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Pravastatin and cardiovascular risk in moderate chronic kidney disease
Atherosclerosis 206 (2009) 512–517
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Pravastatin and cardiovascular risk in moderate chronic kidney disease夽 Haruo Nakamura a,∗,1 , Kyoichi Mizuno b,1 , Yasuo Ohashi c,1 , Tomowo Yoshida d,1 , Koichi Hirao e,1 , Yasufumi Uchida f,1 a
Mitsukoshi Health and Welfare Foundation, STEC Jyoho Building, 1-24-1 Nishishinjuku Shinjuku, Tokyo, 160-0023, Japan Department of Medicine, Nippon Medical School, Tokyo, Japan c Department of Biostatistics/Epidemiology and Preventive Health Sciences, University of Tokyo, Tokyo, Japan d Nippon Kokan Fukuyama Hospital, Fukuyama, Japan e HEC Science Clinic, Yokohama, Japan f Saga Memorial Hospital, Saga, Japan b
a r t i c l e
i n f o
Article history: Received 15 October 2008 Received in revised form 25 January 2009 Accepted 28 March 2009 Available online 5 April 2009 Keywords: Hypercholesterolemia Cardiovascular disease Chronic kidney disease HMG-CoA reductase inhibitors Pravastatin
a b s t r a c t Objectives: To investigate the relation between chronic kidney disease (CKD) and cardiovascular disease (CVD) and retrospectively to evaluate the effect of low dose of pravastatin in Japanese hypercholesterolemic patients with CKD enrolled in the large-scale randomized MEGA Study. Methods: In this post hoc analysis, effect of low dose pravastatin treatment (10–20 mg daily) on the primary prevention of the cardiovascular disease and renal function after 5 years was evaluated in 7196 patients with normal kidney function/mild CKD or moderate CKD. Patients were classified based on an estimated glomerular filtration rate (eGFR) ≥60 or 30–<60 mL/min/1.73 m2 as having normal renal function/mild CKD or moderate CKD, respectively. Since Japanese guidelines do not allow statin use in patients with severe kidney disease, such individuals were excluded. Results: The incidence of CVD events was 35–49% higher in patients with moderate CKD than in those with normal renal function/mild CKD. Notably, in the moderate CKD group pravastatin significantly reduced CHD by 48% (P = 0.02), stroke by 73% (P < 0.01), CVD by 55% (P < 0.01), and total mortality by 51% (P = 0.02). Moreover, the change in eGFR during follow-up in patients with moderate CKD was significantly (P = 0.03) higher in those assigned to receive diet plus pravastatin (+6.3%) compared with those on diet alone (+5.1%). Conclusions: Risk of CVD is higher in patients with moderate CKD compared with those with normal renal function/mild CKD, and was significantly reduced by treatment with pravastatin. Pravastatin also exerted beneficial effects on renal function in patients with moderate CKD. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Since 2003, disorders of renal function have been categorized according to grades based on the glomerular filtration rate (GFR) established by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) [1]. They classified a GFR of ≥90, 60–<90, 30–<60, 15–<30, and <15 mL/min/1.73 m2 as indicative of stage 1 (normal), 2 (mild), 3 (moderate), 4 (severe), and 5 (very severe or end-stage) chronic kidney disease (CKD), respectively. Several epidemiological studies have demonstrated a correlation between renal dysfunction and cardiovascular disease (CVD), and it is known that moderate CKD with a GFR <60 mL/min/1.73 m2 is a potent risk factor for CVD events [2–5].
夽 NCT00211705. ∗ Corresponding author. Tel.: +81 3 3348 5791; fax: +81 3 3348 5795. E-mail address: [email protected] (H. Nakamura). 1 For the MEGA Study Group. 0021-9150/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2009.03.031
The Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study was a large-scale clinical trial that evaluated the effect of pravastatin on the risk of CVD events in patients with mild-to-moderate hypercholesterolemia and no past history of ischemic heart disease and/or stroke [6,7]. The reduction in the relative risk of CVD events was similar to those found in Western statin trials [8–14]. The principal results of the MEGA Study, reported in 2006, showed that mild or moderate changes in lipid profiles associated with pravastatin given as adjunct to diet therapy significantly reduced the relative risk for coronary heart disease (CHD) by 33% and CVD by 26% compared with diet therapy alone [7], and the number needed to treat (NNT) to prevent one CHD or CVD event was 119 and 91, respectively. The aims of the present post hoc analysis of the MEGA Study data were to investigate in Japanese patients whether the presence of CKD increases the incidence of CVD events, to study the risk factors possibly contributing to their development, and to evaluate the usefulness of pravastatin for the prevention of CVD in patients with moderate CKD.
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Table 1 Baseline and on-treatment serum lipids, blood pressure, and fasting plasma glucose in normal/mild CKD and moderate CKD patients stratified by the presence or absence of CVD. CVD free (n = 3519)
CVD case (n = 144)
Baseline
On treatment
Baseline
On treatment
TC (mmol/L) Normal/mild Moderate
6.3 (0.3) 6.3 (0.3)
6.2 (0.4) 6.1 (0.4)
6.3 (0.3) 6.3 (0.3)
6.1 (0.4) 6.2 (0.6)
LDL-C (mmol/L) Normal/mild Moderate
4.1 (0.5) 4.0 (0.4)
3.9 (0.5) 3.9 (0.5)
4.1 (0.5) 4.1 (0.5)
3.9 (0.6) 4.0 (0.6)a
HDL-C (mmol/L) Normal/mild Moderate
1.5 (0.4) 1.5 (0.4)
1.5 (0.4) 1.5 (0.4)
1.4 (0.3)a 1.3 (0.4)a
1.4 (0.3)a 1.3 (0.4)a
TG (mmol/L)b Normal/mild Moderate
1.4 (1.0–1.9) 1.5 (1.1–2.1)
1.4 (1.1–1.9) 1.4 (1.1–1.9)
1.7 (1.2–2.2)a 1.6 (1.2–2.6)a
1.6 (1.3–2.1)a 1.5 (1.1–2.0)a
SBP (mmHg) Normal/mild Moderate
131.7 (16.5) 132.8 (17.1)
130.9 (12.7) 132.6 (13.3)
137.7 (16.8)a 136.3 (14.7)
139.2 (15.0)a 138.6 (13.6)a
DBP (mmHg) Normal/mild Moderate
78.8 (10.2) 78.7 (10.0)
77.9 (7.8) 77.7 (7.4)
80.5 (11.0) 79.3 (9.3)
80.0 (9.2)a 80.2 (8.5)a
FPG (mmol/L) Normal/mild Moderate
6.0 (1.7) 5.9 (1.7)
6.2 (1.7) 6.0 (1.6)
7.2 (2.4)a 6.6 (2.2)a
7.3 (1.9)a 7.2 (3.4)a
On-treatment values averaged all measurements during follow-up. All data are mean (SD) unless otherwise indicated. TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglycerides; SBP, systolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose. a P < 0.05 versus value at the same time-point in CVD-free group. b Median (interquartile range).
