Vera Krane

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

Summary Background 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. Methods 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. This trial is registered at ClinicalTrials.gov, NCT00125593, and ISRCTN54137607. Findings 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). Interpretation 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. Funding Merck/Schering-Plough Pharmaceuticals; Australian National Health and Medical Research Council; British Heart Foundation; UK Medical Research Council.

Study of Heart and Renal Protection (SHARP): Randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease

BACKGROUND Lowering low-density lipoprotein (LDL) cholesterol with statin therapy has been shown to reduce the incidence of atherosclerotic events in many types of patient, but it remains uncertain whether it is of net benefit among people with chronic kidney disease (CKD). METHODS Patients with advanced CKD (blood creatinine ≥ 1.7 mg/dL [≥ 150 μmol/L] in men or ≥ 1.5 mg/dL [ ≥ 130 μmol/L] in women) with no known history of myocardial infarction or coronary revascularization were randomized in a ratio of 4:4:1 to ezetimibe 10 mg plus simvastatin 20 mg daily versus matching placebo versus simvastatin 20 mg daily (with the latter arm rerandomized at 1 year to ezetimibe 10 mg plus simvastatin 20 mg daily vs placebo). The key outcome will be major atherosclerotic events, defined as the combination of myocardial infarction, coronary death, ischemic stroke, or any revascularization procedure. RESULTS A total of 9,438 CKD patients were randomized, of whom 3,056 were on dialysis. Mean age was 61 years, two thirds were male, one fifth had diabetes mellitus, and one sixth had vascular disease. Compared with either placebo or simvastatin alone, allocation to ezetimibe plus simvastatin was not associated with any excess of myopathy, hepatic toxicity, or biliary complications during the first year of follow-up. Compared with placebo, allocation to ezetimibe 10 mg plus simvastatin 20 mg daily yielded average LDL cholesterol differences of 43 mg/dL (1.10 mmol/L) at 1 year and 33 mg/dL (0.85 mmol/L) at 2.5 years. Follow-up is scheduled to continue until August 2010, when all patients will have been followed for at least 4 years. CONCLUSIONS SHARP should provide evidence about the efficacy and safety of lowering LDL cholesterol with the combination of ezetimibe and simvastatin among a wide range of patients with CKD.

Vitamin D deficiency is associated with sudden cardiac death, combined cardiovascular events, and mortality in haemodialysis patients

Aims Dialysis patients experience an excess mortality, predominantly of sudden cardiac death (SCD). Accumulating evidence suggests a role of vitamin D for myocardial and overall health. This study investigated the impact of vitamin D status on cardiovascular outcomes and fatal infections in haemodialysis patients. Methods and results 25-hydroxyvitamin D [25(OH)D] was measured in 1108 diabetic haemodialysis patients who participated in the German Diabetes and Dialysis Study and were followed up for a median of 4 years. By Cox regression analyses, we determined hazard ratios (HR) for pre-specified, adjudicated endpoints according to baseline 25(OH)D levels: SCD (n = 146), myocardial infarction (MI, n = 174), stroke (n = 89), cardiovascular events (CVE, n = 414), death due to heart failure (n = 37), fatal infection (n = 111), and all-cause mortality (n = 545). Patients had a mean age of 66 ± 8 years (54% male) and median 25(OH)D of 39 nmol/L (interquartile range: 28–55). Patients with severe vitamin D deficiency [25(OH)D of≤ 25 nmol/L] had a 3-fold higher risk of SCD compared with those with sufficient 25(OH)D levels >75 nmol/L [HR: 2.99, 95% confidence interval (CI): 1.39–6.40]. Furthermore, CVE and all-cause mortality were strongly increased (HR: 1.78, 95% CI: 1.18–2.69, and HR: 1.74, 95% CI: 1.22–2.47, respectively), all persisting in multivariate models. There were borderline non-significant associations with stroke and fatal infection while MI and deaths due to heart failure were not meaningfully affected. Conclusion Severe vitamin D deficiency was strongly associated with SCD, CVE, and mortality, and there were borderline associations with stroke and fatal infection. Whether vitamin D supplementation decreases adverse outcomes requires further evaluation.

Randomized Controlled Trial on the Efficacy and Safety of Atorvastatin in Patients with Type 2 Diabetes on Hemodialysis (4D Study): Demographic and Baseline Characteristics

