Effect of statins on cardiovascular events in patients with mild to moderate chronic kidney disease: a systematic review and meta-analysis of randomized clinical trials

BackgroundStatins are commonly used to lower total cholesterol levels in the general population to prevent cardiovascular events. However, the effects of statins in patients with chronic kidney disease remain unclear. We therefore performed a meta-analysis to assess the effects of statin therapy on cardiovascular outcomes in patients with mild to moderate chronic kidney disease.MethodsWe systematically searched PubMed, EmBase, the Cochrane Central Register of Controlled Trials, proceedings of major meetings, and reference lists of articles for relevant literature. Only randomized clinical trials were included. Outcomes analysed included cardiovascular disease, total mortality, myocardial infarction, stroke, cardiovascular death, and possible drug-related adverse events. Subgroup analyses were also performed based on the population characteristics and clinical indexes.ResultsTwelve trials met our inclusion criteria. Overall, statin therapy resulted in a 24% reduction in the risk of cardiovascular disease (RR = 0.76,95% confidence interval [CI], 0.72– 0.80), a 21% reduction in the risk of total mortality (RR = 0.79,95% CI, 0.72–0.86), a 34% reduction in the risk of myocardial infarction (RR = 0.66,95% CI, 0.52–0.83), a 30% reduction in the risk of stroke (RR = 0.70,95% CI, 0.57–0.85), and a 17% reduction in the risk of cardiovascular mortality (RR = 0.83,95% CI, 0.73– 0.93). No statistically significant drug-related adverse events were noted. Subgroup analysis indicated that some important factors such as baseline creatinine level ≥1.5 mg/dL, baseline glomerular filtration rate (GFR), and cardiovascular disease history could affect cardiovascular outcomes.ConclusionStatin therapy had a clear effect on cardiovascular disease, total mortality, stroke, and myocardial infarction in patients with mild to moderate renal disease. Subgroup analysis indicated that baseline GFR, baseline creatinine level, and a history of cardiovascular disease might play an important role in the cardiovascular outcomes.

Related papers:

title: Chronic kidney disease as a global public health problem: approaches and initiatives - a position statement from Kidney Disease Improving Global Outcomes.
abstract: Chronic kidney disease (CKD) is increasingly recognized as a global public health problem. There is now convincing evidence that CKD can be detected using simple laboratory tests, and that treatment can prevent or delay complications of decreased kidney function, slow the progression of kidney disease, and reduce the risk of cardiovascular disease (CVD). Translating these advances to simple and applicable public health measures must be adopted as a goal worldwide. Understanding the relationship between CKD and other chronic diseases is important to developing a public health policy to improve outcomes. The 2004 Kidney Disease Improving Global Outcomes (KDIGO) Controversies Conference on 'Definition and Classification of Chronic Kidney Disease' represented an important endorsement of the Kidney Disease Outcome Quality Initiative definition and classification of CKD by the international community. The 2006 KDIGO Controversies Conference on CKD was convened to consider six major topics: (1) CKD classification, (2) CKD screening and surveillance, (3) public policy for CKD, (4) CVD and CVD risk factors as risk factors for development and progression of CKD, (5) association of CKD with chronic infections, and (6) association of CKD with cancer. This report contains the recommendations from the meeting. It has been reviewed by the conference participants and approved as position statement by the KDIGO Board of Directors. KDIGO will work in collaboration with international and national public health organizations to facilitate implementation of these recommendations.

title: Prevalence of chronic kidney disease in the United States.
abstract: The prevalence and incidence of kidney failure treated by dialysis and transplantation in the United States have increased from 1988 to 2004. Whether there have been changes in the prevalence of earlier stages of chronic kidney disease (CKD) during this period is uncertain.



To update the estimated prevalence of CKD in the United States.



Cross-sectional analysis of the most recent National Health and Nutrition Examination Surveys (NHANES 1988-1994 and NHANES 1999-2004), a nationally representative sample of noninstitutionalized adults aged 20 years or older in 1988-1994 (n = 15,488) and 1999-2004 (n = 13,233).



Chronic kidney disease prevalence was determined based on persistent albuminuria and decreased estimated glomerular filtration rate (GFR). Persistence of microalbuminuria (>30 mg/g) was estimated from repeat visit data in NHANES 1988-1994. The GFR was estimated using the abbreviated Modification of Diet in Renal Disease Study equation reexpressed to standard serum creatinine.



The prevalence of both albuminuria and decreased GFR increased from 1988-1994 to 1999-2004. The prevalence of CKD stages 1 to 4 increased from 10.0% (95% confidence interval [CI], 9.2%-10.9%) in 1988-1994 to 13.1% (95% CI, 12.0%-14.1%) in 1999-2004 with a prevalence ratio of 1.3 (95% CI, 1.2-1.4). The prevalence estimates of CKD stages in 1988-1994 and 1999-2004, respectively, were 1.7% (95% CI, 1.3%-2.2%) and 1.8% (95% CI, 1.4%-2.3%) for stage 1; 2.7% (95% CI, 2.2%-3.2%) and 3.2% (95% CI, 2.6%-3.9%) for stage 2; 5.4% (95% CI, 4.9%-6.0%) and 7.7% (95% CI, 7.0%-8.4%) for stage 3; and 0.21% (95% CI, 0.15%-0.27%) and 0.35% (0.25%-0.45%) for stage 4. A higher prevalence of diagnosed diabetes and hypertension and higher body mass index explained the entire increase in prevalence of albuminuria but only part of the increase in the prevalence of decreased GFR. Estimation of GFR from serum creatinine has limited precision and a change in mean serum creatinine accounted for some of the increased prevalence of CKD.



The prevalence of CKD in the United States in 1999-2004 is higher than it was in 1988-1994. This increase is partly explained by the increasing prevalence of diabetes and hypertension and raises concerns about future increased incidence of kidney failure and other complications of CKD.

title: Prevalence of chronic kidney disease in population-based studies: Systematic review
abstract: BackgroundChronic kidney disease (CKD) is becoming a major public health problem worldwide. This article reviews the published evidence of prevalence of CKD in population-based study samples that used the standardized definition from the Kidney Disease Outcomes Quality Initiative of the National Kidney Foundation (K/DOQI) practice guideline, and particularly focus on performance of serum-creatinine based equations for GFR estimation. We provide a summary of available data about the burden of CKD in various populations.MethodsWe performed a systematic review of available published data in MEDLINE. A combination of various keywords relevant to CKD was used in this research. Related data of included studies were extracted in a systematic way. total of 26 studies were included in this review. The studies were conducted in different populations, and the number of study participants ranged from 237 to 65181. The median prevalence of CKD was 7.2% in persons aged 30 years or older. In persons aged 64 years or older prevalence of CKD varied from 23.4% to 35.8%. Importantly, the prevalence of CKD strongly depended on which estimating equations were used. The Modification of Diet in Renal Disease Study (MDRD) equation was likely to be preferred in recent epidemiological studies compared to the adjusted Cockcroft-Gault (CG) equation.ConclusionWorldwide, CKD is becoming a common disease in the general population. Accurately detecting CKD in special groups remains inadequate, particularly among elderly persons, females or other ethnic groups such as Asians.