2. Method 2.1. Study design The design and principal findings of the MEGA Study have been reported previously [6,7]. Briefly, a total of 7832 men and postmenopausal women aged 40–70 years with total cholesterol (TC) levels 5.69–6.98 mmol/L (220–270 mg/dL) and no history of CHD and/or stroke were recruited. The patients were randomly assigned to receive diet counseling alone (diet group) or Step I diet plus pravastatin 10–20 mg/day (diet plus pravastatin group). Patients in both groups were counseled to follow the National Cholesterol Education Program (NCEP) Step I diet with reduced daily caloric intake, saturated fats, and cholesterol [15]. Major exclusion criteria included familial hypercholesterolemia, history of CVD, cancer, severe renal dysfunction (serum creatinine ≥ 1.5 mg/dL), significant liver disease, and secondary hyperlipidemia. Treatment in the diet plus pravastatin group was initiated at 10 mg/day, and thereafter
could be adjusted to 20 mg/day (the highest approved dose in Japan) if TC remained >5.69 mmol/L. Patients in both groups whose TC was >6.98 mmol/L even after enhancement of assigned treatment could be switched to other aggressive treatments including other statins. The primary endpoint was a composite of the first occurrence of a CHD event including fatal and nonfatal myocardial infarction, angina pectoris, cardiac/sudden death, and coronary revascularization. The average follow-up period was 5.3 years and 98.7% of patients completed follow-up. In the diet group, the percentage of patients who received a statin (mostly pravastatin) was 24.5% at 5 years due to poorly controlled total cholesterol after randomization. In the diet + pravastatin group, 90.4% of patients continued receiving pravastatin at 5 years. In this post hoc analysis, 636 patients from the main ITT dataset were excluded either because their creatinine level was not recorded (n = 620) or they had severe CKD (<30 mL/min/1.73 m2 ; n = 16); thus the 5-year data on 7196 patients were analyzed. Estimated GFR (eGFR) was estimated by the Modified Diet and Renal
Table 2 Baseline and on-treatment eGFR (mL/min/1.73 m2 ) in all, male, and female patients with normal/mild CKD and moderate CKD. Normal/mild CKD
Moderate CKD
Baseline
On treatment [% change]
P-value
Baseline
On treatment [% change]
All Diet Diet plus pravastatin
P-value
72.5 (10.3) 73.0 (10.6)
69.9 ± 9.7 [–3.6] 70.4 ± 10.0 [–3.6]
0.76
52.5 (5.6) 52.6 (5.7)
55.2 ± 7.6 [+5.1] 55.9 ± 8.0 [+6.3]
0.03
Men Diet Diet plus pravastatin
73.5 (10.7) 73.9 (11.3)
71.2 ± 9.9 [–3.1] 71.8 ± 10.7 [–2.8]
0.67
53.5 (5.1) 53.1 (5.5)
55.5 ± 7.6 [+3.7] 56.8 ± 8.4 [+7.0]
<0.001
Women Diet Diet plus pravastatin
72.0 (10.1) 72.6 (10.1)
69.0 ± 9.5 [–4.2] 69.7 ± 9.6 [–4.0]
0.92
52.2 (5.7) 52.4 (5.7)
55.1 ± 7.6 [+5.6] 55.5 ± 7.9 [+5.9]
0.46
On-treatment values averaged all measurements during follow-up. Percent changes were averaged in each individual versus baseline. All data are mean (SD). P-values were calculated by comparing % changes from baseline between the diet group and diet plus pravastatin group.
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Table 3 Incidence of major cardiovascular events in patients with normal/mild CKD and moderate CKD on diet therapy alone. No. of events/1000 person-years
CHD Stroke Ischemic stroke Hemorrhagic stroke CHD + ischemic stroke CVD Total mortality
Normal/mild CKD (n = 2156)
Moderate CKD (n = 1516)
40 (4.1) 28 (2.8) 21 (2.1) 6 (0.6) 60 (6.1) 73 (7.5) 29 (2.9)
40 (5.7) 29 (4.1) 22 (3.1) 7 (1.0) 60 (8.7) 71 (10.3) 34 (4.8)
HR (95%CI)a
P-valuea
Adjusted HR (95%CI)b
P-valueb
1.49 (0.95–2.33) 1.35 (0.79–2.31) 1.49 (0.81–2.75) 1.10 (0.36–3.38) 1.46 (1.01–2.10) 1.37 (0.98–1.92) 1.46 (0.88–2.44)
0.08 0.27 0.20 0.87 0.04 0.06 0.14
1.49 (0.95–2.34) 1.31 (0.76–2.24) 1.46 (0.79–2.71) 1.04 (0.34–3.22) 1.46 (1.01–2.11) 1.37 (0.98–1.92) 1.52 (0.91–2.54)
0.08 0.33 0.23 0.94 0.04 0.07 0.11
CKD, chronic kidney disease; CHD, coronary heart disease; CVD, cardiovascular disease. a Estimated by Cox proportional hazard model adjusted by sex and age. b Estimated by Cox multiple hazard model adjusted by sex, age, baseline HDL-C, hypertension, diabetes and smoking status.
Disease (MDRD) equation for Japanese patients [16]; serum creatinine level (SCr) was adjusted because enzymatic determination was used. Patients were classified based on an eGFR level ≥60 or 30–<60 mL/min/1.73 m2 as having normal renal function/mild CKD or moderate CKD, respectively.
showed no significant change from baseline in the normal/mild CKD subset in both treatment arms, whereas in the moderate CKD group eGFR increased by 6.3% in the diet plus pravastatin group, significantly (P = 0.03) higher by 1.2% than in the diet alone group (5.1%; Table 2). The differences in eGFR between treatment groups were larger in men (3.3%; P < 0.001) than in women (0.3%; P = 0.46).
