Relation Between Change in Renal Function and Cardiovascular Outcomes in Atorvastatin-Treated Patients (from the Treating to New Targets [TNT] Study)

Accepted Manuscript Relation Between Change in Renal Function and Cardiovascular Outcomes in Atorvastatin-Treated Patients (From the Treating to New Targets [TNT] Study) James Shepherd, MD, Andrei Breazna, PhD, Prakash C. Deedwania, MD, John C. LaRosa, MD, Nanette K. Wenger, MD, Michael Messig, PhD, Daniel J. Wilson, MD, for the Treating to New Targets Steering Committee and Investigators PII:

S0002-9149(16)30136-9

DOI:

10.1016/j.amjcard.2016.01.014

Reference:

AJC 21660

To appear in:

The American Journal of Cardiology

Received Date: 21 October 2015 Revised Date:

15 January 2016

Accepted Date: 19 January 2016

Please cite this article as: Shepherd J, Breazna A, Deedwania PC, LaRosa JC, Wenger NK, Messig M, Wilson DJ, for the Treating to New Targets Steering Committee and Investigators, Relation Between Change in Renal Function and Cardiovascular Outcomes in Atorvastatin-Treated Patients (From the Treating to New Targets [TNT] Study), The American Journal of Cardiology (2016), doi: 10.1016/ j.amjcard.2016.01.014. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Relation Between Change in Renal Function and Cardiovascular Outcomes in Atorvastatin-Treated Patients (From the Treating to New Targets [TNT] Study)

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James Shepherd, MDa,*, Andrei Breazna, PhDb, Prakash C. Deedwania, MDc, John C. LaRosa, MDd, Nanette K. Wenger, MDe, Michael Messig, PhDb; Daniel J. Wilson, MDb, for the Treating

a

Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.

b

University of California San Francisco School of Medicine, Fresno, California, USA.

d

e

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Pfizer Inc., New York, New York, USA.

c

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to New Targets Steering Committee and Investigators

State University of New York Medical Center, Brooklyn, New York, New York, USA.

Emory University School of Medicine, Atlanta, Georgia, USA.

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Running title: TNT eGFR and CV Outcomes

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The TNT study was funded by Pfizer.

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*Corresponding author: James Shepherd, MD, Vascular Biochemistry Group, University of Glasgow, McGregor Building (2nd Floor), Western Infirmary, Glasgow G11 6NT, UK. Tel.: +44 (0)141 211 2864; Fax: +44 (0)141 553 9516; E-mail: [email protected]

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Abstract Statins may have nephroprotective as well as cardioprotective effects in patients with

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cardiovascular disease. In the Treating to New Targets (TNT) study (NCT00327691), patients with coronary heart disease (CHD) were randomized to atorvastatin 10- or 80-mg/day and

followed for 4.9 years. The relationship between intra-study change in estimated glomerular filtration rate (eGFR) from baseline and the risk of major cardiovascular events (MCVE, defined

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as CHD death, nonfatal non-procedure-related myocardial infarction, resuscitated cardiac arrest or fatal or nonfatal stroke) was assessed among 9500 patients stratified by renal function:

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improving (change in eGFR >+2 mL/min/1.73m2), stable (−2 to +2 mL/min/1.73m2), and worsening (<−2 mL/min/1.73m2). Compared with patients with worsening renal function (1479 patients, 15.6%), the rate of MCVEs was 28% lower among patients with stable renal function (2241 patients, 23.6%) (hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.60 to 0.87;

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P=0.0005), and 64% lower among patients with improving renal function (5780 patients, 60.8%) (HR, 0.36; 95% CI, 0.30 to 0.43; P<0.0001). For each 1-mL/min/1.73 m2 increase in eGFR, the absolute reduction in the rate of MCVEs was 2.7% (HR, 0.973; 95% CI, 0.967 to 0.980;

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P<0.0001). An absolute MCVE rate reduction per 1-mL/min/1.73 m2 increase in eGFR of 2.0% was reported with atorvastatin 10 mg and 3.3% with atorvastatin 80 mg. In conclusion, intra-

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study stabilization or increase in eGFR in atorvastatin-treated CHD patients from the TNT study was associated with a reduced rate of MCVEs. Statin-treated CHD patients with progressive renal impairment are at high risk for future cardiovascular events.