title: Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention
abstract: Since the first description of the association between chronic kidney disease and heart disease, many epidemiological studies have confirmed and extended this finding. As chronic kidney disease progresses, kidney-specific risk factors for cardiovascular events and disease come into play. As a result, the risk for cardiovascular disease is notably increased in individuals with chronic kidney disease. When adjusted for traditional cardiovascular risk factors, impaired kidney function and raised concentrations of albumin in urine increase the risk of cardiovascular disease by two to four times. Yet, cardiovascular disease is frequently underdiagnosed and undertreated in patients with chronic kidney disease. This group of patients should, therefore, be acknowledged as having high cardiovascular risk that needs particular medical attention at an individual level. This view should be incorporated in the development of guidelines and when defining research priorities. Here, we discuss the epidemiology and pathophysiological mechanisms of cardiovascular risk in patients with chronic kidney disease, and discuss methods of prevention.

title: Chronic kidney disease in the developing world.
abstract: Some 85 percent of the world's population lives in low-income or middle-income countries, where the clinical, epidemiologic, and socioeconomic effects of kidney disease are expected to be the greatest. Dr. Rashad Barsoum writes that the obvious task ahead for health authorities in the developing world is to detect and treat the disease at the earliest possible stage.

title: Prevalence of decreased kidney function in Chinese adults aged 35 to 74 years.
abstract: Chronic kidney disease (CKD) is a major public health burden in Western countries but little is known about its impact in developing countries. We estimated the prevalence and absolute burden of CKD in the general adult population in China.



A cross-sectional survey was conducted in a nationally representative sample of 15,540 Chinese adults aged 35 to 74 years in 2000 and 2001. Serum creatinine was measured using the modified kinetic Jaffe reaction method at a central laboratory calibrated to the Cleveland Clinic Foundation laboratory. Glomerular filtration rate (GFR) was estimated using the simplified equation developed by the Modification of Diet in Renal Disease study. CKD was defined as an estimated GFR <60 mL/min/1.73m2.



Overall, the age-standardized prevalences of GFR 60 to 89, 30 to 59, and <30 mL/min/1.73m2 were 39.4%, 2.4%, and 0.14%, respectively, in Chinese adults aged 35 to 74 years. The overall prevalence of CKD (GFR <60 mL/min/1.73m2) was 2.53%, representing 11,966,653 persons (1.31% or 3,185,330 men and 3.82% or 8,781,323 women). The age-specific prevalence of CKD was 0.71%, 1.69%, 3.91%, and 8.14% among persons 35 to 44, 45 to 54, 55 to 64, and 65 to 74 years old, respectively. The age-standardized prevalence of CKD was similar in urban (2.60%) and rural (2.52%) residents but was higher in south China (3.05%) than in north China (1.78%) residents.



Although the prevalence of CKD in China was relatively low, the population absolute burden is substantial. These data warrant a national program aimed at detection, prevention, and treatment of CKD in China.

title: Prevalence and factors associated with CKD: a population study from Beijing.
abstract: Chronic kidney disease (CKD) is considered a serious worldwide public health problem, but data from developing countries are extremely limited.



Cross-sectional study.



A representative sample of 13,925 adults in Beijing, China.



Age (18 to 39, 40 to 59, 60 to 69, and >70 years), sex, urban or rural area, history of chronic respiratory infection and cardiovascular disease, hepatitis B virus infection, smoking, family history (diabetes, hypertension, and CKD), nephrotoxic medications, central obesity, diabetic and hypertension status, and dyslipidemia.



CKD was defined as estimated glomerular filtration rate less than 60 mL/min/1.73 m(2) or markers of kidney damage. Glomerular filtration rate was estimated by using calibrated serum creatinine level and a formula specific for China. Persistent albuminuria and hematuria were considered markers of kidney damage.



The prevalence of CKD in adults in Beijing was 13.0% (95% confidence interval [CI], 11.9 to 14.2). It therefore was estimated that the number of adults in Beijing with CKD was 1.43 million. In subjects aged 18 to 39, 40 to 59, 60 to 69, and older than 70 years, prevalences of CKD were 10.0% (95% CI, 8.9 to 11.3), 14.2% (95% CI, 13.0 to 15.4), 20.8% (95% CI, 18.1 to 23.9), and 30.5% (95% CI, 26.6 to 34.7), respectively. Factors independently associated with decreased kidney function included older age (odds ratio [OR], 1.83; 95% CI, 1.51 to 2.22 per 10-year increase), nephrotoxic medications (OR, 2.19; 95% CI, 1.21 to 3.97), rural area (versus urban area; OR, 0.47; 95% CI, 0.28 to 0.78), history of cardiovascular disease (OR, 2.04; 95% CI, 1.24 to 3.38), high-density lipoprotein cholesterol level less than 40 mg/dL (OR, 3.00; 95% CI, 1.39 to 6.51), and hypertension status (with duration > 10 years; OR, 1.85; 95% CI, 1.19 to 2.88).



Kidney function and indicators of kidney damage were based on single measurements.



CKD is a public health burden in Beijing.

title: Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
abstract: Lowering of LDL cholesterol with standard statin regimens reduces the risk of occlusive vascular events in a wide range of individuals. We aimed to assess the safety and efficacy of more intensive lowering of LDL cholesterol with statin therapy.



We undertook meta-analyses of individual participant data from randomised trials involving at least 1000 participants and at least 2 years' treatment duration of more versus less intensive statin regimens (five trials; 39 612 individuals; median follow-up 5·1 years) and of statin versus control (21 trials; 129 526 individuals; median follow-up 4·8 years). For each type of trial, we calculated not only the average risk reduction, but also the average risk reduction per 1·0 mmol/L LDL cholesterol reduction at 1 year after randomisation.



In the trials of more versus less intensive statin therapy, the weighted mean further reduction in LDL cholesterol at 1 year was 0·51 mmol/L. Compared with less intensive regimens, more intensive regimens produced a highly significant 15% (95% CI 11-18; p<0·0001) further reduction in major vascular events, consisting of separately significant reductions in coronary death or non-fatal myocardial infarction of 13% (95% CI 7-19; p<0·0001), in coronary revascularisation of 19% (95% CI 15-24; p<0·0001), and in ischaemic stroke of 16% (95% CI 5-26; p=0·005). Per 1·0 mmol/L reduction in LDL cholesterol, these further reductions in risk were similar to the proportional reductions in the trials of statin versus control. When both types of trial were combined, similar proportional reductions in major vascular events per 1·0 mmol/L LDL cholesterol reduction were found in all types of patient studied (rate ratio [RR] 0·78, 95% CI 0·76-0·80; p<0·0001), including those with LDL cholesterol lower than 2 mmol/L on the less intensive or control regimen. Across all 26 trials, all-cause mortality was reduced by 10% per 1·0 mmol/L LDL reduction (RR 0·90, 95% CI 0·87-0·93; p<0·0001), largely reflecting significant reductions in deaths due to coronary heart disease (RR 0·80, 99% CI 0·74-0·87; p<0·0001) and other cardiac causes (RR 0·89, 99% CI 0·81-0·98; p=0·002), with no significant effect on deaths due to stroke (RR 0·96, 95% CI 0·84-1·09; p=0·5) or other vascular causes (RR 0·98, 99% CI 0·81-1·18; p=0·8). No significant effects were observed on deaths due to cancer or other non-vascular causes (RR 0·97, 95% CI 0·92-1·03; p=0·3) or on cancer incidence (RR 1·00, 95% CI 0·96-1·04; p=0·9), even at low LDL cholesterol concentrations.



