Boston, MA, June 24 to 27, 2006; 12th Regional Conference of the World Organization of National Colleges, Academies and Academic Associations of General Practicioners/Family Physicians Europe; Florence, Italy, August 27 to 30, 2006; annual meeting of the American College of Clinical Pharmacy; St. Louis, MO, October 26 to 29, 2006; and the World Congress of Nephrology; Rio de Janeiro, Brazil, April 21 to 25, 2007.
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Footnotes |
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See related editorial, "HMG-CoA Reductase Inhibitors and Renal Function," on pages 1100–1103.
Access to UptoDate on-line is available for additional clinical information at http://www.cjasn.org/
Received December 22, 2006. Accepted July 29, 2007.
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