Keywords: estimated glomerular filtration rate; cardiovascular risk; coronary heart disease; atorvastatin

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Introduction Cardiovascular disease (CVD) is associated with progressive renal function decline and

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development of chronic kidney disease (CKD).1 Additionally, rapid declines in renal function correlate with increased cardiovascular (CV) mortality, independent of baseline estimated

glomerular filtration rate (eGFR).2,3 Therefore, change in eGFR over time may be a more potent predictor of CV outcomes than baseline renal function in patients with CVD.4 Clinical trials in

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patients with CVD or its risk factors have suggested that statins may stabilize or improve renal

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function.5-9 However, the relationship between statin-associated stabilization or improvement of renal function and CV outcomes has not been analyzed. In post-hoc analyses of the Treating to New Targets (TNT) study, we noted dose-dependent improvements in renal function5 and significant reductions in CV events10 in atorvastatin-treated patients with coronary heart disease (CHD) with or without CKD. Here, we examined the effect of atorvastatin on renal function over

Methods

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time to assess the relationship between directional change in eGFR and new CV events.

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The TNT study was a prospective, double-blind, parallel-group study conducted between April 1998 and August 2004.11,12 Eligible patients were men and women aged 35 to 75 years

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with clinically evident CHD, defined as previous myocardial infarction (MI), angina with objective evidence of atherosclerotic CHD, or previous coronary revascularization procedure. Patients with nephrotic syndrome were excluded. No protocol-specific exclusions were based on kidney function or baseline creatinine concentration, although such exclusions could occur at the investigator’s discretion. Following an 8-week open-label treatment period with atorvastatin 10 mg/day (baseline), patients with a mean low-density lipoprotein cholesterol (LDL-C) ≤3.4 mmol/L (130 mg/dL) were randomized to atorvastatin 10- or 80-mg/day (Figure 1).

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Only those patients with both a baseline and at least 1 post-baseline serum creatinine measurement were included in this post-hoc analysis. Serum creatinine levels were measured at baseline and after 12, 24, 36, 48, 60, and 72 months of treatment using the modified alkaline

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picrate method of Jaffé.13,14 Samples were analyzed by a central study laboratory blinded to treatment assignment. Standards by the College of American Pathologists were employed for internal quality assurance and external calibration and validation to ensure accuracy and

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reproducibility of the creatinine measurement throughout the study. To provide consistency with previous renal analyses of the TNT data,5,10 eGFR was determined using the 4-component

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Modification of Diet in Renal Disease (MDRD) equation15 and staged according to Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines.16

We used a last observation carried forward (LOCF) analysis to determine the final eGFR measurement. On-treatment change in eGFR was stratified into 1 of 3 categories based on pre-

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defined clinical classifications of change in renal function over time: improving (change in eGFR >+2 mL/min/1.73 m2); stable (−2 to +2 mL/min/1.73 m2); or worsening (<−2 mL/min/1.73 m2). The primary efficacy outcome was time to occurrence of a major CV event (MCVE; CHD death,

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nonfatal non–procedure-related MI, resuscitated cardiac arrest, and fatal or nonfatal stroke). The relationship between change in eGFR and MCVEs was assessed by a multivariable and time-

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dependent Cox proportional hazards model, which included change from baseline to end of study or last available eGFR (continuous scale) as the time-dependent independent variable adjusting for baseline factors including: eGFR, age, sex, smoking status, body mass index (BMI), LDL-C, and history of hypertension (or antihypertensive use), diabetes (or antidiabetic medication use), coronary artery bypass graft (CABG) surgery, percutaneous coronary intervention, angina, cerebrovascular disease, peripheral vascular disease (PVD), congestive heart failure, and

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arrhythmia. We also carried out 2 additional Cox proportional hazards analyses: a multivariable model that included change in eGFR from baseline to Year 1, and a time-dependent model that included all changes in eGFR from baseline to the first event or end of study as the time-

