Background
Patients with end-stage renal disease (ESRD) undergoing haemodialysis have substantially higher cardiovascular disease mortality rates than the general population [
1‐
5]. Accelerated atherosclerosis has been observed in haemodialysis patients [
6] and may contribute to this increased cardiovascular event rate. Treatment of ESRD and its cardiovascular consequences places a large burden upon healthcare providers, and the cost and prevalence are expected to increase greatly over the next decade [
5]. Therefore, controlling risk factors for atherosclerosis may play an important role in preventing cardiovascular events in these individuals.
Hydroxy-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been demonstrated to reduce coronary heart disease morbidity and mortality in several landmark trials [
7‐
14]. The reductions in cardiovascular events also occur in patients with average to lower than average baseline low-density lipoprotein cholesterol (LDL-C) levels [
12,
14] and the benefits of statin therapy can be independent of lipid lowering [
15]. Most haemodialysis patients do not have elevated cholesterol (total and LDL-C) [
16,
17], and the highest mortality risk is often in patients with very low cholesterol levels [
18]. Other chronic diseases and malnutrition may act to lower blood cholesterol and independently increase the risk of death, thereby contributing to the negative association between very low cholesterol and mortality observed in these patients [
19,
20]. Indeed, a recent prospective study suggests that levels of total cholesterol (TC) may be associated with mortality in haemodialysis patients without evidence of inflammation and malnutrition [
20]. Haemodialysis patients have other lipid abnormalities such as lower levels of high-density lipoprotein cholesterol (HDL-C) and elevated intermediate-density lipoprotein (IDL) and triglycerides [
16,
17].
Although the efficacy of statins is well established in conditions associated with increased cardiovascular risk, dialysis patients have generally been excluded from statin outcome trials because of their related co-morbidities and as a result of pharmacokinetic and safety issues. It is not appropriate to extrapolate evidence from patients with normal renal function to patients with ESRD on haemodialysis, and there is a need to investigate the benefit-risk profile of statins specifically in this population. Data from an observational study indicate that statin treatment may improve survival in patients with ESRD [
21]. Mortality was 32% lower in patients with ESRD who received statin treatment compared with patients not receiving statins, a finding that is consistent with other large outcome statin trials [
7,
8,
11]. However, observational studies do not establish a causal relationship and large-scale randomised studies are required [
22]. The Die Deutsche Diabetes Dialyse Studie (4D study) investigated the effect of atorvastatin 20 mg or placebo on cardiovascular mortality, non-fatal myocardial infarction and stroke in 1,255 patients with type 2 diabetes who were on haemodialysis treatment for no more than 2 years [
23]. Initial results presented at the annual meeting of the American Society of Nephrology indicate that the primary endpoint was reduced by 8% after 4 years' treatment with atorvastatin, but this was not significantly different from placebo [
24]. Further large-scale long-term prospective, randomised studies are required to investigate the efficacy and safety of statins for reducing cardiovascular morbidity and mortality, specifically in ESRD patients on haemodialysis [
22].
Rosuvastatin is the most efficacious of the available statins for lowering LDL-C levels, causing reductions of 47% at the initial starting dose of 10 mg [
25]. In addition, rosuvastatin has benefits across the lipid profile, including increases in HDL-C, reductions in small dense LDL and triglyceride-rich lipoprotein particles [
25,
26], and has a safety profile consistent with other available statins [
27]. These properties make it an ideal agent for a study investigating the benefits of statin treatment for the prevention of cardiovascular events in a population of patients at high risk of cardiovascular events. AURORA (A study to evaluate the Use of Rosuvastatin in subjects On Regular haemodialysis: an Assessment of survival and cardiovascular events) is the first large-scale international trial to assess the effects of a statin on cardiovascular morbidity and mortality in ESRD patients on chronic haemodialysis irrespective of baseline lipid levels.