Further reductions in LDL cholesterol safely produce definite further reductions in the incidence of heart attack, of revascularisation, and of ischaemic stroke, with each 1·0 mmol/L reduction reducing the annual rate of these major vascular events by just over a fifth. There was no evidence of any threshold within the cholesterol range studied, suggesting that reduction of LDL cholesterol by 2-3 mmol/L would reduce risk by about 40-50%.



UK Medical Research Council, British Heart Foundation, European Community Biomed Programme, Australian National Health and Medical Research Council, and National Heart Foundation.

title: Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention.
abstract: Chronic kidney disease1 (CKD) is a worldwide public health problem. In the United States, there is a rising incidence and prevalence of kidney failure, with poor outcomes and high cost. The number of individuals with kidney failure treated by dialysis and transplantation exceeded 320 000 in 1998 and is expected to surpass 650 000 by 2010.1,2 There is an even higher prevalence of earlier stages of CKD (Table 1).1,3 Kidney failure requiring treatment with dialysis or transplantation is the most visible outcome of CKD. However, cardiovascular disease (CVD) is also frequently associated with CKD, which is important because individuals with CKD are more likely to die of CVD than to develop kidney failure,4 CVD in CKD is treatable and potentially preventable, and CKD appears to be a risk factor for CVD. In 1998, the National Kidney Foundation (NKF) Task Force on Cardiovascular Disease in Chronic Renal Disease issued a report emphasizing the high risk of CVD in CKD.5 This report showed that there was a high prevalence of CVD in CKD and that mortality due to CVD was 10 to 30 times higher in dialysis patients than in the general population  The task force recommended that patients with CKD be considered in the “highest risk group” for subsequent CVD events and that treatment recommendations based on CVD risk stratification should take into account the highest-risk status of patients with CKD. 

View this table:

TABLE 1. Stages of CKD 





Figure 1. Cardiovascular mortality defined by death due to arrhythmias, cardiomyopathy, cardiac arrest, myocardial infarction, atherosclerotic heart disease, and pulmonary edema in general population (GP; National Center for Health Statistics [NCHS] multiple cause of mortality data files International Classification of Diseases, 9th Revision [ICD 9] codes 402, 404, 410 to 414, and …

title: Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies.
abstract: Chronic kidney disease (CKD) is a major public health problem. Conflicting evidence exists among community-based studies as to whether CKD is an independent risk factor for adverse cardiovascular outcomes. After subjects with a baseline history of cardiovascular disease were excluded, data from four publicly available, community-based longitudinal studies were pooled: Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Framingham Heart Study, and Framingham Offspring Study. Serum creatinine levels were indirectly calibrated across studies. CKD was defined by a GFR between 15 and 60 ml/min per 1.73 m(2). A composite of myocardial infarction, fatal coronary heart disease, stroke, and death was the primary study outcome. Cox proportional hazards models were used to adjust for study, demographic variables, educational status, and other cardiovascular risk factors. The total population included 22,634 subjects; 18.4% of the population was black, and 7.4% had CKD. There were 3262 events. In adjusted analyses, CKD was an independent risk factor for the composite study outcome (hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.07-1.32), and there was a significant interaction between kidney function and race. Black individuals with CKD had an adjusted HR of 1.76 (95% CI, 1.35-2.31), whereas whites had an adjusted HR of 1.13 (95% CI, 1.02-1.26). CKD is a risk factor for the composite outcome of all-cause mortality and cardiovascular disease in the general population and a more pronounced risk factor in blacks than in whites. It is hypothesized that this effect may be due to more frequent or more severe subclinical vascular disease secondary to hypertension or diabetes in black individuals.

title: Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency.
abstract: Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency.



Little is known about the prevalence of cardiovascular disease (CVD) and associated risk factors in individuals with mild renal insufficiency (RI). Furthermore, the long-term outcomes associated with mild RI in the community have not been described.



Serum creatinine (SCr) was measured in 6233 adult participants of the Framingham Heart Study (mean age 54 years, 54% women). Mild RI was defined as SCr 136 to 265 micromol/liter (1.5 to 3.0 mg/dl) in men and 120 to 265 micromol/liter (1.4 to 3.0 mg/dl) in women. The lower limits for mild RI were defined by the sex-specific 95th percentile SCr values in a healthy subgroup of our sample. The upper limit for mild RI was chosen to exclude those subjects with more advanced renal failure. Cox proportional hazards analyses were used to determine the relationship of baseline RI to CVD and all-cause mortality.



At baseline, 8.7% of men (N = 246) and 8.0% of women (N = 270) had mild RI. Nineteen percent of the subjects with mild RI had prevalent CVD. During 15 years of follow-up, there were 1000 CVD events and 1406 deaths. In women, mild RI was not associated with increased risk for CVD events [hazards ratio (HR) 1.04, 95% CI, 0.79 to 1.37] or all-cause mortality (HR 1.08, 95% CI, 0.87 to 1.34). In men, mild RI showed no significant associations with CVD events (HR 1.17, 95% CI, 0.88 to 1.57), but it was associated with all-cause mortality in age-adjusted (HR 1.42, 95% CI, 1.12 to 1.79) and multivariable adjusted (HR 1.31, 95% CI, 1.02 to 1.67) analyses.



