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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)

Open AccessPublished:January 28, 2016DOI:https://doi.org/10.1016/j.amjcard.2016.01.014
      Statins may have nephroprotective as well as cardioprotective effects in patients with 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 relation between intrastudy change in estimated glomerular filtration rate (eGFR) from baseline and the risk of major cardiovascular events (MCVEs, defined as CHD death, nonfatal non–procedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or nonfatal stroke) was assessed among 9,500 patients stratified by renal function: improving (change in eGFR more than +2 ml/min/1.73 m2), stable (−2 to +2 ml/min/1.73 m2), and worsening (less than −2 ml/min/1.73 m2). Compared with patients with worsening renal function (1,479 patients, 15.6%), the rate of MCVEs was 28% lower in patients with stable renal function (2,241 patients, 23.6%) (hazard ratio [HR] 0.72; 95% confidence interval [CI] 0.60 to 0.87; p = 0.0005) and 64% lower in patients with improving renal function (5,780 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; 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, intrastudy stabilization or increase in eGFR in atorvastatin-treated patients with CHD 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.
      Cardiovascular disease (CVD) is associated with a progressive decrease in renal function and development of chronic kidney disease (CKD).
      • Elsayed E.F.
      • Tighiouart H.
      • Griffith J.
      • Kurth T.
      • Levey A.S.
      • Salem D.
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      • Weiner D.E.
      Cardiovascular disease and subsequent kidney disease.
      Additionally, rapid declines in renal function correlate with increased cardiovascular (CV) mortality, independent of baseline estimated glomerular filtration rate (eGFR).
      • Rifkin D.E.
      • Shlipak M.G.
      • Katz R.
      • Fried L.F.
      • Siscovick D.
      • Chonchol M.
      • Newman A.B.
      • Sarnak M.J.
      Rapid kidney function decline and mortality risk in older adults.
      • Shlipak M.G.
      • Katz R.
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      • Rifkin D.
      • Sarnak M.J.
      Rapid decline of kidney function increases cardiovascular risk in the elderly.
      Therefore, change in eGFR over time may be a more potent predictor of CV outcomes than baseline renal function in patients with CVD.
      • Matsushita K.
      • Selvin E.
      • Bash L.D.
      • Franceschini N.
      • Astor B.C.
      • Coresh J.
      Change in estimated GFR associates with coronary heart disease and mortality.
      Clinical trials in patients with CVD or its risk factors have suggested that statins may stabilize or improve renal function.
      • Shepherd J.
      • Kastelein J.J.
      • Bittner V.
      • Deedwania P.
      • Breazna A.
      • Dobson S.
      • Wilson D.J.
      • Zuckerman A.
      • Wenger N.K.
      Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to New Targets (TNT) study.
      • Athyros V.G.
      • Mikhailidis D.P.
      • Papageorgiou A.A.
      • Symeonidis A.N.
      • Pehlivanidis A.N.
      • Bouloukos V.I.
      • Elisaf M.
      The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study.
      • Kimura K.
      • Shimano H.
      • Yokote K.
      • Urashima M.
      • Teramoto T.
      Effects of pitavastatin (LIVALO tablet) on the estimated glomerular filtration rate (eGFR) in hypercholesterolemic patients with chronic kidney disease. Sub-analysis of the LIVALO Effectiveness and Safety (LIVES) study.
      • Vidt D.G.
      • Ridker P.M.
      • Monyak J.T.
      • Schreiber M.J.
      • Cressman M.D.
      Longitudinal assessment of estimated glomerular filtration rate in apparently healthy adults: a post hoc analysis from the JUPITER study (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin).
      • Geng Q.
      • Ren J.
      • Song J.
      • Li S.
      • Chen H.
      Meta-analysis of the effect of statins on renal function.
      However, the relation 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 function
      • Shepherd J.
      • Kastelein J.J.
      • Bittner V.
      • Deedwania P.
      • Breazna A.
      • Dobson S.
      • Wilson D.J.
      • Zuckerman A.
      • Wenger N.K.
      Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to New Targets (TNT) study.
      and significant reductions in CV events
      • Shepherd J.
      • Kastelein J.J.
      • Bittner V.
      • Deedwania P.
      • Breazna A.
      • Dobson S.
      • Wilson D.J.
      • Zuckerman A.
      • Wenger N.K.
      Intensive lipid lowering with atorvastatin in patients with coronary heart disease and chronic kidney disease: the TNT (Treating to New Targets) study.
      in atorvastatin-treated patients with coronary heart disease (CHD) with or without CKD. Here, we examined the effect of atorvastatin on renal function over time to assess the relation between directional change in eGFR and new CV events.