Discussion
Patients with ESRD have an increased risk of cardiovascular morbidity and mortality [
2,
4], and this contributes to the large burden this disease places upon healthcare providers [
5]. A number of studies have indicated that patients on dialysis with very low TC levels have a higher rate of mortality [
18,
20]. Both small dense LDL and triglyceride-rich lipoproteins have been implicated in the development of cardiovascular disease [
29‐
32] and are common in patients with ESRD and on haemodialysis [
16,
33‐
37]. Triglyceride-rich lipoproteins, in particular IDL, are prevalent and predictive of atherosclerosis in haemodialysis patients [
17]. Thus, modifying lipid levels with a statin should have beneficial effects on cardiovascular outcomes in these patients. Large outcome studies also indicate that the positive effects of statins occur irrespective of baseline lipid levels [
12,
14]. While the efficacy of statins for altering the lipid profile has been studied previously in ESRD patients [
38‐
42], their long-term benefits on cardiovascular outcomes in this population have not yet been examined and dialysis patients have generally been excluded from statin outcome trials.
Several studies examining outcome after statin treatment have recently been completed or are in progress in patients with related conditions. In a study in renal transplant patients, fluvastatin reduced the risk of cardiac death or non-fatal myocardial infarction by 35% compared with subjects receiving placebo (risk ratio 0.65 [95% confidence intervals 0.48–0.88]; p = 0.005) [
43]. Initial findings of the 4D study did not demonstrate a significant difference between atorvastatin 20 mg and placebo treatment; however, LDL-C levels were reduced during the study period [
24]. Another study is ongoing; the Study of Heart And Renal Protection (SHARP) aims to assess the effects of simvastatin and the cholesterol-absorption inhibitor ezetimibe among patients with chronic kidney disease [
18]. AURORA is the first international, prospective, randomised, double-blind, placebo-controlled study to assess whether statin therapy alone can reduce the incidence of coronary events in ESRD patients on chronic haemodialysis.
Most haemodialysis patients do not have elevated LDL-C and, in accordance with findings from the Heart Protection Study, the AURORA trial will randomise patients irrespective of their baseline lipid levels [
12]. Patients on haemodialysis have lower levels of HDL-C and higher triglycerides compared with control subjects [
16]. Accordingly, a statin with efficacy across the lipid profile would be appropriate to assess the benefits of treatment in ESRD patients. Rosuvastatin is the most efficacious statin reported for lowering LDL-C [
44], and has benefits across the lipid profile. In a study of hypercholesterolaemic patients, rosuvastatin has been shown to increase HDL-C by 7.7–9.6% compared with 4.4–5.7% for atorvastatin and 5.2–6.0% for simvastatin across the 10–40 mg dose range [
44]. In addition, rosuvastatin has been shown to substantially lower triglyceride-rich lipoproteins in both hypercholesterolaemic and hypertriglyceridaemic patients [
45]. The effects of haemodialysis upon excretion of statins should also be considered. On the basis of pharmacokinetic, pharmacodynamic and safety data obtained from a pilot study, rosuvastatin 10 mg can be safely administered to patients with ESRD on chronic haemodialysis (data on file, AstraZeneca).
In addition to their ability to modify lipid levels, statins produce other effects that may benefit ESRD patients. Oxidative stress has been implicated in the pathogenesis of cardiovascular disease, and it is enhanced in patients with renal insufficiency [
46,
47]. Recently, statins have been reported to have anti-oxidant effects [
48], which may be of benefit to these patients. Statins may also have additional non-lipid or pleiotropic effects, for example, improving endothelial function [
15]. Endothelial dysfunction has been implicated in the development of cardiovascular disease and has been shown to be closely associated with the degree of renal insufficiency [
49]. Pre-clinical experiments have shown that rosuvastatin can improve endothelial function [
50], although this has yet to be verified in a clinical situation. Finally, left ventricular hypertrophy and heart failure can also develop in ESRD patients on haemodialysis [
51]. Statin therapy has been reported to reduce left ventricular hypertrophy [
52] and retrospective analyses indicate that these agents can also help to prevent heart failure [
53]. These properties could provide an additional beneficial effect in ESRD patients.