2.2. Statistical analysis 3.2. CKD and risk of CVD events Differences of patient characteristics were analyzed by Student’s t-test and P-values ≤ 0.05 were considered significant. The incidence of endpoint events was compared by Cox proportional hazards model adjusted by sex, age, high-density lipoprotein cholesterol (HDL-C), hypertension, diabetes mellitus, and smoking status. 2.3. Role of funding source The authors, comprising the steering committee, were responsible for the study design, statistical plan, and reporting of results. Randomization, data collection, and data analysis were conducted by an independent center established by contract research organization. All study organization, conduct, and data analyses were undertaken independently of the sponsors. 3. Results 3.1. Patients and effect of pravastatin on biochemical variables Among 7196 patients retrospectively analyzed, those identified as having normal renal function/mild CKD and moderate CKD accounted for 4218 (58.6%) and 2978 (41.4%) patients, respectively. Those with moderate CKD were older at 60 years versus 57 years and included higher proportions of women (75.7% versus 63.5%) and hypertensive patients (46.3% versus 40.8%) and lower rates of smokers (12.5% versus 16.8%) and diabetic patients (18.8% versus 23.0%) compared with the normal/mild CKD group. Moreover, triglycerides (TG) and systolic blood pressure (SBP) levels were significantly higher in the moderate CKD group compared with the normal/mild CKD group, at 1.5 mmol/L versus 1.4 mmol/L and 132.9 mmHg versus 131.8 mmHg, respectively. At 5 years, among patients assigned diet plus pravastatin lowdensity lipoprotein cholesterol (LDL-C) was significantly reduced by 18.1% in the normal/mild CKD group and by 18.9% in the moderate CKD group, whereas high density lipoprotein cholesterol (HDLC) was significantly increased by 4.9% and by 4.5%, respectively. In the diet alone group, similar such parameters were found in the patients who developed CVD (n = 144) and those who did not (n = 3519). In patients treated with pravastatin LDL-C, SBP, and diastolic blood pressure (DBP) remained high and HDL-C low in the moderate CKD patients who developed CVD compared with those who remained CVD free (Table 1). Analysis of eGFR during treatment
Table 3 compares major events in patients in the moderate CKD and normal/mild CKD groups assigned diet alone. A significant increase in the relative risk of CHD plus ischemic stroke was found in the moderate CKD group (hazard ratio [HR], 1.46; 95%CI, 1.01–2.10; P = 0.04). This risk remained significantly increased (HR, 1.46; 95%CI, 1.01–2.11; P = 0.04) even after adjustment for other factors associated with CVD risk. Furthermore, in the moderate CKD group compared with the normal/mild CKD group, higher HRs for CHD (1.49; 95%CI, 0.95–2.34), stroke (1.31; 95%CI, 0.76–2.24), CVD (1.37; 95%CI, 0.98–1.92), and total mortality (1.52; 95%CI, 0.91–2.54) were found, although they were not statistically significant. 3.3. Effects of pravastatin on major cardiovascular events Pravastatin’s effects on major endpoints such as CHD, stroke, CVD, and total mortality in the moderate CKD group are shown in Fig. 1. In these patients the risk of experiencing any one of four endpoints was significantly reduced by pravastatin, with observed reductions of 48% (P = 0.02), 73% (P < 0.01), 55% (P < 0.01), and 51% (P = 0.02) for each, respectively, and also in patients with moderate CKD the effects were greater than those in the total study cohort (in whom relative risk reductions of 30%, 32%, 29%, and 33%, respectively, were noted). The Kaplan–Meier curves started to diverge after 3 years for CHD, after 1 year for stroke, and after 2 years for total mortality. A marked risk reduction in patients with moderate CKD compared with the total group was found, confirming the beneficial effect of pravastatin in individuals with moderate CKD. The effects of pravastatin in all patients, in those with moderate CKD, and in those with normal/mild CKD are summarized in Fig. 2. In patients with moderate CKD, the relative risk reduction and NNT for CHD, all stroke, ischemic stroke, CHD plus ischemic stroke, total CVD events, and total mortality were 48% (NNT, 82), 73% (72), 82% (84), 59% (44), 55% (41), and 51% (86), respectively. Meanwhile, no risk reduction was found in those with normal/mild CKD. 3.4. Safety In patients with moderate CKD, there were no significant differences in serious adverse events or subjective complaints of side effects between the two treatment arms (diet group, 11.3%; diet plus pravastatin group, 10.5%; P = 0.088). No major difference of abnormal laboratory findings was seen in patients with moder-
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Fig. 1. Kaplan–Meier curves for major endpoints in the patients with moderate CKD. CHD, coronary heart disease; CVD, cardiovascular disease.
Fig. 2. Hazard ratios (HR) and number needed to treat (NNT) to prevent one endpoint event in moderate CKD patients. Square size indicates number of events. HR, 95% confidence interval (95%CI), and P-values for moderate CKD and normal/mild CKD were estimated by Cox proportional hazards model adjusted by sex, age, baseline HDL-C, hypertension, diabetes, and smoking status. CHD, coronary heart disease; CVD, cardiovascular disease.