      Methods

      The TNT study was a prospective, double-blind, parallel-group study conducted from April 1998 to August 2004.
      • Waters D.D.
      • Guyton J.R.
      • Herrington D.M.
      • McGowan M.P.
      • Wenger N.K.
      • Shear C.
      Treating to New Targets (TNT) study: does lowering low-density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit?.
      • LaRosa J.C.
      • Grundy S.M.
      • Waters D.D.
      • Shear C.
      • Barter P.
      • Fruchart J.C.
      • Gotto A.M.
      • Greten H.
      • Kastelein J.J.
      • Shepherd J.
      • Wenger N.K.
      Intensive lipid lowering with atorvastatin in patients with stable coronary disease.
      Eligible patients were men and women aged 35 to 75 years 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. After 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).
      Figure thumbnail gr1
      Figure 1Flow chart of TNT participants included in this analysis.
      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 picrate method of Jaffé.
      • Bartels H.
      • Bohmer M.
      • Heierli C.
      Serum creatinine determination without protein precipitation.
      • Junge W.
      • Wilke B.
      • Halabi A.
      • Klein G.
      Determination of reference intervals for serum creatinine, creatinine excretion and creatinine clearance with an enzymatic and a modified Jaffé method.
      Samples were analyzed by a central study laboratory blinded to treatment assignment. Standards by the College of American Pathologists were used for internal quality assurance and external calibration and validation to ensure accuracy and reproducibility of the creatinine measurement throughout the study. To provide consistency with previous renal analyses of the TNT data,
      • Shepherd J.
      • Kastelein J.J.
      • Bittner V.
      • Deedwania P.
      • Breazna A.
      • Dobson S.
      • Wilson D.J.
      • Zuckerman A.
      • Wenger N.K.
      Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to New Targets (TNT) study.
      • Shepherd J.
      • Kastelein J.J.
      • Bittner V.
      • Deedwania P.
      • Breazna A.
      • Dobson S.
      • Wilson D.J.
      • Zuckerman A.
      • Wenger N.K.
      Intensive lipid lowering with atorvastatin in patients with coronary heart disease and chronic kidney disease: the TNT (Treating to New Targets) study.
      eGFR was determined using the 4-component Modification of Diet in Renal Disease (MDRD) equation
      • Levey A.S.
      • Bosch J.P.
      • Lewis J.B.
      • Greene T.
      • Rogers N.
      • Roth D.
      A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group.
      and staged according to Kidney Disease Outcomes Quality Initiative guidelines.
      National Kidney Foundation
      K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.
      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 predefined clinical classifications of change in renal function over time: improving (change in eGFR more than +2 ml/min/1.73 m2), stable (−2 to +2 ml/min/1.73 m2), or worsening (less than −2 ml/min/1.73 m2). The primary efficacy outcome was time to occurrence of a major cardiovascular event (MCVE; CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, or fatal or nonfatal stroke). The relation between change in eGFR and MCVEs was assessed by a multivariable and time-dependent Cox proportional hazards model, which included change from baseline to the end of study or last available eGFR (continuous scale) as the time-dependent independent variable adjusting for baseline factors including eGFR, age, gender, 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 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-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 pairwise comparison for continuous variables, and Fisher's exact test for overall test and logistic regression analysis with pairwise comparisons for categorical variables. Changes in eGFR from baseline to final measurement were compared by an analysis of covariance model 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 using SAS (version 9.12 or later).