Patients with type 2 diabetes on dialysis are at a substantially increased risk of cardiovascular and cerebrovascular diseases. Dyslipidemia characterized by moderately elevated low-density lipoprotein cholesterol and high triglycerides and low high-density lipoprotein cholesterol levels is common in this population. We hypothesized that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors would reduce vascular morbidity and mortality in this patient group. The ‘Deutsche Diabetes Dialyse Studie’ (4D study) is a prospective, randomized, double-blind study involving 178 dialysis centers throughout Germany. Between March 1998 and October 2002, 1,255 patients were randomized to either atorvastatin 20 mg or placebo; 677 men and 578 women, aged 30–83 years, have been enrolled. The study will be terminated as soon as the predefined number of 424 patients with primary combined end points (i.e., cardiovascular death, nonfatal myocardial infarction, or fatal/nonfatal stroke) will have occurred. The total cohort had the following characteristics at baseline: the mean age was 65.7 years, 54% were men, 89% had a history of hypertension, 21% had coronary artery disease, 17.8% had a history of stroke or a transient ischemic attack, and 45% suffered from peripheral arterial disease. The mean time interval between the diagnosis of diabetes and the onset of dialysis was 17.4 years. On average, the patients were on hemodialysis for 8.3 months. Mean lipid and lipoprotein levels were: total cholesterol 219 ± 43 mg/dl, low-density lipoprotein cholesterol 126 ± 30 mg/dl, high-density lipoprotein cholesterol 36 ± 13 mg/dl, and triglycerides 264 ± 167 mg/dl. The results of the study will provide important information on the efficacy and safety of atorvastatin to support its use in patients with an impaired renal function who are at a high risk of vascular morbidity and mortality.

Homoarginine, Cardiovascular Risk, and Mortality

Background— Homoarginine is an amino acid derivative that may increase nitric oxide availability and enhance endothelial function. The effect of the level of homoarginine on cardiovascular outcome and mortality is unknown. Methods and Results— We assessed cardiovascular and all-cause mortality according to homoarginine levels in a cohort of 3305 subjects referred for coronary angiography from the LUdwigshafen RIsk and Cardiovascular Health (LURIC) Study. After investigating the relation of homoarginine with kidney function and markers of endothelial dysfunction, we explored its effects on adverse outcomes in a second high-risk cohort of 1244 patients with type 2 diabetes mellitus receiving maintenance hemodialysis (4D study [Die Deutsche Diabetes Dialyse Studie]). In the LURIC study, mean serum homoarginine levels were 2.6±1.1 &mgr;mol/L. During a median follow-up of 7.7 years, 766 patients died. After adjustments for age and sex, patients in the lowest quartile (<1.85 &mgr;mol/L) had a >4-fold higher rate of dying of cardiovascular disease (hazard ratio 4.1, 95% confidence interval 3.0 to 5.7) than patients in the highest quartile (>3.1 &mgr;mol/L). Lower homoarginine levels were associated with lower estimated glomerular filtration rate and higher levels of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. Hemodialysed patients had lower mean homoarginine levels of 1.2±0.5 &mgr;mol/L and experienced a 5-fold increased mortality rate compared with LURIC patients (608 deaths during a median follow-up of 4 years). Homoarginine consistently affected mortality, which was 2-fold higher in 4D study patients in the lowest quartile (<0.87 &mgr;mol/L) than in patients in the highest quartile (>1.4 &mgr;mol/L). Conclusions— Homoarginine levels are independently associated with cardiovascular and all-cause mortality in patients referred for coronary angiography and in patients undergoing hemodialysis. Future studies are needed to elucidate the underlying pathomechanisms.

Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD

Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR <60ml/min/1.73m2 at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.

Effect of statins on atrial fibrillation: collaborative meta-analysis of published and unpublished evidence from randomised controlled trials

Objective To examine whether statins can reduce the risk of atrial fibrillation. Design Meta-analysis of published and unpublished results from larger scale statin trials, with comparison of the findings against the published results from smaller scale or shorter duration studies. Data sources Medline, Embase, and Cochrane’s CENTRAL up to October 2010. Unpublished data from longer term trials were obtained through contact with investigators. Study selection Randomised controlled trials comparing statin with no statin or comparing high dose versus standard dose statin; all longer term trials had at least 100 participants and at least six months’ follow-up. Results In published data from 13 short term trials (4414 randomised patients, 659 events), statin treatment seemed to reduce the odds of an episode of atrial fibrillation by 39% (odds ratio 0.61, 95% confidence interval 0.51 to 0.74; P<0.001), but there was significant heterogeneity (P<0.001) between the trials. In contrast, among 22 longer term and mostly larger trials of statin versus control (105 791 randomised patients, 2535 events), statin treatment was not associated with a significant reduction in atrial fibrillation (0.95, 0.88 to 1.03; P=0.24) (P<0.001 for test of difference between the two sets of trials). Seven longer term trials of more intensive versus standard statin regimens (28 964 randomised patients and 1419 events) also showed no evidence of a reduction in the risk of atrial fibrillation (1.00, 0.90 to 1.12; P=0.99). Conclusions The suggested beneficial effect of statins on atrial fibrillation from published shorter term studies is not supported by a comprehensive review of published and unpublished evidence from larger scale trials.