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ate CKD: AST > 100 IU/L was 1.1% in the diet group and 1.2% in diet plus pravastatin (P = 0.94) whereas ALT > 100 IU/L was 2.7% and 2.5% (P = 0.73); BUN > 40 mg/dL was 10.6% and 8.4% (P = 0.04), creatinine > 4.0 mg/dL was 0.2% and 0.3% (P = 0.41), and creatine kinase > 500 IU/L was 2.6% and 2.6% (P = 0.96). In both the moderate CKD group and normal/mild CKD group no significant difference was found between treatment arms in total cancer incidence/1000 person-years or the rate of any organ-specific type of cancer. 4. Discussion During follow-up, lipid parameters and SBP/DBP did not change significantly in either the moderate CKD or normal/mild CKD patients randomized to diet group. In this treatment arm, patients with moderate CKD who developed CVD had higher SBP and DBP on treatment and their LDL-C remained elevated and HDL-C low compared with those with normal/mild CKD. Therefore we speculate that the higher risk of CVD in patients with moderate CKD might be related to their having greater severity of baseline risk: older age, hypertension, high TG level, and elevated SBP coupled with persistent elevation of SBP/DBP and LDL-C and low HDL-C during follow-up. These results, for the first time, demonstrate that risk factors not only at baseline but also during treatment influence the increase in CVD in patients with moderate CKD. Marked reductions of CHD by 48%, stroke by 73%, CVD by 55%, and total mortality by 51% were found in patients with moderate CKD who received treatment with pravastatin. This is consistent with the results of previous statin trials that have examined the cardiovascular effects of these drugs in patients with mild and moderate CKD. A meta-analysis of three trials of pravastatin 40 mg/day demonstrated significant 23% and 14% reductions for CHD and total mortality, respectively, in patients with moderate CKD [17]. Although relatively few patients had renal dysfunction in the Heart Protection Study, a subgroup analysis showed that simvastatin elicited great benefit in reduction of major CVD events in patients with elevated serum creatinine at baseline [12]. A subgroup analysis of the Anglo-Scandinavian Cardiac Outcome Trial-Lipid Lowering Arm (ASCOT-LLA) showed a significant 39% relative risk reduction in nonfatal myocardial infarction and CHD death in patients with renal dysfunction [13]. In the present analysis, considering that the benefit of pravastatin appeared early during follow-up (stroke and CVD events significantly reduced at 1 year; total mortality and CHD at 2 years) it is tempting to speculate that pravastatin both improves dyslipidemia and exerts known pleiotropic effects such as alleviation of endothelial dysfunction, chronic inflammation, and platelet adhesiveness in patients with moderate CKD—because chronic inflammation and endothelial dysfunction have been shown to play more important roles in cardiovascular pathology in patients with moderate CKD compared with in those without CKD [18]. The marked reduction of stroke risk in moderate CKD patients we observed also suggests a role of pravastatin’s ancillary effects, because the relation between LDL-C and stroke is weaker than that between LDL-C and coronary events [19]. In the present analysis, observed benefits of pravastatin were greater in patients with moderate CKD than in the group with eGFR > 60 mL/min/1.73 m2 despite the drug’s exerting similar reductions of LDL-C in both groups. Although it did not show significant heterogeneity in treatment effect, the Treating to New Targets (TNT) study demonstrated good efficacy against major CVD events of more intensive LDL-C lowering with atorvastatin in patients with moderate CKD whereas a lesser effect on major CVD events was seen in those with normal renal function [20]. In contrast, however, the meta-analysis of three pravastatin trials conducted by Tonelli et al. [17] found no difference of the drug’s effects on reducing CVD events among patients with moderate CKD, mild CKD, and normal renal function. Further investigation is needed to clarify whether statins either individ-
ually or as a class exert differing benefits in patients with and without CKD. In this study, we observed that pravastatin improved renal function in patients with moderate CKD. Significantly (P = 0.03) greater changes in eGFR during follow-up were found in the diet plus pravastatin group (+6.3%) versus in the diet group (+5.1%). Similar results have been reported in previous statin trials. In the CARE Study [2], among individuals with a baseline GFR < 60 mL/min/1.73 m2 there was a slightly slower loss of renal function in those who were treated with pravastatin compared with those on placebo. In the Pravastatin Pooling Project [21] significantly less acute renal failure and fewer patients with decreasing GFR were noted in the active treatment group. Moreover, a meta-analysis of 27 studies including 39,704 patients showed significantly slower loss of renal function, by 1.22 mL/min/1.73 m2 eGFR annually, in patients receiving statins versus control groups—very similar to the present data [22]. We also observed that in moderate CKD there was no difference between baseline and follow-up eGFR levels in patients who did and did not develop CVD (data not shown), indicating that the benefits of statin treatment for CVD and for renal function were provided independent of each other. This retrospective analysis also confirmed pravastatin’s safety in the setting of moderate CKD, with no difference of serious adverse events, abnormal laboratory tests, or increased cancer incidence detected versus in normal/mild CKD patients. The issue of drug safety is especially important in patients with renal dysfunction; thus evidence in favor of long-term safety of pravastatin in moderate CKD is reassuring because of the need for chronic treatment in such patients. A limitation of this post hoc analysis could be selection bias related to our inclusion and exclusion criteria. In particular, excluding patients with high creatinine levels and/or poorly controlled diabetes could lead to inclusion of a high proportion of older women and fewer diabetic patients. Therefore careful consideration of our results is needed. Yet, the similarity between the patients with normal/mild and moderate CKD in the diet alone and the diet + pravastatin groups maintains fair comparability of these patients despite the possible selection bias. Although subsets of patients were excluded, those with moderate CKD had a significantly higher CVD risk, suggesting that moderate CKD contributes to CVD risk independent of other influences in-mild-to moderate hypercholesterolemic Japanese patients because a significant relation remained after adjusting for CVD risk factors. Selection bias would not alter this result because of the small number of patients with moderate CKD who were excluded. Another limitation is the use of eGFR, which was used because clinical data related to renal function such as proteinuria were not systematically collected. Randomized trials are required to determine whether persons with high risk or with severe CKD (eGFR < 30 mL/min/1.73 m2 ) would benefit from statin therapy. Yet, the present results extend the observations among persons or populations at higher risk, because many of our patients had hypertension (50%) and diabetes (about 20%)—although this was a post hoc analysis of a primary prevention study. In conclusion, pravastatin treatment on a background of standard dietary advice significantly reduced CVD and total mortality risk, and had beneficial effects on renal function. Notably, this analysis confirmed the safety of long-term pravastatin therapy in patients with moderately severe CKD. Contributors Dr. Nakamura had full access to all the study data, and takes responsibility for the integrity of those presented and the accuracy of the analysis. The manuscript itself was drafted by Dr. Nakamura.
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Professor Ohashi is the study statistician. The Japanese Ministry of Health, Labour and Welfare funded the study for the first 2 years; thereafter this was done by Daiichi-Sankyo, Ltd., Tokyo. Research funds for the present post hoc analysis were provided by DaiichiSankyo. The MEGA Study was initiated by the Japanese Ministry of Health, Labour and Welfare, which assigned Dr. Nakamura as project leader when he was acting as Professor of Internal Medicine at the National Defense Medical College. Dr. Nakamura organized the MEGA Study Group, comprising 1320 hospitals across Japan. The MEGA Study Group was established as an independent project organization, and this was maintained throughout the study and analysis. Conflict of interest statement Drs. Nakamura, Mizuno, and Ohashi have reported receiving travel grants or lecture fees from Daiichi Sankyo and from other pharmaceutical companies making competing products. Drs. Hirao, Yoshida, and Uchida declare that they have no conflict of interest. Acknowledgments We thank all the study participants, physicians, co-medical staff, and our co-workers, and particularly Professor Andrew Tonkin for reviewing the manuscript. References [1] Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003;139:137–47. [2] Tonelli M, Moyé L, Sacks FM, et al. Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency. Ann Intern Med 2003;138:98–104. [3] Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events and hospitalization. N Engl J Med 2004;351:1296–305. [4] Keith DS, Nichols GA, Gullion CM, et al. Longitudinal follow-up and outcomes among population with chronic kidney disease in a large managed care organization. Arch Intern Med 2004;164:659–63. [5] Anavekar NS, McMurray JJ, Valazquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 2004;351:1285–95.