The AURORA study should provide valuable information on the utility of statin treatment for the reduction of cardiovascular events in patients with ESRD. As an atherogenic lipid profile and endothelial dysfunction are often present in individuals with ESRD and contribute to the development of atherosclerosis, it is anticipated that rosuvastatin will improve cardiovascular outcomes in this patient population. Furthermore, it is hoped that AURORA will produce data on the cost effectiveness (cost due to hospitalisation and cost per year of life saved) and long-term safety of rosuvastatin treatment in ESRD patients receiving chronic haemodialysis. This study will also generate a large database of information from a well-documented cohort, which may be valuable in the epidemiological evaluation of cardiovascular risk in patients with ESRD.
Appendix
Executive Steering Committee
Professor B Fellström (Principal Investigator; Uppsala, Sweden), Professor F Zannad (Toul, France), Professor R Schmieder (Erlangen, Germany), Dr H Holdaas (Olso, Norway), Dr A Jardine (Glasgow, UK).
Steering Committee
Executive Steering Committee members plus Dr K Bannister (Adelaide, Australia), Dr J Beutler (Utrecht, The Netherlands), Professor D Chae (Kyungki-Do, South Korea), Professor SM Cobbe (Glasgow, UK), Dr B Espinoza Vazquez (Colonia Toriello Guerra, Mexico), Professor C Gronhagen-Riska (Helsinki, Finland), Dr J Lima (Sao Paulo, Brazil), Professor R Lins (Antwerpen, Belgium), Dr A McMahon (Edmonton, Canada), Professor G Mayer (Innsbruck, Austria), Professor H Parving (Gentofte, Denmark), Professor G Remuzzi (Bergamo, Italy), Dr O Samuelsson (Goteborg, Sweden), Professor S Sonkodi (Szeged, Hungary), Dr G Suleymanlar (Antalya, Turkey), Professor V Tesar (Prague, Czech Republic), Dr D Tsakiris (Veria, Greece), Professor V Todorov (Pleven, Bulgaria), Professor A Wiecek (Katowice, Poland), Professor R Wûthrich (Gallen, Switzerland).
Data and Safety Monitoring Board
Professor H Dargie (Chair; Glasgow, UK), Professor E Ritz (Heidelberg, Germany), Professor H Wedel (Goteborg, Sweden), Professor AH Zwinderman (Amsterdam, The Netherlands).
Clinical Endpoint Committee
Professor SM Cobbe (Chair; Glasgow, UK), Dr A Brady (Glasgow, UK), Dr C Deighan (Glasgow, UK), Dr A Gaw (Glasgow, UK), Professor P Macfarlane (Glasgow, UK), Professor D Stott (Glasgow, UK).
Competing interests
This study is sponsored by AstraZeneca. The authors also have affiliations with other pharmaceutical companies including Pfizer (AJ, BF, HH, RS, FZ), Bristol-Myers Squibb (AJ, HH, RS), Novartis (AJ, BF, HH, RS, FZ), Fujisawa (AJ, BF), Roche (AJ, BF, HH, RS), Merck (AJ, BF, HH, RS), Schering-Plough (BF, HH), Wyeth (AJ, BF), GlaxoSmithKline (AJ, BF, HH), Servier (AJ), Actelion (AJ), Pharmalink (BF). These relate to personal or institutional-affiliated receipt of income in the areas: Research grants, honoraria and Consultant fees presently or during the last five years. The authors WW and HR are employed by AstraZeneca.
Authors' contributions
Author BF is the Principal Investigator of the study and contributed to the concept and design of the study
Authors FZ, RS, HH, AJ and WW contributed to the design of the study
Author HR contributed to the planned statistical analyses of the study and sample size determination.
All authors read and approved the final manuscript.