Mild RI in the community is common and is associated with a high prevalence of CVD. The association of RI with risk for adverse outcomes is strongly related to coexisting CVD and CVD risk factors.

title: Premature cardiovascular disease in chronic renal failure
abstract: There is a remarkable lack of reliable information about the determinants of risk of cardiovascular disease (CVD) among patients with chronic renal failure. Indeed, such patients have often been deliberately excluded from randomised trials of treatments of CVD, perhaps because of concerns about drug safety. But the absolute risk of CVD among them may be large, so the potential absolute benefits of treatments may also be large, and may well exceed any increased hazards. Hence, as well as further investigation of the underlying mechanisms of cardiac disease, it would be helpful to have some large-scale randomised trials in a wide range of renal patients of interventions (such as cholesterol-lowering drugs, antihypertensives, aspirin, B-vitamins, and antioxidant vitamins) that are of proven or suspected benefit in other settings. If safe and effective treatments can be identified, and started early in the natural history of renal failure, the exceptionally high risk of CVD experienced by these patients could be decreased before and after end-stage renal failure has occurred.

title: Association between statin treatment and outcome in relation to renal function in survivors of myocardial infarction.
abstract: As statins are recommended at discharge to all patients following myocardial infarction (MI), we studied their use and efficacy in renal disease by analyzing the data, in the nationwide SWEDEHEART registry, of 42,814 consecutive survivors of MI with available creatinine/dialysis data but without statin therapy on admission. The estimated glomerular filtration rate (eGFR) was determined by the Modification of Diet in Renal Disease Study formula and the patients classified into the five traditional stages of kidney disease. The 1-year survival in relation to prescription of statin at discharge was assessed in a Cox regression analysis adjusted by a propensity score that described each individual's likelihood of being treated with a statin, established by 36 baseline characteristics and in-hospital therapies. Statin use at discharge decreased with increased renal impairment from 81% in eGFR stage 1 to 31% in eGFR stage 5. After adjusting for the propensity score and discharge medication, statin use was associated with a significant reduction in overall risk of death (hazard ratio 0.63), with a statistically significant interaction between statin therapy and the stage of renal function. Thus, statin use at discharge was associated with improved 1-year survival of patients in stages 2-4 (mild-to-severe) of renal insufficiency. This effect appears attenuated in those with stage 5 renal failure.

title: The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial
abstract: Lowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic stroke, and the need for coronary revascularisation in people without kidney disease, but its effects in people with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients.  This randomised double-blind trial included 9270 patients with chronic kidney disease (3023 on dialysis and 6247 not) with no known history of myocardial infarction or coronary revascularisation. Patients were randomly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily versus matching placebo. The key prespecified outcome was first major atherosclerotic event (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure). All analyses were by intention to treat.   4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0·85 mmol/L (SE 0·02; with about two-thirds compliance) during a median follow-up of 4·9 years and produced a 17% proportional reduction in major atherosclerotic events (526 [11·3%] simvastatin plus ezetimibe vs 619 [13·4%] placebo; rate ratio [RR] 0·83, 95% CI 0·74–0·94; log-rank p=0·0021). Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infarction or died from coronary heart disease (213 [4·6%] vs 230 [5·0%]; RR 0·92, 95% CI 0·76–1·11; p=0·37) and there were significant reductions in non-haemorrhagic stroke (131 [2·8%] vs 174 [3·8%]; RR 0·75, 95% CI 0·60–0·94; p=0·01) and arterial revascularisation procedures (284 [6·1%] vs 352 [7·6%]; RR 0·79, 95% CI 0·68–0·93; p=0·0036). After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not. The excess risk of myopathy was only two per 10 000 patients per year of treatment with this combination (9 [0·2%] vs 5 [0·1%]). There was no evidence of excess risks of hepatitis (21 [0·5%] vs 18 [0·4%]), gallstones (106 [2·3%] vs 106 [2·3%]), or cancer (438 [9·4%] vs 439 [9·5%], p=0·89) and there was no significant excess of death from any non-vascular cause (668 [14·4%] vs 612 [13·2%], p=0·13).  Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease.

title: Effects of statins in patients with chronic kidney disease: meta-analysis and meta-regression of randomised controlled trials
abstract: To analyse the benefits and harms of statins in patients with chronic kidney disease (pre-dialysis, dialysis, and transplant populations). Design Meta-analysis.  Cochrane Central Register of Controlled Trials, Medline, Embase, and Renal Health Library (July 2006).  Randomised and quasi-randomised controlled trials of statins compared with placebo or other statins in chronic kidney disease.  Two reviewers independently assessed trials for inclusion, extracted data, and assessed trial quality. Differences were resolved by consensus. Treatment effects were summarised as relative risks or weighted mean differences with 95% confidence intervals by using a random effects model.  Fifty trials (30 144 patients) were included. Compared with placebo, statins significantly reduced total cholesterol (42 studies, 6390 patients; weighted mean difference −42.28 mg/dl (1.10 mmol/l), 95% confidence interval −47.25 to −37.32), low density lipoprotein cholesterol (39 studies, 6216 patients; −43.12 mg/dl (1.12 mmol/l), −47.85 to −38.40), and proteinuria (g/24 hours) (6 trials, 311 patients; −0.73 g/24 hour, −0.95 to −0.52) but did not improve glomerular filtration rate (11 studies, 548 patients; 1.48 ml/min (0.02 ml/s), −2.32 to 5.28). Fatal cardiovascular events (43 studies, 23 266 patients; relative risk 0.81, 0.73 to 0.90) and non-fatal cardiovascular events (8 studies, 22 863 patients; 0.78, 0.73 to 0.84) were reduced with statins, but statins had no significant effect on all cause mortality (44 studies, 23 665 patients; 0.92, 0.82 to 1.03). Meta-regression analysis showed that treatment effects did not vary significantly with stage of chronic kidney disease. The side effect profile of statins was similar to that of placebo. Most of the available studies were small and of suboptimal quality; mortality data were provided by a few large trials only.  Statins significantly reduce lipid concentrations and cardiovascular end points in patients with chronic kidney disease, irrespective of stage of disease, but no benefit on all cause mortality or the role of statins in primary prevention has been established. Reno-protective effects of statins are uncertain because of relatively sparse data and possible outcomes reporting bias.

title: Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO).
abstract: Chronic kidney disease (CKD) is a worldwide public health problem, with adverse outcomes of kidney failure, cardiovascular disease (CVD), and premature death. A simple definition and classification of kidney disease is necessary for international development and implementation of clinical practice guidelines.  Improving Global Outcomes (KDIGO) conducted a survey and sponsored a controversies conference to (1) provide a clear understanding to both the nephrology and nonnephrology communities of the evidence base for the definition and classification recommended by Kidney Disease Quality Outcome Initiative (K/DOQI), (2) develop global consensus for the adoption of a simple definition and classification system, and (3) identify a collaborative research agenda and plan that would improve the evidence base and facilitate implementation of the definition and classification of CKD. The K/DOQI definition and classification were accepted, with clarifications. CKD is defined as kidney damage or glomerular filtration rate (GFR) <60 mL/min/1.73 m(2) for 3 months or more, irrespective of cause. Kidney damage in many kidney diseases can be ascertained by the presence of albuminuria, defined as albumin-to-creatinine ratio >30 mg/g in two of three spot urine specimens. GFR can be estimated from calibrated serum creatinine and estimating equations, such as the Modification of Diet in Renal Disease (MDRD) Study equation or the Cockcroft-Gault formula. Kidney disease severity is classified into five stages according to the level of GFR. Kidney disease treatment by dialysis and transplantation should be noted. Simple, uniform classifications of CKD by cause and by risks for kidney disease progression and CVD should be developed.