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Pravastatin and cardiovascular risk in moderate chronic kidney disease夽 Haruo Nakamura a,∗,1 , Kyoichi Mizuno b,1 , Yasuo Ohashi c,1 , Tomowo Yoshida d,1 , Koichi Hirao e,1 , Yasufumi Uchida f,1 a
Mitsukoshi Health and Welfare Foundation, STEC Jyoho Building, 1-24-1 Nishishinjuku Shinjuku, Tokyo, 160-0023, Japan Department of Medicine, Nippon Medical School, Tokyo, Japan c Department of Biostatistics/Epidemiology and Preventive Health Sciences, University of Tokyo, Tokyo, Japan d Nippon Kokan Fukuyama Hospital, Fukuyama, Japan e HEC Science Clinic, Yokohama, Japan f Saga Memorial Hospital, Saga, Japan b
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Article history: Received 15 October 2008 Received in revised form 25 January 2009 Accepted 28 March 2009 Available online 5 April 2009 Keywords: Hypercholesterolemia Cardiovascular disease Chronic kidney disease HMG-CoA reductase inhibitors Pravastatin
a b s t r a c t Objectives: To investigate the relation between chronic kidney disease (CKD) and cardiovascular disease (CVD) and retrospectively to evaluate the effect of low dose of pravastatin in Japanese hypercholesterolemic patients with CKD enrolled in the large-scale randomized MEGA Study. Methods: In this post hoc analysis, effect of low dose pravastatin treatment (10–20 mg daily) on the primary prevention of the cardiovascular disease and renal function after 5 years was evaluated in 7196 patients with normal kidney function/mild CKD or moderate CKD. Patients were classified based on an estimated glomerular filtration rate (eGFR) ≥60 or 30–<60 mL/min/1.73 m2 as having normal renal function/mild CKD or moderate CKD, respectively. Since Japanese guidelines do not allow statin use in patients with severe kidney disease, such individuals were excluded. Results: The incidence of CVD events was 35–49% higher in patients with moderate CKD than in those with normal renal function/mild CKD. Notably, in the moderate CKD group pravastatin significantly reduced CHD by 48% (P = 0.02), stroke by 73% (P < 0.01), CVD by 55% (P < 0.01), and total mortality by 51% (P = 0.02). Moreover, the change in eGFR during follow-up in patients with moderate CKD was significantly (P = 0.03) higher in those assigned to receive diet plus pravastatin (+6.3%) compared with those on diet alone (+5.1%). Conclusions: Risk of CVD is higher in patients with moderate CKD compared with those with normal renal function/mild CKD, and was significantly reduced by treatment with pravastatin. Pravastatin also exerted beneficial effects on renal function in patients with moderate CKD. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Since 2003, disorders of renal function have been categorized according to grades based on the glomerular filtration rate (GFR) established by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) [1]. They classified a GFR of ≥90, 60–<90, 30–<60, 15–<30, and <15 mL/min/1.73 m2 as indicative of stage 1 (normal), 2 (mild), 3 (moderate), 4 (severe), and 5 (very severe or end-stage) chronic kidney disease (CKD), respectively. Several epidemiological studies have demonstrated a correlation between renal dysfunction and cardiovascular disease (CVD), and it is known that moderate CKD with a GFR <60 mL/min/1.73 m2 is a potent risk factor for CVD events [2–5].
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The Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study was a large-scale clinical trial that evaluated the effect of pravastatin on the risk of CVD events in patients with mild-to-moderate hypercholesterolemia and no past history of ischemic heart disease and/or stroke [6,7]. The reduction in the relative risk of CVD events was similar to those found in Western statin trials [8–14]. The principal results of the MEGA Study, reported in 2006, showed that mild or moderate changes in lipid profiles associated with pravastatin given as adjunct to diet therapy significantly reduced the relative risk for coronary heart disease (CHD) by 33% and CVD by 26% compared with diet therapy alone [7], and the number needed to treat (NNT) to prevent one CHD or CVD event was 119 and 91, respectively. The aims of the present post hoc analysis of the MEGA Study data were to investigate in Japanese patients whether the presence of CKD increases the incidence of CVD events, to study the risk factors possibly contributing to their development, and to evaluate the usefulness of pravastatin for the prevention of CVD in patients with moderate CKD.
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Table 1 Baseline and on-treatment serum lipids, blood pressure, and fasting plasma glucose in normal/mild CKD and moderate CKD patients stratified by the presence or absence of CVD. CVD free (n = 3519)
CVD case (n = 144)
Baseline
On treatment
Baseline
On treatment
TC (mmol/L) Normal/mild Moderate
6.3 (0.3) 6.3 (0.3)
6.2 (0.4) 6.1 (0.4)
6.3 (0.3) 6.3 (0.3)
6.1 (0.4) 6.2 (0.6)
LDL-C (mmol/L) Normal/mild Moderate
4.1 (0.5) 4.0 (0.4)
3.9 (0.5) 3.9 (0.5)
4.1 (0.5) 4.1 (0.5)
3.9 (0.6) 4.0 (0.6)a
HDL-C (mmol/L) Normal/mild Moderate
1.5 (0.4) 1.5 (0.4)
1.5 (0.4) 1.5 (0.4)
1.4 (0.3)a 1.3 (0.4)a
1.4 (0.3)a 1.3 (0.4)a
TG (mmol/L)b Normal/mild Moderate
1.4 (1.0–1.9) 1.5 (1.1–2.1)
1.4 (1.1–1.9) 1.4 (1.1–1.9)
1.7 (1.2–2.2)a 1.6 (1.2–2.6)a
1.6 (1.3–2.1)a 1.5 (1.1–2.0)a
SBP (mmHg) Normal/mild Moderate
131.7 (16.5) 132.8 (17.1)
130.9 (12.7) 132.6 (13.3)
137.7 (16.8)a 136.3 (14.7)
139.2 (15.0)a 138.6 (13.6)a
DBP (mmHg) Normal/mild Moderate
78.8 (10.2) 78.7 (10.0)
77.9 (7.8) 77.7 (7.4)
80.5 (11.0) 79.3 (9.3)
80.0 (9.2)a 80.2 (8.5)a
FPG (mmol/L) Normal/mild Moderate
6.0 (1.7) 5.9 (1.7)
6.2 (1.7) 6.0 (1.6)
7.2 (2.4)a 6.6 (2.2)a
7.3 (1.9)a 7.2 (3.4)a
On-treatment values averaged all measurements during follow-up. All data are mean (SD) unless otherwise indicated. TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglycerides; SBP, systolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose. a P < 0.05 versus value at the same time-point in CVD-free group. b Median (interquartile range).