      Results

      In TNT, 10,001 patients were randomly assigned to double-blind treatment with either atorvastatin 10 or 80 mg/day with a median follow-up of 4.9 years.
      • Waters D.D.
      • Guyton J.R.
      • Herrington D.M.
      • McGowan M.P.
      • Wenger N.K.
      • Shear C.
      Treating to New Targets (TNT) study: does lowering low-density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit?.
      • LaRosa J.C.
      • Grundy S.M.
      • Waters D.D.
      • Shear C.
      • Barter P.
      • Fruchart J.C.
      • Gotto A.M.
      • Greten H.
      • Kastelein J.J.
      • Shepherd J.
      • Wenger N.K.
      Intensive lipid lowering with atorvastatin in patients with stable coronary disease.
      Of the 9,656 patients with both baseline and post-baseline eGFR measurements, 67.8% (n = 6,549) had an eGFR ≥60 ml/min/1.73 m2, whereas 32.2% (n = 3,107) 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.
      • Shepherd J.
      • Kastelein J.J.
      • Bittner V.
      • Deedwania P.
      • Breazna A.
      • Dobson S.
      • Wilson D.J.
      • Zuckerman A.
      • Wenger N.K.
      Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to New Targets (TNT) study.
      • Shepherd J.
      • Kastelein J.J.
      • Bittner V.
      • Deedwania P.
      • Breazna A.
      • Dobson S.
      • Wilson D.J.
      • Zuckerman A.
      • Wenger N.K.
      Intensive lipid lowering with atorvastatin in patients with coronary heart disease and chronic kidney disease: the TNT (Treating to New Targets) study.
      A total of 156 patients experienced an MCVE before the first post-baseline eGFR assessment and were excluded, leaving 9,500 patients eligible for this analysis (Figure 1).
      In this TNT renal subgroup, 417 patients (8.8%) receiving atorvastatin 10 mg and 340 patients (7.1%) receiving atorvastatin 80 mg experienced an MCVE, corresponding to a 19% 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 (±SD) 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 atorvastatin 80-mg group. As seen in the total TNT renal cohort,
      • Shepherd J.
      • Kastelein J.J.
      • Bittner V.
      • Deedwania P.
      • Breazna A.
      • Dobson S.
      • Wilson D.J.
      • Zuckerman A.
      • Wenger N.K.
      Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to New Targets (TNT) study.
      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 ml/min/1.73 m2 (+6.7%) and a shift toward higher eGFR values with a broader distribution, as 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 = 9,656), this increase in eGFR was observed in both treatment groups regardless of baseline CKD status.
      • Shepherd J.
      • Kastelein J.J.
      • Bittner V.
      • Deedwania P.
      • Breazna A.
      • Dobson S.
      • Wilson D.J.
      • Zuckerman A.
      • Wenger N.K.
      Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to New Targets (TNT) study.
      Figure thumbnail gr2
      Figure 2Frequency distribution of eGFR in the TNT renal cohort (n = 9,656) at baseline (top) and at last visit before primary end point (bottom).
      In the present analysis (n = 9,500), 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 increase in eGFR was associated with a 2.7% absolute reduction in the rate of MCVEs (HR 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 1 ml/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 end points for both atorvastatin 10- and 80-mg treatments, but the reduction in the rate of events associated with increasing eGFR was significantly greater in patients receiving atorvastatin 80 mg (absolute event rate reduction per 1 ml/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 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 1,479 patients (15.6%) with worsening renal function, 2,241 patients (23.6%) with stable renal function, and 5,780 patients (60.8%) with improving renal function over 5 years of follow-up. Subjects with worsening renal function were significantly older and more likely women, and had a higher BMI, greater likelihood of hypertension or diabetes, and higher prevalence of CABG, PVD, and cerebrovascular disease at baseline than those with stable or improving renal function (Table 1).
      Table 1Baseline characteristics of patients included in this analysis, stratified by directional change in estimated glomerular filtration rate
      Baseline characteristic