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dependent independent variable. Both models adjusted for baseline eGFR, change in LDL-C, and treatment. Comparisons of baseline characteristics were based on 1-way analysis of variance with pair-wise comparison for continuous variables, and Fisher’s exact test for overall test and

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logistic regression analysis with pair-wise comparisons for categorical variables. Changes in eGFR from baseline to final measurement were compared by an analysis of covariance model

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adjusting for baseline eGFR. A similar model compared change from baseline to Month 3 in LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using a Cox proportional hazards model. Two-sided log-rank P-values <0.05 were regarded as significant. All analyses were performed

Results

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using SAS (version 9.12 or later).

In TNT, 10,001 patients were randomly assigned to double-blind treatment with either

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atorvastatin 10- or 80-mg/day with a median follow-up of 4.9 years.11,12 Of the 9656 patients

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with both baseline and post-baseline eGFR measurements, 67.8% (n=6549) had an eGFR ≥60 mL/min/1.73 m2, while 32.2% (n=3107) had an eGFR <60 mL/min/1.73 m2 (predominantly CKD Stage 3); the baseline characteristics of this TNT renal cohort have been previously reported.5,10 A total of 156 patients experienced an MCVE prior to the first post-baseline eGFR assessment and were excluded, leaving 9500 patients eligible for this analysis (Figure 1). In this TNT renal subgroup, 417 patients (8.8%) receiving atorvastatin 10 mg and 340 (7.1%) patients receiving atorvastatin 80 mg experienced an MCVE, corresponding to a 19%

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reduction in MCVE risk in patients receiving atorvastatin 80- versus 10-mg (HR, 0.81; 95% CI, 0.70 to 0.93; P=0.0030). Mean (±standard deviation) eGFR at baseline was 65.6±11.4 mL/min/1.73 m2 in the atorvastatin 10-mg group and 65.0±11.2 mL/min/1.73 m2 in the

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atorvastatin 80-mg group. As seen in the total TNT renal cohort,5 mean eGFR increased

progressively from baseline in both treatment groups. Overall, mean eGFR rose from 65.3±11.3 mL/min/1.73 m2 at baseline to 69.7±14.6 mL/min/1.73 m2 at study end, an increase of 4.4±9.8

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mL/min/1.73 m2 (+6.7%) and a shift towards higher eGFR values with a broader distribution, as

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shown for the total renal cohort (Figure 2). Mean eGFR increased by 3.6±9.8 mL/min/1.73 m2 (+5.5%) in the atorvastatin 10-mg arm and 5.2±9.8 mL/min/1.73 m2 (+8.0%) in the atorvastatin 80-mg arm. The difference in least-squares mean change in eGFR from baseline between the treatment groups of 1.6 mL/min/1.73 m2 was significant (95% CI, 1.20 to 1.99; P<0.0001). In the total TNT renal cohort (n=9656), this increase in eGFR was observed in both treatment

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groups regardless of baseline CKD status.5

In the present analysis (n=9500), change from baseline eGFR was significantly associated with MCVEs, major coronary events, all-cause, and CV mortality. Overall, a 1-mL/min/1.73 m2

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increase in eGFR was associated with a 2.7% absolute reduction in the rate of MCVEs (HR,

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0.973; 95% CI, 0.967 to 0.980; P<0.0001). Results from the 1-year eGFR change sensitivity analysis had a lower level of predictability and a marginally insignificant effect (HR per 1mL/min/1.73 m2 increase, 0.990; 95% CI, 0.979 to 1.002; P=0.090). Using the time-dependent model, changes in renal function significantly predicted MCVEs (HR per 1-mL/min/1.73 m2 increase, 0.965; 95% CI, 0.959 to 0.972; P<0.001) to a similar extent as the original model. Change in eGFR was associated with CV endpoints for both atorvastatin 10- and 80-mg treatments, but the reduction in the rate of events associated with increasing eGFR was