2. Method 2.1. Study design The design and principal findings of the MEGA Study have been reported previously [6,7]. Briefly, a total of 7832 men and postmenopausal women aged 40–70 years with total cholesterol (TC) levels 5.69–6.98 mmol/L (220–270 mg/dL) and no history of CHD and/or stroke were recruited. The patients were randomly assigned to receive diet counseling alone (diet group) or Step I diet plus pravastatin 10–20 mg/day (diet plus pravastatin group). Patients in both groups were counseled to follow the National Cholesterol Education Program (NCEP) Step I diet with reduced daily caloric intake, saturated fats, and cholesterol [15]. Major exclusion criteria included familial hypercholesterolemia, history of CVD, cancer, severe renal dysfunction (serum creatinine ≥ 1.5 mg/dL), significant liver disease, and secondary hyperlipidemia. Treatment in the diet plus pravastatin group was initiated at 10 mg/day, and thereafter
could be adjusted to 20 mg/day (the highest approved dose in Japan) if TC remained >5.69 mmol/L. Patients in both groups whose TC was >6.98 mmol/L even after enhancement of assigned treatment could be switched to other aggressive treatments including other statins. The primary endpoint was a composite of the first occurrence of a CHD event including fatal and nonfatal myocardial infarction, angina pectoris, cardiac/sudden death, and coronary revascularization. The average follow-up period was 5.3 years and 98.7% of patients completed follow-up. In the diet group, the percentage of patients who received a statin (mostly pravastatin) was 24.5% at 5 years due to poorly controlled total cholesterol after randomization. In the diet + pravastatin group, 90.4% of patients continued receiving pravastatin at 5 years. In this post hoc analysis, 636 patients from the main ITT dataset were excluded either because their creatinine level was not recorded (n = 620) or they had severe CKD (<30 mL/min/1.73 m2 ; n = 16); thus the 5-year data on 7196 patients were analyzed. Estimated GFR (eGFR) was estimated by the Modified Diet and Renal
Table 2 Baseline and on-treatment eGFR (mL/min/1.73 m2 ) in all, male, and female patients with normal/mild CKD and moderate CKD. Normal/mild CKD
Moderate CKD
Baseline
On treatment [% change]
P-value
Baseline
On treatment [% change]
All Diet Diet plus pravastatin
P-value
72.5 (10.3) 73.0 (10.6)
69.9 ± 9.7 [–3.6] 70.4 ± 10.0 [–3.6]
0.76
52.5 (5.6) 52.6 (5.7)
55.2 ± 7.6 [+5.1] 55.9 ± 8.0 [+6.3]
0.03
Men Diet Diet plus pravastatin
73.5 (10.7) 73.9 (11.3)
71.2 ± 9.9 [–3.1] 71.8 ± 10.7 [–2.8]
0.67
53.5 (5.1) 53.1 (5.5)
55.5 ± 7.6 [+3.7] 56.8 ± 8.4 [+7.0]
<0.001
Women Diet Diet plus pravastatin
72.0 (10.1) 72.6 (10.1)
69.0 ± 9.5 [–4.2] 69.7 ± 9.6 [–4.0]
0.92
52.2 (5.7) 52.4 (5.7)
55.1 ± 7.6 [+5.6] 55.5 ± 7.9 [+5.9]
0.46
On-treatment values averaged all measurements during follow-up. Percent changes were averaged in each individual versus baseline. All data are mean (SD). P-values were calculated by comparing % changes from baseline between the diet group and diet plus pravastatin group.
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Table 3 Incidence of major cardiovascular events in patients with normal/mild CKD and moderate CKD on diet therapy alone. No. of events/1000 person-years
CHD Stroke Ischemic stroke Hemorrhagic stroke CHD + ischemic stroke CVD Total mortality
Normal/mild CKD (n = 2156)
Moderate CKD (n = 1516)
40 (4.1) 28 (2.8) 21 (2.1) 6 (0.6) 60 (6.1) 73 (7.5) 29 (2.9)
40 (5.7) 29 (4.1) 22 (3.1) 7 (1.0) 60 (8.7) 71 (10.3) 34 (4.8)
HR (95%CI)a
P-valuea
Adjusted HR (95%CI)b
P-valueb
1.49 (0.95–2.33) 1.35 (0.79–2.31) 1.49 (0.81–2.75) 1.10 (0.36–3.38) 1.46 (1.01–2.10) 1.37 (0.98–1.92) 1.46 (0.88–2.44)
0.08 0.27 0.20 0.87 0.04 0.06 0.14
1.49 (0.95–2.34) 1.31 (0.76–2.24) 1.46 (0.79–2.71) 1.04 (0.34–3.22) 1.46 (1.01–2.11) 1.37 (0.98–1.92) 1.52 (0.91–2.54)
0.08 0.33 0.23 0.94 0.04 0.07 0.11
CKD, chronic kidney disease; CHD, coronary heart disease; CVD, cardiovascular disease. a Estimated by Cox proportional hazard model adjusted by sex and age. b Estimated by Cox multiple hazard model adjusted by sex, age, baseline HDL-C, hypertension, diabetes and smoking status.
Disease (MDRD) equation for Japanese patients [16]; serum creatinine level (SCr) was adjusted because enzymatic determination was used. Patients were classified based on an eGFR level ≥60 or 30–<60 mL/min/1.73 m2 as having normal renal function/mild CKD or moderate CKD, respectively.
showed no significant change from baseline in the normal/mild CKD subset in both treatment arms, whereas in the moderate CKD group eGFR increased by 6.3% in the diet plus pravastatin group, significantly (P = 0.03) higher by 1.2% than in the diet alone group (5.1%; Table 2). The differences in eGFR between treatment groups were larger in men (3.3%; P < 0.001) than in women (0.3%; P = 0.46).