title: Assessing the quality of reports of randomized clinical trials: is blinding necessary?
abstract: It has been suggested that the quality of clinical trials should be assessed by blinded raters to limit the risk of introducing bias into meta-analyses and systematic reviews, and into the peer-review process. There is very little evidence in the literature to substantiate this. This study describes the development of an instrument to assess the quality of reports of randomized clinical trials (RCTs) in pain research and its use to determine the effect of rater blinding on the assessments of quality. A multidisciplinary panel of six judges produced an initial version of the instrument. Fourteen raters from three different backgrounds assessed the quality of 36 research reports in pain research, selected from three different samples. Seven were allocated randomly to perform the assessments under blind conditions. The final version of the instrument included three items. These items were scored consistently by all the raters regardless of background and could discriminate between reports from the different samples. Blind assessments produced significantly lower and more consistent scores than open assessments. The implications of this finding for systematic reviews, meta-analytic research and the peer-review process are discussed.

title: The Interpretation of Random-Effects Meta-Analysis in Decision Models
abstract: This article shows that the interpretation of the random-effects models used in meta-analysis to summarize heterogeneous treatment effects can have a marked effect on the results from decision models. Sources of variation in meta-analysis include the following: random variation in outcome definition (amounting to a form of measurement error), variation between the patient groups in different trials, variation between protocols, and variation in the way a given protocol is implemented. Each of these alternatives leads to a different model for how the heterogeneity in the effect sizes previously observed might relate to the effect size(s) in a future implementation. Furthermore, these alternative models require different computations and, when the net benefits are nonlinear in the efficacy parameters, result in different expected net benefits. The authors’ analysis suggests that the mean treatment effect from a random-effects meta-analysis will only seldom be an appropriate representation of the efficacy expected in a future implementation. Instead, modelers should consider either the predictive distribution of a future treatment effect, or they should assume that the future implementation will result in a distribution of treatment effects. A worked example, in a probabilistic, Bayesian posterior framework, is used to illustrate the alternative computations and to show how parameter uncertainty can be combined with variation between individuals and heterogeneity in meta-analysis.

title: Meta-analysis in clinical trials.
abstract: This paper examines eight published reviews each reporting results from several related trials. Each review pools the results from the relevant trials in order to evaluate the efficacy of a certain treatment for a specified medical condition. These reviews lack consistent assessment of homogeneity of treatment effect before pooling. We discuss a random effects approach to combining evidence from a series of experiments comparing two treatments. This approach incorporates the heterogeneity of effects in the analysis of the overall treatment efficacy. The model can be extended to include relevant covariates which would reduce the heterogeneity and allow for more specific therapeutic recommendations. We suggest a simple noniterative procedure for characterizing the distribution of treatment effects in a series of studies.

title: Measuring inconsistency in meta-analyses
abstract: Cochrane Reviews have recently started including the quantity I 2 to help readers assess the consistency of the results of studies in meta-analyses. What does this new quantity mean, and why is assessment of heterogeneity so important to clinical practice? 

Systematic reviews and meta-analyses can provide convincing and reliable evidence relevant to many aspects of medicine and health  Their value is especially clear when the results of the studies they include show clinically important effects of similar magnitude. However, the conclusions are less clear when the included studies have differing results. In an attempt to establish whether studies are consistent, reports of meta-analyses commonly present a statistical test of heterogeneity. The test seeks to determine whether there are genuine differences underlying the results of the studies (heterogeneity), or whether the variation in findings is compatible with chance alone (homogeneity). However, the test is susceptible to the number of trials included in the meta-analysis. We have developed a new quantity, I 2, which we believe gives a better measure of the consistency between trials in a meta-analysis.

Assessment of the consistency of effects across studies is an essential part of meta-analysis. Unless we know how consistent the results of studies are, we cannot determine the generalisability of the findings of the meta-analysis. Indeed, several hierarchical systems for grading evidence state that the results of studies must be consistent or homogeneous to obtain the highest grading.2–4

Tests for heterogeneity are commonly used to decide on methods for combining studies and for concluding consistency or inconsistency of  6 But what does the test achieve in practice, and how should the resulting P values be interpreted?

A test for heterogeneity examines the null hypothesis that all studies are evaluating the same effect. The usual test statistic …

title: Effects of Fosinopril and Pravastatin on Cardiovascular Events in Subjects With Microalbuminuria
abstract: Microalbuminuria is associated with increased risk of cardiovascular events. We assessed whether therapeutic intervention aimed at lowering urinary albumin excretion would reduce cardiovascular events in microalbuminuric subjects (15 to 300 mg/24 hours). From the Prevention of Renal and Vascular Endstage Disease (PREVEND) cohort (n=8592), 1439 subjects fulfilled the inclusion criteria of the PREVEND Intervention Trial (PREVEND IT). Of these subjects, 864 were randomized to fosinopril 20 mg or matching placebo and to pravastatin 40 mg or matching placebo. The mean follow-up was 46 months, and the primary end point was cardiovascular mortality and hospitalization for cardiovascular morbidity. Mean age was 51±12 years; 65% of subjects were male, and 3.4% had a previous cardiovascular event. Mean cholesterol level was 5.8±1.0 mmol/L, mean systolic/diastolic blood pressure was 130±18/76±10 mm Hg, and median urinary albumin excretion was 22.8 (15.8 to 41.3) mg/24 hours. The primary end point occurred in 45 subjects (5.2%). Fosinopril reduced urinary albumin excretion by 26% (P<0.001). Subjects treated with fosinopril showed a 40% lower incidence of the primary end point (hazard ratio 0.60 [95% CI 0.33 to 1.10], P=0.098, log-rank). Pravastatin did not reduce urinary albumin excretion, and subjects treated with pravastatin showed a 13% lower incidence of the primary end point than subjects in the placebo group (0.87 [0.49 to 1.57], P=0.649, log-rank). In microalbuminuric subjects, treatment with fosinopril had a significant effect on urinary albumin excretion. In addition, fosinopril treatment was associated with a trend in reducing cardiovascular events. Treatment with pravastatin did not result in a significant reduction in urinary albumin excretion or cardiovascular events.

title: Pravastatin and cardiovascular risk in moderate chronic kidney disease.
abstract: 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.



In this post hoc analysis, effect of low dose pravastatin treatment (10-20mg 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) >or=60 or 30-<60mL/min/1.73m(2) 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.



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%).



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.

title: MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial
abstract: Individuals with diabetes are at increased risk of cardiovascular morbidity and mortality, although typically their plasma concentrations of LDL cholesterol are similar to those in the general population. Previous evidence about the effects of lowering cholesterol in people with diabetes has been limited, and most diabetic patients do not currently receive cholesterol-lowering therapy despite their increased risk.



5963 UK adults (aged 40-80 years) known to have diabetes, and an additional 14573 with occlusive arterial disease (but no diagnosed diabetes), were randomly allocated to receive 40 mg simvastatin daily or matching placebo. Prespecified analyses in these prior disease subcategories, and other relevant subcategories, were of first major coronary event (ie, non-fatal myocardial infarction or coronary death) and of first major vascular event (ie, major coronary event, stroke or revascularisation). Analyses were also conducted of subsequent vascular events during the scheduled treatment period. Comparisons are of all simvastatin-allocated versus all placebo-allocated participants (ie, intention to treat), which yielded an average difference in LDL cholesterol of 1.0 mmol/L (39 mg/dL) during the 5-year treatment period.