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significantly greater in patients receiving atorvastatin 80 mg (absolute event rate reduction per 1mL/min/1.73 m2 increase in eGFR: 2.0% with atorvastatin 10 mg; 3.3% with atorvastatin 80 mg; interaction P=0.0107). This corresponds to a 7.1% absolute reduction in MCVE rate for the

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observed increase of 3.6 mL/min/1.73 m2 in eGFR with atorvastatin 10 mg, and a 16.2%

reduction in MCVE rate for the 5.2-mL/min/1.73 m2 increase in eGFR with atorvastatin 80 mg. Classification of the directional change in eGFR (baseline to last observation) identified

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1479 patients (15.6%) with worsening renal function, 2241 patients (23.6%) with stable renal function, and 5780 patients (60.8%) with improving renal function over 5 years of follow-up.

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Individuals with worsening renal function were significantly older and more likely female, and had a higher BMI, greater likelihood of hypertension or diabetes, and higher prevalence of CABG, PVD, and cerebrovascular disease at baseline, than patients with stable or improving renal function (Table 1).

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Mean eGFR in patients whose renal function worsened was significantly lower at baseline versus those whose renal function remained stable, but significantly higher than those with improving renal function (Table 2). A higher proportion of patients with improving renal

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function, and a lower proportion of those with worsening or stable renal function, were assigned to atorvastatin 80 mg, and this trend was significant across renal subgroups (Table 2). Compared

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with the subgroup with worsening renal function, the relative risk of MCVEs was 28% lower in patients with stable renal function, and 64% lower in patients with improving renal function (Table 2; Figure 3). We confirmed these results using a predictive analysis utilizing Year-1 change in eGFR (Figure 4).

Reductions from baseline to Month 3 in LDL-C and triglyceride levels among patients with improving renal function were significantly greater versus those with worsening renal

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function (Table 2). Decreases in LDL-C and triglycerides at 3 months were also greater in patients with stable renal function compared with worsening renal function, but not significantly

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so. Change in HDL-C showed no significant differences across renal subgroups (Table 2).

Discussion

In the TNT trial, CV event reductions following atorvastatin therapy were achieved both

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in patients with and without CKD at baseline.10 This current analysis has revealed that change in eGFR over the course of the trial was predictive of MCVEs when using a LOCF analysis.

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Although the association with MCVE risk was diluted in the 1-year eGFR sensitivity analysis, the time-dependent model captured the predictive value of change in eGFR in a similar manner to the LOCF model. MCVE risk was strongly related to the directional change in eGFR. Compared with those with worsening renal function, patients with improving renal function experienced a 64% reduction in relative MCVE risk, while patients with stable renal function

change in eGFR.

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experienced a 28% reduction; these results were confirmed in an analysis based on Year-1

The observation that CV risk may change concurrently with renal function is not

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new.2,3,17 Until now, however, few studies have commented on the relationship between

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improving renal function and CV events.17 To our knowledge, this analysis is one of the first to suggest that stabilization (as well as improvement) of renal function with statin therapy is strongly associated with a reduction in CV events in patients with CHD. These observations are supported by a subanalysis of the Greek Atorvastatin and Coronary Heart disease Evaluation (GREACE) trial, in which CHD patients receiving atorvastatin had a 12% increase in creatinine clearance versus a 5.2% decline in those receiving usual care.6 A multivariate model predicted

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that each 5% increase in creatinine clearance was associated with a 16% reduction in CHDassociated events.6 On the basis of this and other TNT subanalyses, the effect of atorvastatin on renal

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function and subsequent MCVE risk appears to be drug-related, dose-dependent, and occurs over a wide range of baseline renal function. Patients with improved renal function were significantly more likely to receive atorvastatin 80 mg, while those with worsening renal function more likely

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received atorvastatin 10 mg. Differences in atorvastatin dose, exposure, and resulting LDL-C and triglyceride reductions may have partly contributed to differences in CV event reduction between

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those with improving versus worsening renal function. Mean LDL-C reductions differed between the group with declining versus stable or improving renal function; however, these differences were numerically small (<0.1 mmol/L [4 mg/dL]). Moreover, statistically significant differences in on-treatment lipid levels were not observed between those with worsening renal function and