2.2. Statistical analysis 3.2. CKD and risk of CVD events Differences of patient characteristics were analyzed by Student’s t-test and P-values ≤ 0.05 were considered significant. The incidence of endpoint events was compared by Cox proportional hazards model adjusted by sex, age, high-density lipoprotein cholesterol (HDL-C), hypertension, diabetes mellitus, and smoking status. 2.3. Role of funding source The authors, comprising the steering committee, were responsible for the study design, statistical plan, and reporting of results. Randomization, data collection, and data analysis were conducted by an independent center established by contract research organization. All study organization, conduct, and data analyses were undertaken independently of the sponsors. 3. Results 3.1. Patients and effect of pravastatin on biochemical variables Among 7196 patients retrospectively analyzed, those identified as having normal renal function/mild CKD and moderate CKD accounted for 4218 (58.6%) and 2978 (41.4%) patients, respectively. Those with moderate CKD were older at 60 years versus 57 years and included higher proportions of women (75.7% versus 63.5%) and hypertensive patients (46.3% versus 40.8%) and lower rates of smokers (12.5% versus 16.8%) and diabetic patients (18.8% versus 23.0%) compared with the normal/mild CKD group. Moreover, triglycerides (TG) and systolic blood pressure (SBP) levels were significantly higher in the moderate CKD group compared with the normal/mild CKD group, at 1.5 mmol/L versus 1.4 mmol/L and 132.9 mmHg versus 131.8 mmHg, respectively. At 5 years, among patients assigned diet plus pravastatin lowdensity lipoprotein cholesterol (LDL-C) was significantly reduced by 18.1% in the normal/mild CKD group and by 18.9% in the moderate CKD group, whereas high density lipoprotein cholesterol (HDLC) was significantly increased by 4.9% and by 4.5%, respectively. In the diet alone group, similar such parameters were found in the patients who developed CVD (n = 144) and those who did not (n = 3519). In patients treated with pravastatin LDL-C, SBP, and diastolic blood pressure (DBP) remained high and HDL-C low in the moderate CKD patients who developed CVD compared with those who remained CVD free (Table 1). Analysis of eGFR during treatment
Table 3 compares major events in patients in the moderate CKD and normal/mild CKD groups assigned diet alone. A significant increase in the relative risk of CHD plus ischemic stroke was found in the moderate CKD group (hazard ratio [HR], 1.46; 95%CI, 1.01–2.10; P = 0.04). This risk remained significantly increased (HR, 1.46; 95%CI, 1.01–2.11; P = 0.04) even after adjustment for other factors associated with CVD risk. Furthermore, in the moderate CKD group compared with the normal/mild CKD group, higher HRs for CHD (1.49; 95%CI, 0.95–2.34), stroke (1.31; 95%CI, 0.76–2.24), CVD (1.37; 95%CI, 0.98–1.92), and total mortality (1.52; 95%CI, 0.91–2.54) were found, although they were not statistically significant. 3.3. Effects of pravastatin on major cardiovascular events Pravastatin’s effects on major endpoints such as CHD, stroke, CVD, and total mortality in the moderate CKD group are shown in Fig. 1. In these patients the risk of experiencing any one of four endpoints was significantly reduced by pravastatin, with observed reductions of 48% (P = 0.02), 73% (P < 0.01), 55% (P < 0.01), and 51% (P = 0.02) for each, respectively, and also in patients with moderate CKD the effects were greater than those in the total study cohort (in whom relative risk reductions of 30%, 32%, 29%, and 33%, respectively, were noted). The Kaplan–Meier curves started to diverge after 3 years for CHD, after 1 year for stroke, and after 2 years for total mortality. A marked risk reduction in patients with moderate CKD compared with the total group was found, confirming the beneficial effect of pravastatin in individuals with moderate CKD. The effects of pravastatin in all patients, in those with moderate CKD, and in those with normal/mild CKD are summarized in Fig. 2. In patients with moderate CKD, the relative risk reduction and NNT for CHD, all stroke, ischemic stroke, CHD plus ischemic stroke, total CVD events, and total mortality were 48% (NNT, 82), 73% (72), 82% (84), 59% (44), 55% (41), and 51% (86), respectively. Meanwhile, no risk reduction was found in those with normal/mild CKD. 3.4. Safety In patients with moderate CKD, there were no significant differences in serious adverse events or subjective complaints of side effects between the two treatment arms (diet group, 11.3%; diet plus pravastatin group, 10.5%; P = 0.088). No major difference of abnormal laboratory findings was seen in patients with moder-
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Fig. 1. Kaplan–Meier curves for major endpoints in the patients with moderate CKD. CHD, coronary heart disease; CVD, cardiovascular disease.
Fig. 2. Hazard ratios (HR) and number needed to treat (NNT) to prevent one endpoint event in moderate CKD patients. Square size indicates number of events. HR, 95% confidence interval (95%CI), and P-values for moderate CKD and normal/mild CKD were estimated by Cox proportional hazards model adjusted by sex, age, baseline HDL-C, hypertension, diabetes, and smoking status. CHD, coronary heart disease; CVD, cardiovascular disease.