Both among the participants who presented with diabetes and among those who did not, there were highly significant reductions of about a quarter in the first event rate for major coronary events, for strokes, and for revascularisations. For the first occurrence of any of these major vascular events among participants with diabetes, there was a definite 22% (95% CI 13-30) reduction in the event rate (601 [20.2%] simvastatin-allocated vs 748 [25.1%] placebo-allocated, p<0.0001), which was similar to that among the other high-risk individuals studied. There were also highly significant reductions of 33% (95% CI 17-46, p=0.0003) among the 2912 diabetic participants who did not have any diagnosed occlusive arterial disease at entry, and of 27% (95% CI 13-40, p=0.0007) among the 2426 diabetic participants whose pretreatment LDL cholesterol concentration was below 3.0 mmol/L (116 mg/dL). The proportional reduction in risk was also about a quarter among various other subcategories of diabetic patient studied, including: those with different duration, type, or control of diabetes; those aged over 65 years at entry or with hypertension; and those with total cholesterol below 5.0 mmol/L (193 mg/dL). In addition, among participants who had a first major vascular event following randomisation, allocation to simvastatin reduced the rate of subsequent events during the scheduled treatment period.



The present study provides direct evidence that cholesterol-lowering therapy is beneficial for people with diabetes even if they do not already have manifest coronary disease or high cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rate of first major vascular events by about a quarter in a wide range of diabetic patients studied. After making allowance for non-compliance, actual use of this statin regimen would probably reduce these rates by about a third. For example, among the type of diabetic patient studied without occlusive arterial disease, 5 years of treatment would be expected to prevent about 45 people per 1000 from having at least one major vascular event (and, among these 45 people, to prevent about 70 first or subsequent events during this treatment period). Statin therapy should now be considered routinely for all diabetic patients at sufficiently high risk of major vascular events, irrespective of their initial cholesterol concentrations.

title: Simvastatin for secondary prevention of all-cause mortality and major coronary events in patients with mild chronic renal insufficiency.
abstract: A potentially modifiable risk factor for cardiovascular disease in patients with mild chronic renal insufficiency is dyslipidemia. Few studies examined the effects of statins on all-cause mortality and major coronary events in patients with renal dysfunction.



We performed a post hoc analysis from the Randomized Trial of Cholesterol Lowering in 4,444 Patients with Coronary Heart Disease: The Scandinavian Simvastatin Survival Study. Of 4,444 participants, 2,314 (52.1%) had mild chronic renal insufficiency defined as an estimated glomerular filtration rate less than 75 mL/min/1.73 m(2) (<1.25 mL/s), measured using the Modification of Diet in Renal Disease equation. The primary end point was all-cause mortality.



During the follow-up period, simvastatin use was associated with decreased all-cause mortality (adjusted hazard ratio [HR], 0.69; confidence interval [CI], 0.54 to 0.89) in the 2,314 participants with mild chronic renal insufficiency. Rates of major coronary events (adjusted HR, 0.67; CI, 0.56 to 0.79) and coronary revascularization (adjusted HR, 0.62; CI, 0.49 to 0.77) also were significantly lower in the simvastatin group. No significant decreases in stroke incidence were observed in the simvastatin group (adjusted HR, 0.88; CI, 0.55 to 1.39). The side-effect profile was similar between the 2 treatment groups.



Simvastatin therapy appears to be effective and safe for the secondary prevention of all-cause mortality and major coronary events in patients with mild chronic renal dysfunction.

title: Long-term fluvastatin reduces the hazardous effect of renal impairment on four-year atherosclerotic outcomes (a LIPS substudy).
abstract: Mild renal impairment is an important risk factor for late cardiovascular complications. This substudy of the Lescol Intervention Prevention Study (LIPS) assessed the effect of fluvastatin on outcome of patients who had renal dysfunction and those who did not. Complete data for creatinine clearance calculation (Cockcroft-Gault formula) were available for 1,558 patients (92.9% of the LIPS population). Patients were randomized to fluvastatin or placebo after successful completion of a first percutaneous coronary intervention. Follow-up time was 3 to 4 years. The effect of baseline creatinine clearance on coronary atherosclerotic events (cardiac death, nonfatal myocardial infarction, and coronary reinterventions not related to restenosis) was evaluated. Baseline creatinine clearance (logarithmic transformation) was inversely associated with an incidence of adverse events among patients who received placebo (hazard ratio 0.99, 95% confidence interval 0.982 to 0.998, p = 0.01). However, no association was noted between creatinine clearance and the incidence of adverse events among patients who received fluvastatin (hazard ratio 1.0, 95% confidence interval 0.99 to 1.0, p = 0.63). No further deterioration in creatinine clearance was observed during follow-up, regardless of baseline renal function or allocated treatment. Occurrence of adverse events was not related to changes in renal function during follow-up. Fluvastatin therapy markedly decreased the risk of coronary atherosclerotic events after percutaneous intervention in patients who had lower values of creatinine clearance at baseline. The benefit of fluvastatin was unrelated to any effect on renal function.

title: Effect of lovastatin on primary prevention of cardiovascular events in mild CKD and kidney function loss: a post hoc analysis of the Air Force/Texas Coronary Atherosclerosis Prevention Study.
abstract: Chronic kidney disease (CKD) is associated with an increased risk of incident cardiovascular disease (CVD); however, the role of statins for the primary prevention of acute cardiovascular events in patients with CKD and the effect of statins on kidney function loss in persons without prevalent CVD have not been studied.



Post hoc analysis of the Air Force/Texas Coronary Atherosclerosis Prevention Study.



Multicenter, randomized, double-blind, placebo-controlled trial of 5,608 men and 997 women without CVD randomly assigned to treatment with lovastatin or placebo.



Placebo or lovastatin, 20 mg/d.



First major acute cardiovascular event in participants with mild CKD and kidney function loss in persons with or without CKD. Estimated glomerular filtration rate was calculated using the 4-variable Modification of Diet in Renal Disease Study equation.



At baseline, mean estimated glomerular filtration rate in participants with CKD (n = 304) was 53.0 +/- 6.0 mL/min/1.73 m(2). After an average follow-up of 5.3 +/- 0.8 years, the incidence of a fatal and nonfatal CVD event was lower in participants with CKD receiving lovastatin than in those receiving placebo (adjusted relative risk [RR], 0.31; 95% CI, 0.13-0.72; P = 0.01). Tests for interaction suggested that the benefit of lovastatin was independent of the presence of CKD. Lovastatin did not reduce the annualized mean decrease in estimated glomerular filtration rate (-1.3 +/- 0.07 vs -1.4 +/- 0.07 mL/min/1.73 m(2)/y, respectively; P = 0.1) or the frequency of a > or = 25% decrease in kidney function (adjusted RR, 1.10; 95% CI, 0.96-1.28; P = 0.2) or incident CKD (adjusted RR, 1.04; 95% CI, 0.86-1.27; P = 0.6).



