Background: Statins reduce the incidence of cardiovascular events in patients at high cardiovascular risk. However, a benefit of statins in such patients who are undergoing hemodialysis has not been proved.

Methods: We conducted an international, multicenter, randomized, double-blind, prospective trial involving 2,776 patients, 50–80 years of age, who were undergoing maintenance hemodialysis. We randomly assigned patients to receive rosuvastatin, 10 mg daily, or placebo. The combined primary endpoint was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary endpoints included death from all causes and individual cardiac and vascular events.

Results: After 3 months, the mean reduction in low-density lipoprotein (LDL) cholesterol levels was 43 % in patients receiving rosuvastatin, from a mean baseline level of 100 mg/dL (2.6 mmol/L). During a median follow-up period of 3.8 years, 396 patients in the rosuvastatin group and 408 patients in the placebo group reached the primary endpoint (9.2 and 9.5 events per 100 patient-years, respectively; hazard ratio for the combined endpoint in the rosuvastatin group vs. the placebo group, 0.96; 95 % confidence interval [CI], 0.84–1.11; P = 0.59). Rosuvastatin had no effect on individual components of the primary endpoint. There was also no significant effect on all-cause mortality (13.5 vs. 14.0 events per 100 patient-years; hazard ratio, 0.96; 95 % CI, 0.86–1.07; P = 0.51).

Conclusions: In patients undergoing hemodialysis, the initiation of treatment with rosuvastatin lowered the LDL cholesterol level but had no significant effect on the composite primary endpoint of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (ClinicalTrials.gov number, NCT0024033).

This study complemented the 4D study by expanding participants to include hemodialysis patients secondary to any cause not limiting them to patients with DM only. The negative outcome of 4D prompted AURORA investigators to readjust sample size and reduced the anticipated benefit of statins’ intervention. This was reflected as an increase in the number of primary outcome events required to reach the same level of significance. The investigators avoided the relatively young age in their participants, which is appropriate for the composite endpoint of cardiovascular death and nonfatal MI or stroke.

The active intervention achieved a significant drop of serum total and LDL cholesterol after 3 months of randomization. This reduction should have sufficed to show the anticipated clinical benefit. Convergence of the lipid level curves in both arms toward the end of the study might imply more patients on the placebo arm discontinued their placebo to start different statins (not reported in the study). Such lack of desired difference between both arms in any case would question the intervention value.

It was interesting to see no difference between intention to treat and per protocol analyses. However, the high dropout rate (50 %) [7] and lack of precise definition of cardiovascular death endpoint, even though it was centrally adjudicated, put the study power at risk.

There was a heterogeneity in the duration of time on HD with some patients treated for less than 1 year while others more than 7 years. This may confound the CVD risk profile of these patients and impact power. Also, the inclusion of around 20–25 % of patients with DM may introduce another risk confounder. In fact, a post hoc analysis of AURORA suggested a beneficial and protective effect against CV events and death in diabetic patients treated with rosuvastatin [8]. This observation was at odds with the 4D data that showed no beneficial effect in HD patients with diabetes and even an increased risk of ischemic stroke in those treated with atorvastatin [9].

The variable duration of follow-up is a limitation as some patients were followed up for over 5 years while others less than 12 months. This would clearly impact the risks of dialysis-related events.

The use of composite endpoint is not without its problems, when such endpoints are interrelated and easily overlapping [6].

AURORA was another negative trial of lipid-lowering intervention in patients on hemodialysis.

Background: Lowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischemic stroke, and the need for coronary revascularization 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.