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ate CKD: AST > 100 IU/L was 1.1% in the diet group and 1.2% in diet plus pravastatin (P = 0.94) whereas ALT > 100 IU/L was 2.7% and 2.5% (P = 0.73); BUN > 40 mg/dL was 10.6% and 8.4% (P = 0.04), creatinine > 4.0 mg/dL was 0.2% and 0.3% (P = 0.41), and creatine kinase > 500 IU/L was 2.6% and 2.6% (P = 0.96). In both the moderate CKD group and normal/mild CKD group no significant difference was found between treatment arms in total cancer incidence/1000 person-years or the rate of any organ-specific type of cancer. 4. Discussion During follow-up, lipid parameters and SBP/DBP did not change significantly in either the moderate CKD or normal/mild CKD patients randomized to diet group. In this treatment arm, patients with moderate CKD who developed CVD had higher SBP and DBP on treatment and their LDL-C remained elevated and HDL-C low compared with those with normal/mild CKD. Therefore we speculate that the higher risk of CVD in patients with moderate CKD might be related to their having greater severity of baseline risk: older age, hypertension, high TG level, and elevated SBP coupled with persistent elevation of SBP/DBP and LDL-C and low HDL-C during follow-up. These results, for the first time, demonstrate that risk factors not only at baseline but also during treatment influence the increase in CVD in patients with moderate CKD. Marked reductions of CHD by 48%, stroke by 73%, CVD by 55%, and total mortality by 51% were found in patients with moderate CKD who received treatment with pravastatin. This is consistent with the results of previous statin trials that have examined the cardiovascular effects of these drugs in patients with mild and moderate CKD. A meta-analysis of three trials of pravastatin 40 mg/day demonstrated significant 23% and 14% reductions for CHD and total mortality, respectively, in patients with moderate CKD [17]. Although relatively few patients had renal dysfunction in the Heart Protection Study, a subgroup analysis showed that simvastatin elicited great benefit in reduction of major CVD events in patients with elevated serum creatinine at baseline [12]. A subgroup analysis of the Anglo-Scandinavian Cardiac Outcome Trial-Lipid Lowering Arm (ASCOT-LLA) showed a significant 39% relative risk reduction in nonfatal myocardial infarction and CHD death in patients with renal dysfunction [13]. In the present analysis, considering that the benefit of pravastatin appeared early during follow-up (stroke and CVD events significantly reduced at 1 year; total mortality and CHD at 2 years) it is tempting to speculate that pravastatin both improves dyslipidemia and exerts known pleiotropic effects such as alleviation of endothelial dysfunction, chronic inflammation, and platelet adhesiveness in patients with moderate CKD—because chronic inflammation and endothelial dysfunction have been shown to play more important roles in cardiovascular pathology in patients with moderate CKD compared with in those without CKD [18]. The marked reduction of stroke risk in moderate CKD patients we observed also suggests a role of pravastatin’s ancillary effects, because the relation between LDL-C and stroke is weaker than that between LDL-C and coronary events [19]. In the present analysis, observed benefits of pravastatin were greater in patients with moderate CKD than in the group with eGFR > 60 mL/min/1.73 m2 despite the drug’s exerting similar reductions of LDL-C in both groups. Although it did not show significant heterogeneity in treatment effect, the Treating to New Targets (TNT) study demonstrated good efficacy against major CVD events of more intensive LDL-C lowering with atorvastatin in patients with moderate CKD whereas a lesser effect on major CVD events was seen in those with normal renal function [20]. In contrast, however, the meta-analysis of three pravastatin trials conducted by Tonelli et al. [17] found no difference of the drug’s effects on reducing CVD events among patients with moderate CKD, mild CKD, and normal renal function. Further investigation is needed to clarify whether statins either individ-
ually or as a class exert differing benefits in patients with and without CKD. In this study, we observed that pravastatin improved renal function in patients with moderate CKD. Significantly (P = 0.03) greater changes in eGFR during follow-up were found in the diet plus pravastatin group (+6.3%) versus in the diet group (+5.1%). Similar results have been reported in previous statin trials. In the CARE Study [2], among individuals with a baseline GFR < 60 mL/min/1.73 m2 there was a slightly slower loss of renal function in those who were treated with pravastatin compared with those on placebo. In the Pravastatin Pooling Project [21] significantly less acute renal failure and fewer patients with decreasing GFR were noted in the active treatment group. Moreover, a meta-analysis of 27 studies including 39,704 patients showed significantly slower loss of renal function, by 1.22 mL/min/1.73 m2 eGFR annually, in patients receiving statins versus control groups—very similar to the present data [22]. We also observed that in moderate CKD there was no difference between baseline and follow-up eGFR levels in patients who did and did not develop CVD (data not shown), indicating that the benefits of statin treatment for CVD and for renal function were provided independent of each other. This retrospective analysis also confirmed pravastatin’s safety in the setting of moderate CKD, with no difference of serious adverse events, abnormal laboratory tests, or increased cancer incidence detected versus in normal/mild CKD patients. The issue of drug safety is especially important in patients with renal dysfunction; thus evidence in favor of long-term safety of pravastatin in moderate CKD is reassuring because of the need for chronic treatment in such patients. A limitation of this post hoc analysis could be selection bias related to our inclusion and exclusion criteria. In particular, excluding patients with high creatinine levels and/or poorly controlled diabetes could lead to inclusion of a high proportion of older women and fewer diabetic patients. Therefore careful consideration of our results is needed. Yet, the similarity between the patients with normal/mild and moderate CKD in the diet alone and the diet + pravastatin groups maintains fair comparability of these patients despite the possible selection bias. Although subsets of patients were excluded, those with moderate CKD had a significantly higher CVD risk, suggesting that moderate CKD contributes to CVD risk independent of other influences in-mild-to moderate hypercholesterolemic Japanese patients because a significant relation remained after adjusting for CVD risk factors. Selection bias would not alter this result because of the small number of patients with moderate CKD who were excluded. Another limitation is the use of eGFR, which was used because clinical data related to renal function such as proteinuria were not systematically collected. Randomized trials are required to determine whether persons with high risk or with severe CKD (eGFR < 30 mL/min/1.73 m2 ) would benefit from statin therapy. Yet, the present results extend the observations among persons or populations at higher risk, because many of our patients had hypertension (50%) and diabetes (about 20%)—although this was a post hoc analysis of a primary prevention study. In conclusion, pravastatin treatment on a background of standard dietary advice significantly reduced CVD and total mortality risk, and had beneficial effects on renal function. Notably, this analysis confirmed the safety of long-term pravastatin therapy in patients with moderately severe CKD. Contributors Dr. Nakamura had full access to all the study data, and takes responsibility for the integrity of those presented and the accuracy of the analysis. The manuscript itself was drafted by Dr. Nakamura.
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Professor Ohashi is the study statistician. The Japanese Ministry of Health, Labour and Welfare funded the study for the first 2 years; thereafter this was done by Daiichi-Sankyo, Ltd., Tokyo. Research funds for the present post hoc analysis were provided by DaiichiSankyo. The MEGA Study was initiated by the Japanese Ministry of Health, Labour and Welfare, which assigned Dr. Nakamura as project leader when he was acting as Professor of Internal Medicine at the National Defense Medical College. Dr. Nakamura organized the MEGA Study Group, comprising 1320 hospitals across Japan. The MEGA Study Group was established as an independent project organization, and this was maintained throughout the study and analysis. Conflict of interest statement Drs. Nakamura, Mizuno, and Ohashi have reported receiving travel grants or lecture fees from Daiichi Sankyo and from other pharmaceutical companies making competing products. Drs. Hirao, Yoshida, and Uchida declare that they have no conflict of interest. Acknowledgments We thank all the study participants, physicians, co-medical staff, and our co-workers, and particularly Professor Andrew Tonkin for reviewing the manuscript. References [1] Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003;139:137–47. [2] Tonelli M, Moyé L, Sacks FM, et al. Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency. Ann Intern Med 2003;138:98–104. [3] Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events and hospitalization. N Engl J Med 2004;351:1296–305. [4] Keith DS, Nichols GA, Gullion CM, et al. Longitudinal follow-up and outcomes among population with chronic kidney disease in a large managed care organization. Arch Intern Med 2004;164:659–63. [5] Anavekar NS, McMurray JJ, Valazquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 2004;351:1285–95.
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