Glycemic Control and Cardiovascular Events in Diabetic Hemodialysis Patients

Background— Patients on maintenance dialysis treatment experience an excess mortality, predominantly of sudden cardiac death. Poor glycemic control is associated with cardiovascular comorbidities in the general population. This study investigated the impact of glycemic control on cardiac and vascular outcomes in diabetic hemodialysis patients. Methods and Results— Glycohemoglobin A1c (HbA1c) was measured in 1255 hemodialysis patients with type 2 diabetes mellitus who participated in the German Diabetes and Dialysis Study (4D Study) and were followed up for a median of 4 years. Using Cox regression analyses, we determined hazard ratios to reach prespecified, adjudicated end points according to HbA1c levels at baseline: sudden cardiac death (n=160), myocardial infarction (n=200), stroke (n=103), cardiovascular events (n=469), death caused by heart failure (n=41), and all-cause mortality (n=617). Patients had a mean age of 66±8 years (54% male) and mean HbA1c of 6.7±1.3%. Patients with an HbA1c >8% had a >2-fold higher risk of sudden death compared with those with an HbA1c ≤6% (hazard ratio, 2.14; 95% confidence interval, 1.33 to 3.44), persisting in multivariate models. With each 1% increase in HbA1c, the risk of sudden death rose significantly by 18%; similarly, cardiovascular events and mortality increased by 8%. There was a trend for higher risks of stroke and deaths resulting from heart failure, whereas myocardial infarction was not affected. The increased risks of both cardiovascular events and mortality were explained mainly by the impact of HbA1c on sudden death. Conclusions— Poor glycemic control was strongly associated with sudden cardiac death in diabetic hemodialysis patients, which accounted for increased cardiovascular events and mortality. In contrast, myocardial infarction was not affected. Whether interventions achieving tight glycemic control decrease sudden death requires further evaluation. Clinical Trial Registration— URL: http://www.clinicalstudyresults.org. Unique identifier: CT-981–423–239.

Atorvastatin and Low-Density Lipoprotein Cholesterol in Type 2 Diabetes Mellitus Patients on Hemodialysis

BACKGROUND AND OBJECTIVES Patients undergoing maintenance hemodialysis are at high cardiovascular risk. Lowering LDL-cholesterol with statins reduces the incidence rate of cardiovascular events in patients with chronic kidney disease. In contrast, two randomized, prospective, placebo-controlled trials have been completed in hemodialysis patients that showed no significant effects of statins on cardiovascular outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A post hoc analysis was conducted of the 4D (Die Deutsche Diabetes Dialyze) study to investigate whether LDL-cholesterol at baseline is predictive of cardiovascular events and whether the effect of atorvastatin on clinical outcomes depends on LDL-cholesterol at baseline. RESULTS High concentrations of LDL-cholesterol by tendency increased the risks of cardiac endpoints and all-cause mortality. Concordantly, atorvastatin significantly reduced the rates of adverse outcomes in the highest quartile of LDL-cholesterol (≥145 mg/dl, 3.76 mmol/L). The hazard ratios and 95% confidence intervals were 0.69 (0.48 to 1.00) for the composite primary endpoint, 0.58 (0.34 to 0.99) for cardiac death, 0.48 (0.25 to 0.94) for sudden cardiac death, 0.62 (0.33 to 1.17) for nonfatal myocardial infarction, 0.68 (0.47 to 0.98) for all cardiac events combined, and 0.72 (0.52 to 0.99) for death from all causes, respectively. No such decrease was seen in any of the other quartiles of LDL-cholesterol at baseline. CONCLUSIONS In patients with type 2 diabetes mellitus undergoing hemodialysis, atorvastatin significantly reduces the risk of fatal and nonfatal cardiac events and death from any cause if pretreatment LDL-cholesterol is >145 mg/dl (3.76 mmol/L).

Effects of Lowering LDL Cholesterol on Progression of Kidney Disease

Lowering LDL cholesterol reduces the risk of developing atherosclerotic events in CKD, but the effects of such treatment on progression of kidney disease remain uncertain. Here, 6245 participants with CKD (not on dialysis) were randomly assigned to simvastatin (20 mg) plus ezetimibe (10 mg) daily or matching placebo. The main prespecified renal outcome was ESRD (defined as the initiation of maintenance dialysis or kidney transplantation). During 4.8 years of follow-up, allocation to simvastatin plus ezetimibe resulted in an average LDL cholesterol difference (SEM) of 0.96 (0.02) mmol/L compared with placebo. There was a nonsignificant 3% reduction in the incidence of ESRD (1057 [33.9%] cases with simvastatin plus ezetimibe versus 1084 [34.6%] cases with placebo; rate ratio, 0.97; 95% confidence interval [95% CI], 0.89 to 1.05; P=0.41). Similarly, allocation to simvastatin plus ezetimibe had no significant effect on the prespecified tertiary outcomes of ESRD or death (1477 [47.4%] events with treatment versus 1513 [48.3%] events with placebo; rate ratio, 0.97; 95% CI, 0.90 to 1.04; P=0.34) or ESRD or doubling of baseline creatinine (1189 [38.2%] events with treatment versus 1257 [40.2%] events with placebo; rate ratio, 0.93; 95% CI, 0.86 to 1.01; P=0.09). Exploratory analyses also showed no significant effect on the rate of change in eGFR. Lowering LDL cholesterol by 1 mmol/L did not slow kidney disease progression within 5 years in a wide range of patients with CKD.