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stable renal function. Therefore, it is unlikely that lipid lowering alone accounted for the differences in CV event reduction observed across the 3 renal function subgroups. Annual declines in eGFR have been observed in high-risk patients with CVD, CHD, and

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dyslipidemia.18,19 In the TNT renal cohort, a shift towards a higher eGFR with atorvastatin therapy was detected. Moreover, stabilization or improvement of renal function occurred in

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~84% of TNT patients included in this current analysis. This observation is notable and may be clinically relevant: CVD has been independently associated with a more rapid decline in renal function,1 and atherosclerosis may foreshadow underlying renal microvascular disease.20 Indeed, TNT patients with worsening renal function had significantly higher prevalence of CV risk factors and target organ damage at baseline, including PVD, heart failure, and stroke.

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Tonelli et al first noted a beneficial effect of statins on renal function in CHD patients with an eGFR <40 mL/min/1.73 m2, in whom progression of renal disease was slowed significantly with pravastatin versus placebo.18 For atorvastatin, beneficial effects on renal

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function have been observed in a number of trials across a wide range of patient populations, including those with CHD, diabetes, and CKD.5,6,21,22 The mechanism behind atorvastatin’s effect on renal function is unclear. LDL-C has been linked to mesangial cell proliferation in the

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kidney23 and increased production of inflammatory markers. In addition to lipid effects,

atorvastatin has demonstrated reductions in markers of inflammation and oxidative stress.24,25

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Thus, potent statins with anti-inflammatory properties may act to slow kidney disease progression in addition to reducing CV risk. However, the Study of Heart and Renal Protection (SHARP) trial found no effect of simvastatin plus ezetimibe versus placebo on progression of kidney disease in a large cohort of non-dialysis patients with moderate CKD.26 Also, a recent

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analysis of the PLANET I and II trials demonstrated that rosuvastatin was associated with significantly greater declines in eGFR versus atorvastatin.27 Moreover, atorvastatin was associated with significantly greater reductions in proteinuria,27 indicating that—together with

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the SHARP findings—renoprotection may not be a class effect. We acknowledge several limitations of this analysis in addition to those previously

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discussed for TNT.10 To provide consistency with previous analyses of the TNT renal population,5,10 we utilized the modified MDRD equation, which is known to underestimate renal function in the normal range compared with direct measurements of GFR.28 Proteinuria, which may help define CV risk in conjunction with eGFR,29 was not systematically assessed in TNT. Finally, the observed renal benefit may be limited to patients with CHD and normal renal function, or those with milder degrees of renal impairment (Stage 3 CKD).

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Acknowledgements Assistance with statistical analyses was provided by Dr. Chuan-Chuan Wun, PhD,

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formerly of Pfizer, and Mr. Sean Spanyers, MSc, at inVentiv Health Clinical, and was funded by Pfizer. Editorial assistance was provided by Dr. Shirley Smith, PhD, at Engage Scientific and was funded by Pfizer.

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Role of the Funding Source

The TNT study was funded by Pfizer. The sponsor contributed to study design and

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conduct; collection, management, analysis, and interpretation of study data; and preparation, review, and approval of the manuscript. Employees of Pfizer who met ICJME criteria for authorship are listed as co-authors. The corresponding author had full access to the study data and was responsible for the decision to submit the manuscript for publication.

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Disclosures

Dr. Shepherd: AstraZeneca, GlaxoSmithKline, Merck, Oxford Biosensors, Pfizer, Nicox, Roche, Schering-Plough (consulting fees); AstraZeneca, Merck, Abbott, Schering-Plough, Pfizer

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(lecture fees). Dr. Deedwania: Pfizer, AstraZeneca (consulting and lecture fees). Dr. LaRosa: Pfizer, Merck, Bristol-Myers Squibb, AstraZeneca (consulting fees); Pfizer (lecture fees). Dr.

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Wenger: AstraZeneca, Abbott, Merck, Medtronic, Pfizer (consulting fees); Gilead Sciences, Abbott, Eli Lilly, Pfizer, Merck, National Heart, Lung, and Blood Institute (grant support). Drs Breazna and Messig: Pfizer (full-time employees). Dr. Wilson: Pfizer (prior full-time employee).

