In this trial, we examined the potential benefits of statin therapy with regard to the increased cardiovascular risk associated with maintenance hemodialysis therapy.1,2,4,16,17 We found no effect of rosuvastatin on the primary end point of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. Analyses of individual components of the primary end point and of several secondary end points were consistent with the main finding. Rosuvastatin had no benefit in any subgroup examined, including patients with diabetes.16,17

The lack of a benefit of rosuvastatin was observed despite a mean 43% reduction in the LDL cholesterol level at 3 months and the expected benefits with regard to other lipid levels.3,6-10,14 As expected in a population of patients undergoing hemodialysis, baseline cholesterol levels were not high. However, in the subgroup analyses (Figure 3), there was no benefit at any baseline LDL cholesterol level or in groups with preexisting cardiovascular disease, regardless of the lipid level. Previous studies4 have shown an inconsistent (or inverse) relationship between the LDL cholesterol level and outcomes in patients undergoing hemodialysis.1,2,4 Our findings suggest that in such patients, a reduction of the LDL cholesterol level with statins does not necessarily reduce cardiovascular risk.

In the 4D study,14,18 1225 patients with type 2 diabetes undergoing maintenance hemodialysis received either atorvastatin at a dose of 20 mg or placebo. Although the median LDL cholesterol level was reduced by 42% with atorvastatin, there was no significant reduction in the composite primary cardiovascular end point. In contrast, previous trials and post hoc analyses have shown benefits of statin therapy in patients with diabetes, including diabetes with less advanced chronic kidney disease.19-22 The lack of a benefit of statin therapy in the 4D and AURORA studies suggests that cardiovascular disease in patients undergoing hemodialysis differs from that in other patients.23,24

Other trials examining cardiovascular outcomes in patients with chronic kidney disease have been limited to post hoc assessments of patients recruited for cardiovascular prevention trials,19-21 studies of modest size,22 and studies involving patients treated by means of renal transplantation.3,25 In these studies, statin therapy has been shown to reduce the incidence of cardiovascular events.6-10,26 These results contrast with the lack of benefit in patients undergoing hemodialysis seen in our trial and raise the questions of whether statin therapy becomes ineffective with worsening renal disease and, if so, at which stage? These questions may be answered by the ongoing Study of Heart and Renal Protection (SHARP) (ClinicalTrials.gov number, NCT00125593),27 which will evaluate the benefit of simvastatin plus ezetimibe in patients across the spectrum of renal dysfunction.

There are several caveats to consider with regard to interpretation of our results. First, we excluded patients who were already receiving statins. Although we do not have a registry that would enable us to examine this excluded group systematically, we estimate that it may account for as many as 35 to 40% of all patients with end-stage renal disease. This group may include patients who had previously had cardiac events or had undergone cardiovascular interventions and may also include patients for whom statins were initiated at earlier stages of progressive kidney disease. We also observed a lower-than-predicted yearly event rate for the primary end point.1,2,16,28 Thus, we cannot rule out selection bias or the possibility that investigators excluded patients whom they believed warranted statin therapy.

Another issue is that we recruited patients who were 50 to 80 years of age, even though the increase in cardiovascular risk affects all age groups of patients undergoing hemodialysis therapy28 and is disproportionately higher among younger patients. Thus, possible benefits in younger patients, most of whom will ultimately receive transplants, were not explored in our trial. Finally, a high proportion of patients discontinued the study medication during the study; this is a reflection of the difficulties in performing clinical trials in this population, with high incidences of adverse events and hospitalization for coexisting illness, as well as the unpredictable availability of renal transplants. The main reasons for discontinuation of therapy were transplantation, adverse events, and study end points. It is possible that the withdrawal rate masks the potential benefit of statin therapy, although the high discontinuation rate is partly a consequence of the high event rate and is consistent with the findings of the 4D study.14,18

Increasingly, the benefits of statin therapy are attributed to pleiotropic effects that are independent of a lowering of the LDL cholesterol level, and they include improvements with respect to endothelial function and inflammation29 and a reduction of the high-sensitivity C-reactive protein level. In the recent Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) (NCT00239681),10 involving subjects without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels (≥2.0 mg per liter), rosuvastatin reduced both the high-sensitivity C-reactive protein level (by 37%) and major cardiovascular events (by 44%). In contrast, in our trial, although high-sensitivity C-reactive protein levels were elevated at baseline (by 5.0 mg per liter) and were decreased by rosuvastatin, there was no reduction in cardiovascular events. This finding may reflect different causes of elevated high-sensitivity C-reactive protein levels in patients undergoing hemodialysis.

AURORA and 4D are not the only studies to show a lack of benefit of statin therapy in specific populations. Patients in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) (NCT00206310)30 and the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca Heart Failure Study (GISSI-HF) (NCT00336336)31 trial had heart failure and low ejection fractions. Like the patient population in our study, patients in these two trials had advanced disease associated with coexisting conditions and had significant reductions in lipid and high-sensitivity C-reactive protein levels with statin treatment, but no reduction in cardiovascular end points.

Safety concerns have limited the use of statin therapy in patients with renal disease.1,2 We observed no increase in the incidence of muscle-related adverse events, rhabdomyolysis, or liver disease in the rosuvastatin group as compared with the placebo group. Five cases of rhabdomyolysis were reported during the trial (in two patients receiving placebo and in three patients receiving rosuvastatin). Concern has also been expressed about an excess risk of cancer related to statin therapy,32,33 but no increase in the number of new cancer diagnoses was seen in our trial. In the 4D study,14,18 atorvastatin was associated with an increased incidence of stroke, although the numbers were small. We found no significant effect of rosuvastatin on the incidence of stroke, but there was a marginal increase in hemorrhagic strokes in patients with diabetes who received rosuvastatin (12 events, vs. 2 events in patients with diabetes in the placebo group; P=0.03), which is consistent with the findings of the 4D study.14,18 Although concern was expressed about an increase in physician-reported cases of diabetes with rosuvastatin in the JUPITER trial,10 we did not find an excess of new-onset diabetes.

In conclusion, the AURORA trial evaluated the effect of rosuvastatin on cardiovascular events in a population of patients with end-stage renal disease. Despite significantly reducing the levels of LDL cholesterol and high-sensitivity C-reactive protein, treatment with rosuvastatin was not associated with a reduction in the combined end point of myocardial infarction, stroke, or death from cardiovascular causes.