      (at randomization)
      Change in estimated glomerular filtration rate (ml/min/1.73 m2)
      Worsening (<−2)

      (n=1479)
      Stable (−2 to +2)

      (n=2241)
      Improving (>+2)

      (n=5780)
      Men1113 (75%)1761 (79%)
      p <0.05 versus patients with worsening renal function.
      4829 (84%)
      p <0.05 versus patients with worsening renal function.
      Mean age (years)63.5±8.861.2±8.8
      p <0.05 versus patients with worsening renal function.
      60.3±8.7
      p <0.05 versus patients with worsening renal function.
      White1378 (93%)2100 (94%)5471 (95%)
      p <0.05 versus patients with worsening renal function.
      Current smoker201 (14%)322 (14%)713 (12%)
      Systolic blood pressure (mmHg)135.1±18.1131.2±16.5
      p <0.05 versus patients with worsening renal function.
      129.3±16.3
      p <0.05 versus patients with worsening renal function.
      Diastolic blood pressure (mmHg)78.1±9.778.0±9.577.9±9.4
      Low-density lipoprotein cholesterol (mmol/l [mg/dl])2.52±0.46 [97.6±17.6]2.51±0.44 [97.0±17.2]2.52±0.46 [97.6±17.6]
      High-density lipoprotein cholesterol (mmol/l [mg/dl])1.22±0.30 [47.2±11.5]1.24±0.28 [47.9±10.9]
      p <0.05 versus patients with worsening renal function.
      1.22±0.28 [47.2±10.8]
      Total cholesterol (mmol/l [mg/dl])4.54±0.64 [175.4±24.6]4.50±0.60 [173.9±23.1]4.52±0.62 [174.7±23.8]
      Triglycerides (mmol/l [mg/dl])1.74±0.83 [154.3±73.4]1.65±0.77 [146.1±68.4]
      p <0.05 versus patients with worsening renal function.
      1.70±0.79 [150.3±69.6]
      p <0.05 versus patients with worsening renal function.
      MDRD estimated glomerular filtration rate (ml/min/1.73 m2)65.0±13.768.3±11.1
      p <0.05 versus patients with worsening renal function.
      64.2±10.5
      p <0.05 versus patients with worsening renal function.
      Body mass index (kg/m2)29.1±5.128.4±4.7
      p <0.05 versus patients with worsening renal function.
      28.4±4.3
      p <0.05 versus patients with worsening renal function.
      Chronic kidney disease
      eGFR <60 ml/min/1.73 m2.
      542 (37%)529 (24%)
      p <0.05 versus patients with worsening renal function.
      1978 (34%)
      Angina pectoris1214 (82%)1805 (81%)4725 (82%)
      Myocardial infarction864 (58%)1294 (58%)3352 (58%)
      Coronary angioplasty762 (52%)1211 (54%)3170 (55%)
      p <0.05 versus patients with worsening renal function.
      Coronary artery bypass graft779 (53%)1039 (46%)
      p <0.05 versus patients with worsening renal function.
      2588 (45%)
      p <0.05 versus patients with worsening renal function.
      Hypertension995 (67%)1220 (54%)
      p <0.05 versus patients with worsening renal function.
      2918 (50%)
      p <0.05 versus patients with worsening renal function.
      Diabetes mellitus388 (26%)300 (13%)
      p <0.05 versus patients with worsening renal function.
      706 (12%)
      p <0.05 versus patients with worsening renal function.
      Peripheral vascular disease272 (18%)260 (12%)
      p <0.05 versus patients with worsening renal function.
      571 (10%)
      p <0.05 versus patients with worsening renal function.
      Congestive heart failure215 (15%)151 (7%)
      p <0.05 versus patients with worsening renal function.
      349 (6%)
      p <0.05 versus patients with worsening renal function.
      Cerebrovascular disease109 (7%)117 (5%)
      p <0.05 versus patients with worsening renal function.
      252 (4%)
      p <0.05 versus patients with worsening renal function.
      Values are number (%) or mean ±SD.
      p <0.05 versus patients with worsening renal function.
      eGFR <60 ml/min/1.73 m2.
      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 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 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 using year 1 change in eGFR (Figure 4).
      Table 2Clinical outcomes in the renal function subgroups
      Change in estimated glomerular filtration rate (ml/min/1.73 m2)
      Worsening (<−2)