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28. Rule AD, Larson TS, Bergstralh EJ, Slezak JM, Jacobsen SJ, Cosio FG. Using serum creatinine to estimate glomerular filtration rate: accuracy in good health and in chronic kidney disease. Ann Intern Med 2004;141:929-937. 29. Bello AK, Hemmelgarn B, Lloyd A, James MT, Manns BJ, Klarenbach S, Tonelli M. Associations among estimated glomerular filtration rate, proteinuria, and adverse cardiovascular outcomes. Clin J Am Soc Nephrol 2011;6:1418-1426.

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Figure Legends Figure 1. Flow chart of TNT participants included in this analysis. eGFR = estimated glomerular

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filtration rate; TNT = Treating to New Targets.

Figure 2. Frequency distribution of eGFR in the TNT renal cohort (n=9656) at baseline (top) and at last visit prior to primary endpoint (bottom). eGFR = estimated glomerular filtration rate; TNT

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= Treating to New Targets.

Figure 3. Kaplan-Meier curves for time to primary endpoint in defined renal subgroups using a LOCF analysis. Renal function was defined as improving (change in eGFR >+2 mL/min/1.73 m2), stable (−2 to +2 mL/min/1.73 m2), or worsening (<−2 mL/min/1.73 m2). K-M = Kaplan-

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Meier; LOCF = last observation carried forward.

Figure 4. Kaplan-Meier curves for time to primary endpoint in defined renal subgroups using a predictive model incorporating change in eGFR over 1 year. Renal function was defined as

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improving (change in eGFR >+2 mL/min/1.73 m2), stable (−2 to +2 mL/min/1.73 m2), or worsening (<−2 mL/min/1.73 m2). eGFR = estimated glomerular filtration rate; K-M = Kaplan-

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Meier.

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Table 1 Baseline characteristics of patients included in this analysis, stratified by directional change in estimated glomerular

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filtration rate Change in estimated glomerular filtration rate (mL/min/1.73 m2) Baseline characteristic

Worsening (<−2)

Stable (−2 to +2)

Improving (>+2)

(n=1479)

(n=2241)

(n=5780)

1761 (79%)*

4829 (84%)*

63.5±8.8

61.2±8.8*

60.3±8.7*

1378 (93%)

2100 (94%)

5471 (95%)*

201 (14%)

322 (14%)

713 (12%)

135.1±18.1

131.2±16.5*

129.3±16.3*

78.1±9.7

78.0±9.5

77.9±9.4

2.52±0.46

2.51±0.44

2.52±0.46

[97.6±17.6]

[97.0±17.2]

[97.6±17.6]

1.22±0.30

1.24±0.28

1.22±0.28

[47.2±11.5]

[47.9±10.9]*

[47.2±10.8]

4.54±0.64

4.50±0.60

4.52±0.62

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(at randomization)

1113 (75%)

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Men Mean age (years) White

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Current smoker Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg)

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Low-density lipoprotein cholesterol (mmol/L [mg/dL])

High-density lipoprotein cholesterol (mmol/L [mg/dL])

Total cholesterol (mmol/L [mg/dL])

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[173.9±23.1]

[174.7±23.8]

1.74±0.83

1.65±0.77

1.70±0.79

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Triglycerides (mmol/L [mg/dL])

[175.4±24.6]

[146.1±68.4]*

[150.3±69.6]*

MDRD estimated glomerular filtration rate (mL/min/1.73 m2)

65.0±13.7

68.3±11.1*

64.2±10.5*

Body mass index (kg/m2)

29.1±5.1

28.4±4.7*

28.4±4.3*

Chronic kidney disease†

542 (37%)

529 (24%)*

1978 (34%)

1214 (82%)

1805 (81%)

4725 (82%)

864 (58%)

1294 (58%)

3352 (58%)

762 (52%)

1211 (54%)

3170 (55%)*

779 (53%)

1039 (46%)*

2588 (45%)*

995 (67%)