Unable to determine the cause and duration of kidney disease, and information regarding proteinuria was not available.



Lovastatin is effective for the primary prevention of CVD in patients with CKD, but is not effective in decreasing kidney function loss in persons with no CVD.

title: Pravastatin for Secondary Prevention of Cardiovascular Events in Persons with Mild Chronic Renal Insufficiency
abstract: Are statins effective and safe in patients with renal insufficiency?  This subgroup analysis of a large randomized, double-blind, placebo-controlled trial shows that pravastatin reduces risk for future cardiovascular events in men and women with recent myocardial infarction, total cholesterol level less than 6.21 mmol/L (240 mg/dL), and mild renal insufficiency. Adverse events were few and were similar in nature and frequency to those that have been reported in patients without renal insufficiency.  Pravastatin appears to be safe and effective for secondary prevention of cardiovascular events in patients with mild chronic renal insufficiency. The Editors Chronic renal insufficiency is a common condition that may affect as many as 6 million Americans (1) and is associated with high rates of cardiovascular disease. Regardless of diabetic status, persons with chronic renal insufficiency have cardiovascular mortality rates at least 10 times higher than the general population (2). This excess burden of illness appears to be due to a higher prevalence of traditional cardiovascular risks (3-5) and possibly also to nontraditional risk factors, such as homocysteinemia, hyperparathyroidism, and chronic inflammation (6, 7). Chronic renal insufficiency encompasses all levels of renal dysfunction, up to and including dialysis dependence, but an emerging body of literature suggests that even very mild renal disease increases cardiovascular risk (8-10). Although there is no universally accepted definition of chronic renal insufficiency, previous studies on cardiovascular disease have used creatinine clearance less than or equal to 75 mL/min to identify persons with this condition (11, 12). Drugs that inhibit 3-hydroxy-3methylglutaryl coenzyme A reductase (statins) are known to reduce mortality in hyperlipidemic persons with coronary disease in the general population (13). However, no published information is available about the efficacy of statins in persons who also have chronic renal insufficiency. Surprisingly, the prevalence of statin use in this subgroup is less than 25% (11). There is no a priori reason to suspect that statins would be less effective in chronic renal insufficiency; however, lack of proven efficacy or concerns about toxicity may contribute to nonprescription in patients with this condition. To evaluate the efficacy and safety of pravastatin in chronic renal insufficiency, we analyzed data from a subset of participants in a previously conducted randomized trial who had a creatinine clearance less than or equal to 75 mL/min.  Study Group and Design The design of the Cholesterol and Recurrent Events (CARE) trial has been described in detail elsewhere (14). Briefly, this was a randomized, double-blind, placebo-controlled trial in men and postmenopausal women who had had acute myocardial infarction between 3 and 20 months before randomization and had total plasma cholesterol levels less than 6.21 mmol/L (<240 mg/dL). Participants with 2+ proteinuria or greater on routine dipstick testing or serum creatinine values more than 1.5 times the upper limit of normal (as defined by the central study laboratory) were specifically excluded from the CARE study. After stratification according to clinical center, eligible persons were assigned by computer-generated random order to receive 40 mg of pravastatin (Pravachol, Bristol-Myers Squibb, Princeton, New Jersey) once daily, or placebo. Treatment allocation was concealed by a centrally maintained code. Participants continued to take all prescribed medication that they were receiving at baseline. All study-specific laboratory measurements were performed at a central facility. Our analysis used the same cardiovascular end points specified by the original CARE trial. The primary end point was death from coronary disease (including fatal myocardial infarction, sudden death, death during a coronary intervention, and death from other coronary causes) or a symptomatic nonfatal myocardial infarction confirmed by serum creatine kinase measurements. Secondary end points included major coronary events (fatal coronary disease, nonfatal myocardial infarction, coronary artery bypass surgery, or coronary angioplasty), all-cause mortality, stroke, and coronary revascularization. A committee that was blinded to serum lipid levels and treatment assignment determined outcomes. The adequacy of blinding was not formally assessed. Definitions of Renal Insufficiency The CockcroftGault equation for creatinine clearance is widely used and is known to correlate well with glomerular filtration rate (15). We initially selected a creatinine clearance less than or equal to 75 mL/min as our primary definition of mild chronic renal insufficiency. Recently published guidelines suggest defining renal function in terms of an equation derived from the Modification of Diet in Renal Disease (MDRD) Study (16). This equation expresses glomerular filtration rate in mL/min per 1.73 m2 of body surface area and is defined by 186 PCr 1.154 age in years 0.203 1.210 (if black) 0.742 (if female), where PCr is plasma creatinine concentration in mg/dL. Mildly decreased glomerular filtration rate is defined as 60 to 89 mL/min per 1.73 m2. Although the MDRD equation has not been used as extensively as the CockcroftGault equation, its use is becoming more common. We performed additional analyses by defining mild chronic renal insufficiency as a glomerular filtration rate less than 75 mL/min per 1.73 m2. Subgroup Analysis We performed several additional analyses to evaluate the potential interactions among pravastatin use, chronic renal insufficiency, and certain subgroups. These subgroups were determined according to published recommendations (17) and were defined by diabetic status, serum lipid levels at baseline, different levels of renal function, and proteinuria (defined as detectable protein on routine urine dipstick testing). Statistical Analysis All analyses were performed on an intention-to-treat basis; P values are two sided. The effect of pravastatin on the rate of the primary end point was assessed by using the log-rank test. All other hazard ratios (HRs) and associated 95% CIs were assessed with Cox proportional-hazards models, adjusting for covariates that might confound the relationship between treatment assignment and outcomes. Review of the loglog survival curves for each model showed no evidence that the proportional hazards assumption was violated. There was no evidence of effect modification by center, and stratifying models by center did not affect the results. Analyses were performed by using SAS software, version 8.2 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Source The CARE trial and this substudy on renal insufficiency are investigator-initiated studies funded by Bristol-Myers Squibb. The data were collected and analyzed by and are now maintained at the coordinating center at the University of Texas School of Public Health, Houston, Texas. The authors had unlimited access to the data used in this analysis. The sponsor is entitled to comment on manuscripts before submission, and the authors may consider these comments, but the rights to publication reside contractually with the investigators. The sponsor maintained information on adverse events and other trial data, as required by federal regulations.  Baseline Characteristics Of the 4159 persons in the original trial, 1711 had chronic renal insufficiency according to the primary definition (creatinine clearance 75 mL/min) . Participants with renal insufficiency were older, were more likely to be women and to have a history of hypertension or congestive heart failure, and had slightly higher systolic blood pressure than those without renal insufficiency. Dipstick-positive proteinuria was slightly more common in persons with chronic renal insufficiency. Persons with renal insufficiency in the pravastatin and placebo groups were similar at baseline (Table 1).  Flow of participants through the study. Table 1. Baseline Characteristics in Participants according to Creatinine Clearance and Treatment Status Adherence to Therapy and Use of Co-Medications Rates of therapy discontinuation between the pravastatin and placebo groups were similar among participants with renal insufficiency (46 of 844 participants vs. 54 of 867 participants; P >0.2). Rates of use of -adrenergic blockers, aspirin, and angiotensin-converting enzyme inhibitors were similar between treatment groups at baseline and during annual follow-up visits. Angiotensin-receptor antagonists were not widely available when the CARE study was conducted. Cardiovascular Event Rates in Participants with Chronic Renal Insufficiency The cumulative incidence of the primary end point and of major coronary events were similar in persons with and without chronic renal insufficiency. Two hundred fifteen of the 1711 participants with renal insufficiency experienced the primary end point, compared with 271 of the 2448 participants with normal renal function (11.1%) (adjusted HR, 1.20 [95% CI, 0.94 to 1.51]). Participants with chronic renal insufficiency had higher rates of all-cause mortality (unadjusted HR, 1.63 [CI, 1.33 to 2.00]) and stroke (unadjusted HR, 1.98 [CI, 1.40 to 2.80]) than those without. However, after adjustment for baseline factors, these differences were no longer statistically significant. Pravastatin Use in Chronic Renal Insufficiency Median duration of follow-up was 58.9 months in the participants with chronic renal insufficiency; complete follow-up data were available for all participants in this subgroup. Persons in the pravastatin group with and without renal insufficiency had similar changes in plasma lipid levels in response to therapy. Among those with renal insufficiency, pravastatin was associated with statistically significant reductions in mean low-density lipoprotein cholesterol level (by 0.96 m