      (n=1479)
      Stable (−2 to +2)
      p-values versus patients with worsening renal function.


      (n=2241)
      Improving (>+2)
      p-values versus patients with worsening renal function.


      (n=5780)
      Number (%) of patients with primary end point208 (14.1%)235 (10.5%)314 (5.4%)
      Hazard ratio (95% confidence interval) for primary end point1.000.72 (0.60, 0.87)p=0.00050.36 (0.30, 0.43)p<0.0001
      Serum creatinine (μmol/l [mg/dl])
       Baseline104.3±22.1 [1.18±0.25]99.9±15.9 [1.13±0.18]p<0.0001107.0±16.8 [1.21±0.19]p<0.0001
       Change from baseline
      Change from baseline to final visit.
      20.3±31.8 [0.23±0.36]–0.18±4.24 [–0.002±0.048]p<0.0001–14.1±8.0 [–0.16±0.09]p<0.0001
      Estimated glomerular filtration rate (ml/min/1.73 m2)
       Baseline65.0±13.768.3±11.1p<0.000164.2±10.5p=0.0203
       Change from baseline
      Change from baseline to the last measurement prior to primary end point.
      –10.9±6.9–0.98±0.41p<0.000110.3±5.9p<0.0001
      Lipids: Change from baseline (mmol/l [mg/dl])
      Change from baseline to month 3.
       Low-density lipoprotein cholesterol–0.25±0.55 [–9.7±21.3]–0.26±0.53 [–10.1±20.5]p=0.2892–0.34±0.55 [–13.1±21.3]p<0.0001
       High-density lipoprotein cholesterol–0.001±0.147 [–0.04±5.68]0.005±0.142 [0.19±5.49]p=0.0906–0.004±0.139 [–0.15±5.38]p=0.5485
       Triglycerides–0.08±0.57 [–7.1±50.4]–0.09±0.60 [–8.0±53.1]p=0.0728–0.14±0.59 [–12.4±52.2]p<0.0001
      Atorvastatin 10 mg833 (56.3%)1185 (52.9%)2719 (47.0%)
      Atorvastatin 80 mg646 (43.7%)1056 (47.1%)3061 (53.0%)
      Overall p-value (trend)
      p-value based on Cochran-Armitage test for trend.
      p<0.0001
      Values are number (%) or mean ±SD unless otherwise stated.
      p-values versus patients with worsening renal function.
      Change from baseline to final visit.
      Change from baseline to the last measurement prior to primary end point.
      § Change from baseline to month 3.
      p-value based on Cochran-Armitage test for trend.
      Figure thumbnail gr3
      Figure 3Kaplan-Meier curves for time to primary end point in defined renal subgroups using an LOCF analysis. Renal function was defined as improving (change in eGFR more than +2 ml/min/1.73 m2), stable (−2 to +2 ml/min/1.73 m2), or worsening (less than −2 ml/min/1.73 m2). K-M = Kaplan-Meier.
      Figure thumbnail gr4
      Figure 4Kaplan-Meier curves for time to primary end point in defined renal subgroups using a predictive model incorporating change in eGFR over 1 year. Renal function was defined as improving (change in eGFR more than +2 ml/min/1.73 m2), stable (−2 to +2 ml/min/1.73 m2), or worsening (less than −2 ml/min/1.73 m2). K-M = Kaplan-Meier.
      Reductions from baseline to month 3 in LDL-C and triglyceride levels in patients with improving renal function were significantly greater versus those with worsening renal 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 so. Change in HDL-C showed no significant differences across renal subgroups (Table 2).