1220 (54%)*

2918 (50%)*

388 (26%)

300 (13%)*

706 (12%)*

272 (18%)

260 (12%)*

571 (10%)*

215 (15%)

151 (7%)*

349 (6%)*

109 (7%)

117 (5%)*

252 (4%)*

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[154.3±73.4]

Angina pectoris Myocardial infarction

Diabetes mellitus Peripheral vascular disease Congestive heart failure Cerebrovascular disease

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Hypertension

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Coronary artery bypass graft

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Coronary angioplasty

Values are number (%) or mean ± standard deviation. *P<0.05 versus patients with worsening renal function.

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eGFR <60 mL/min/1.73 m2.

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MDRD = Modification of Diet in Renal Disease.

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Table 2 Clinical outcomes in the renal function subgroups

(n=1479) Number (%) of patients with primary endpoint

208 (14.1%) 1.00

primary endpoint Serum creatinine (µmol/L [mg/dL]) Baseline

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104.3±22.1

(n=2241)

(n=5780)

235 (10.5%)

314 (5.4%)

99.9±15.9

P=0.0005

0.36 (0.30, 0.43)

P<0.0001

P<0.0001

107.0±16.8

P<0.0001

[1.18±0.25]

[1.13±0.18]

20.3±31.8

–0.18±4.24

[0.23±0.36]

[–0.002±0.048]

65.0±13.7

68.3±11.1

P<0.0001

64.2±10.5

P=0.0203

–10.9±6.9

–0.98±0.41

P<0.0001

10.3±5.9

P<0.0001

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Change from baseline†

Improving (>+2)*

0.72 (0.60, 0.87)

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Hazard ratio (95% confidence interval) for

Stable (−2 to +2)*

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Worsening (<−2)

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Change in estimated glomerular filtration rate (mL/min/1.73 m2)

[1.21±0.19] P<0.0001

–14.1±8.0

P<0.0001

[–0.16±0.09]

Baseline Change from baseline‡

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Estimated glomerular filtration rate (mL/min/1.73 m2)

Lipids: Change from baseline (mmol/L [mg/dL])§

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Triglycerides

–0.26±0.53

[–9.7±21.3]

[–10.1±20.5]

–0.001±0.147

0.005±0.142

[–0.04±5.68]

[0.19±5.49]

–0.08±0.57

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[–7.1±50.4]

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High-density lipoprotein cholesterol

–0.25±0.55

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Low-density lipoprotein cholesterol

–0.09±0.60

P=0.2892

–0.34±0.55

P<0.0001

[–13.1±21.3] P=0.0906

–0.004±0.139

P=0.5485

[–0.15±5.38] P=0.0728

[–8.0±53.1]

–0.14±0.59

P<0.0001

[–12.4±52.2]

Atorvastatin 10 mg

833 (56.3%)

1185 (52.9%)

2719 (47.0%)

Atorvastatin 80 mg

646 (43.7%)

1056 (47.1%)

3061 (53.0%)

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Overall P-value (trend)ǁ

Values are number (%) or mean ± standard deviation unless otherwise stated.

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*P-values versus patients with worsening renal function. Change from baseline to final visit.

‡

Change from baseline to the last measurement prior to primary endpoint.

§

Change from baseline to Month 3.

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†

P-value based on Cochran-Armitage test for trend.

P<0.0001

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15 464 entered open-label run-in period

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3005 excluded

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10 003 underwent randomization (2 not given drug)

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9656 with complete renal data (both baseline and follow-up assessments of eGFR)

345 with missing creatinine data

156 without post-baseline eGFR measurement prior to major cardiovascular event

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9500 included in eGFR analysis of primary endpoint

5461 excluded 4634 did not meet randomization criteria 195 had ischemic events 197 had adverse events 70 did not comply with treatment 16 died 349 for other reasons

1479 with worsening renal function (∆eGFR:<−2 mL/min/1.73 m2)

2241 with stable renal function (∆eGFR: −2 to +2 mL/min/1.73 m2)

5780 with improving renal function (∆eGFR: >+2 mL/min/1.73 m2)

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