title: Epidemiology of cardiovascular disease in chronic renal disease.
abstract: The risk of cardiovascular disease in patients with chronic renal disease appears to be far greater than in the general population. For example, among patients treated by hemodialysis or peritoneal dialysis, the prevalence of coronary artery disease is approximately 40% and the prevalence of left ventricular hypertrophy is approximately 75%. Cardiovascular mortality has been estimated to be approximately 9% per year. Even after stratification by age, gender, race, and the presence or absence of diabetes, cardiovascular mortality in dialysis patients is 10 to 20 times higher than in the general population. Patients with chronic renal disease should be considered in the highest risk group for subsequent cardiovascular events. Cardiac failure is more common in chronic renal disease patients than in the general population, and is an independent predictor of death in chronic renal disease. Among hemodialysis and peritoneal dialysis patients, the prevalence of cardiac failure is approximately 40%. Both coronary artery disease and left ventricular hypertrophy are risk factors for the development of cardiac failure. In practice, it is difficult to determine whether cardiac failure reflects left ventricular dysfunction or extracellular fluid volume overload. Patients who develop clinical manifestations of cardiac failure should be evaluated for cardiovascular disease.

title: Association between cholesterol level and mortality in dialysis patients: role of inflammation and malnutrition
abstract: ContextTotal cholesterol level is inversely associated with mortality in dialysis
patients, a group at high risk of cardiovascular disease (CVD). This paradox
may be explained by systemic inflammation and/or malnutrition, which are associated
with lower cholesterol levels and higher mortality.ObjectiveTo determine the relationship between cholesterol level and outcome
in patients undergoing dialysis, accounting for inflammation and malnutrition.
1998 who recently initiated dialysis, from 79 clinics, classified by absence
or presence of inflammation and/or malnutrition (defined as serum albumin
levels <3.6 mg/dL, C-reactive protein ≥10 mg/L, or interleukin 6 ≥3.09
pg/mL).Main Outcome MeasuresAll-cause and cardiovascular disease mortality.ResultsDuring a median follow-up of 2.4 years, 324 deaths (159 CVD deaths),
153 renal transplantations, and 10 losses to follow-up occurred. Average serum
cholesterol level was lower in the presence of inflammation/malnutrition than
in its absence. In a Cox model adjusted for age, race, and sex, a 40-mg/dL
(1.0-mmol/L) increment in baseline total serum cholesterol level was associated
with a decreased risk of all-cause mortality overall (relative hazard [RH],
0.92; 95% confidence interval [CI], 0.87-0.98) and in the presence of inflammation/malnutrition
(RH, 0.89; CI, 0.84-0.95). In contrast, serum cholesterol level was associated
with an increased risk in the absence of inflammation/malnutrition (RH, 1.32;
95% CI, 1.07-1.63). For CVD mortality, an inverse trend was not statistically
significant in the presence of inflammation/malnutrition, and a positive association
was evident in the absence of inflammation/malnutrition (RH, 1.41; 95% CI,
1.04-1.89). Further adjustment for traditional CVD risk factors, dialysis
modality, comorbidity, and inflammatory markers attenuated the inverse association
but strengthened the positive association.ConclusionsThe inverse association of total cholesterol level with mortality in
dialysis patients is likely due to the cholesterol-lowering effect of systemic
inflammation and malnutrition, not to a protective effect of high cholesterol
concentrations. These findings support treatment of hypercholesterolemia in
this population.

title: Statin effects beyond lipid lowering--are they clinically relevant?
abstract: Currently, five different statins (simvastatin,pravastatin, lovastatin, fluvastatin, and atorvastatin) are approved for treatment of hypercholesterolemia in humans and two new compounds (rosuvastatin and NK-104) are under investigation.1,2 Despite differences in their pharmacokinetic profiles, all statins have at least onecharacteristic in common: they block the conversion of HMG-CoA to mevalonic acid with consecutive attenuation of the biosynthesis of cholesterol , which is associated with a reduction in serum total and low-density lipoprotein (LDL) cholesterol of as much as 20–31 and 28–42% during chronic treatment.3 Because of these properties, statins have become the most widely prescribed lipid-lowering drugs in patients with elevatedserum cholesterol levels. Several large trialsdemonstrated that statins are not only safe and well tolerated but also significantly decrease cardiovascular morbidity and mortality in hypercholesterolemic patients in both primary and secondary prevention.4–8 However, the striking benefit achieved with statin treatment in patients with a wide range of cholesterol levels, which cannot be attributed to their cholesterol lowering effect alone, has raised the question about the possible presence of additional effects of statins beyond their impact on serum cholesterol levels. Indeed, in recent years a substantial quantity of data has accumulated showing that statins exert variouseffects on multiple targets, which are independent of their plasma cholesterol lowering properties.



Fig. 1 
The effect of statins on the mevalonate pathway. Statins inhibit conversion of HMG-CoA to mevalonate by competitive inhibition of the rate limiting enzyme HMG-CoA reductase. Herewith, statins not only inhibit the cellular production of cholesterol but also the biosynthesis of several intermediates of the mevalonate pathway (e.g. farnesylpyrophosphate and geranylgeranylpyrophosphate). These so-called isoprenoids are essential for the posttranslational modification of several proteins involved in important intracellular signaling pathways (e.g. the small GTP-binding proteins Ras and Rho).



Many of these so-called pleiotropic effects have been shown to be secondary to the …