      Discussion

      In the TNT trial, CV event reductions after atorvastatin therapy were achieved both in patients with and without CKD at baseline.
      • Shepherd J.
      • Kastelein J.J.
      • Bittner V.
      • Deedwania P.
      • Breazna A.
      • Dobson S.
      • Wilson D.J.
      • Zuckerman A.
      • Wenger N.K.
      Intensive lipid lowering with atorvastatin in patients with coronary heart disease and chronic kidney disease: the TNT (Treating to New Targets) study.
      This current analysis has revealed that change in eGFR over the course of the trial was predictive of MCVEs when using an LOCF analysis. 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, whereas those with stable renal function experienced a 28% reduction; these results were confirmed in an analysis based on year 1 change in eGFR.
      The observation that CV risk may change concurrently with renal function is not new.
      • Rifkin D.E.
      • Shlipak M.G.
      • Katz R.
      • Fried L.F.
      • Siscovick D.
      • Chonchol M.
      • Newman A.B.
      • Sarnak M.J.
      Rapid kidney function decline and mortality risk in older adults.
      • Shlipak M.G.
      • Katz R.
      • Kestenbaum B.
      • Siscovick D.
      • Fried L.
      • Newman A.
      • Rifkin D.
      • Sarnak M.J.
      Rapid decline of kidney function increases cardiovascular risk in the elderly.
      • Weiner D.E.
      • Krassilnikova M.
      • Tighiouart H.
      • Salem D.N.
      • Levey A.S.
      • Sarnak M.J.
      CKD classification based on estimated GFR over three years and subsequent cardiac and mortality outcomes: a cohort study.
      Until now, however, few studies have commented on the relation between improving renal function and CV events.
      • Weiner D.E.
      • Krassilnikova M.
      • Tighiouart H.
      • Salem D.N.
      • Levey A.S.
      • Sarnak M.J.
      CKD classification based on estimated GFR over three years and subsequent cardiac and mortality outcomes: a cohort study.
      To our knowledge, this analysis is one of the first to suggest that stabilization (and 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 patients with CHD receiving atorvastatin had a 12% increase in creatinine clearance versus a 5.2% decrease in those receiving usual care.
      • Athyros V.G.
      • Mikhailidis D.P.
      • Papageorgiou A.A.
      • Symeonidis A.N.
      • Pehlivanidis A.N.
      • Bouloukos V.I.
      • Elisaf M.
      The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study.
      A multivariate model predicted that each 5% increase in creatinine clearance was associated with a 16% reduction in CHD-associated events.
      • Athyros V.G.
      • Mikhailidis D.P.
      • Papageorgiou A.A.
      • Symeonidis A.N.
      • Pehlivanidis A.N.
      • Bouloukos V.I.
      • Elisaf M.
      The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study.
      On the basis of this and other TNT subanalyses, the effect of atorvastatin on renal 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, whereas those with worsening renal function more likely 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 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 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 decreases in eGFR have been observed in high-risk patients with CVD, CHD, and dyslipidemia.
      • Tonelli M.
      • Moye L.
      • Sacks F.M.
      • Cole T.
      • Curhan G.C.
      Effect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease.
      • Collins R.
      • Armitage J.
      • Parish S.
      • Sleight P.
      • Peto R.
      MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial.
      In the TNT renal cohort, a shift toward a higher eGFR with atorvastatin therapy was detected. Moreover, stabilization or improvement of renal function occurred in ∼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 decrease in renal function,
      • Elsayed E.F.
      • Tighiouart H.
      • Griffith J.
      • Kurth T.
      • Levey A.S.
      • Salem D.
      • Sarnak M.J.
      • Weiner D.E.
      Cardiovascular disease and subsequent kidney disease.
      and atherosclerosis may foreshadow underlying renal microvascular disease.
      • Kasiske B.L.
      Relationship between vascular disease and age-associated changes in the human kidney.
      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.
      Tonelli et al
      • Tonelli M.
      • Moye L.
      • Sacks F.M.
      • Cole T.
      • Curhan G.C.
      Effect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease.
      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. For atorvastatin, beneficial effects on renal function have been observed in a number of trials across a wide range of patient populations, including those with CHD, diabetes, and CKD.
      • Shepherd J.
      • Kastelein J.J.
      • Bittner V.
      • Deedwania P.
      • Breazna A.
      • Dobson S.
      • Wilson D.J.
      • Zuckerman A.
      • Wenger N.K.
      Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to New Targets (TNT) study.
      • Athyros V.G.
      • Mikhailidis D.P.
      • Papageorgiou A.A.
      • Symeonidis A.N.
      • Pehlivanidis A.N.
      • Bouloukos V.I.
      • Elisaf M.
      The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study.
      • Colhoun H.M.
      • Betteridge D.J.
      • Durrington P.N.
      • Hitman G.A.
      • Neil H.A.
      • Livingstone S.J.
      • Charlton-Menys V.
      • DeMicco D.A.
      • Fuller J.H.
      Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes: an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS).
      • Deedwania P.C.
      • Stone P.H.
      • Fayyad R.S.
      • Laskey R.E.
      • Wilson D.J.
      Improvement in renal function and reduction in serum uric acid with intensive statin therapy in older patients: a post hoc analysis of the SAGE trial.
      The mechanism behind atorvastatin's effect on renal function is unclear. LDL-C has been linked to mesangial cell proliferation in the kidney
      • Coritsidis G.
      • Rifici V.
      • Gupta S.
      • Rie J.
      • Shan Z.H.
      • Neugarten J.
      • Schlondorff D.
      Preferential binding of oxidized LDL to rat glomeruli in vivo and cultured mesangial cells in vitro.
      and increased production of inflammatory markers. In addition to lipid effects, atorvastatin has demonstrated reductions in markers of inflammation and oxidative stress.
      • Kinlay S.
      • Schwartz G.G.
      • Olsson A.G.
      • Rifai N.
      • Leslie S.J.
      • Sasiela W.J.
      • Szarek M.
      • Libby P.
      • Ganz P.
      High-dose atorvastatin enhances the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL study.
      • Carnevale R.
      • Pignatelli P.
      • Di Santo S.
      • Bartimoccia S.
      • Sanguigni V.
      • Napoleone L.
      • Tanzilli G.
      • Basili S.
      • Violi F.
      Atorvastatin inhibits oxidative stress via adiponectin-mediated NADPH oxidase down-regulation in hypercholesterolemic patients.
      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 nondialysis patients with moderate CKD.
      • Haynes R.
      • Lewis D.
      • Emberson J.
      • Reith C.
      • Agodoa L.
      • Cass A.
      • Craig J.C.
      • de Zeeuw D.
      • Feldt-Rasmussen B.
      • Fellstrom B.
      • Levin A.
      • Wheeler D.C.
      • Walker R.
      • Herrington W.G.
      • Baigent C.
      • Landray M.J.
      Effects of lowering LDL cholesterol on progression of kidney disease.
      Also, a recent analysis of the Prospective Evaluation of Proteinuria and Renal Function in Diabetic/Non-Diabetic Patients with Progressive Renal Disease (PLANET) I and II trials demonstrated that rosuvastatin was associated with significantly greater decreases in eGFR versus atorvastatin.
      • de Zeeuw D.
      • Anzalone D.A.
      • Cain V.A.
      • Cressman M.D.
      • Heerspink H.J.
      • Molitoris B.A.
      • Monyak J.T.
      • Parving H.H.
      • Remuzzi G.
      • Sowers J.R.
      • Vidt D.G.
      Renal effects of atorvastatin and rosuvastatin in patients with diabetes who have progressive renal disease (PLANET I): a randomised clinical trial.
      Moreover, atorvastatin was associated with significantly greater reductions in proteinuria,
      • de Zeeuw D.
      • Anzalone D.A.
      • Cain V.A.
      • Cressman M.D.
      • Heerspink H.J.
      • Molitoris B.A.
      • Monyak J.T.
      • Parving H.H.
      • Remuzzi G.
      • Sowers J.R.
      • Vidt D.G.
      Renal effects of atorvastatin and rosuvastatin in patients with diabetes who have progressive renal disease (PLANET I): a randomised clinical trial.
      indicating that—together with the SHARP findings—renoprotection may not be a class effect.
      We acknowledge several limitations of this analysis in addition to those previously discussed for TNT.
      • Shepherd J.
      • Kastelein J.J.
      • Bittner V.
      • Deedwania P.
      • Breazna A.
      • Dobson S.
      • Wilson D.J.
      • Zuckerman A.
      • Wenger N.K.
      Intensive lipid lowering with atorvastatin in patients with coronary heart disease and chronic kidney disease: the TNT (Treating to New Targets) study.
      To provide consistency with previous analyses of the TNT renal population,
      • Shepherd J.
      • Kastelein J.J.
      • Bittner V.
      • Deedwania P.
      • Breazna A.
      • Dobson S.
      • Wilson D.J.
      • Zuckerman A.
      • Wenger N.K.
      Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to New Targets (TNT) study.
      • Shepherd J.
      • Kastelein J.J.
      • Bittner V.
      • Deedwania P.
      • Breazna A.
      • Dobson S.
      • Wilson D.J.
      • Zuckerman A.
      • Wenger N.K.
      Intensive lipid lowering with atorvastatin in patients with coronary heart disease and chronic kidney disease: the TNT (Treating to New Targets) study.
      we used the modified MDRD equation, which is known to underestimate renal function in the normal range compared with direct measurements of GFR.
      • Rule A.D.
      • Larson T.S.
      • Bergstralh E.J.
      • Slezak J.M.
      • Jacobsen S.J.
      • Cosio F.G.
      Using serum creatinine to estimate glomerular filtration rate: accuracy in good health and in chronic kidney disease.
      Proteinuria, which may help define CV risk in conjunction with eGFR,
      • Bello A.K.
      • Hemmelgarn B.
      • Lloyd A.
      • James M.T.
      • Manns B.J.
      • Klarenbach S.
      • Tonelli M.
      Associations among estimated glomerular filtration rate, proteinuria, and adverse cardiovascular outcomes.
      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).

      Acknowledgment

      Assistance with statistical analyses was provided by Dr. Chuan-Chuan Wun, PhD, formerly of Pfizer (New York, New York), and Mr. Sean Spanyers, MSc, at inVentiv Health Clinical (Princeton, New Jersey) and was funded by Pfizer. Editorial assistance was provided by Dr. Shirley Smith, PhD, at Engage Scientific (Horsham, United Kingdom) and was funded by Pfizer.

      Disclosures

      Dr. Shepherd: AstraZeneca, GlaxoSmithKline, Merck, Oxford Biosensors, Pfizer, Nicox, Roche, Schering-Plough (consulting fees); AstraZeneca, Merck, Abbott, Schering-Plough, Pfizer (lecture fees). Dr. Deedwania: Pfizer, AstraZeneca (consulting and lecture fees). Dr. LaRosa: Pfizer, Merck, Bristol-Myers Squibb, AstraZeneca (consulting fees); Pfizer (lecture fees). Dr. 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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