AURORA

Published

Fellstrom BC, et al. "Rosuvastatin and Cardiovascular Events in Patients Undergoing Hemodialysis". The New England Journal of Medicine. 2009. 360(14):1395-1407.
PubMed • Full text • PDF

Clinical Question

Among patients with ESRD on HD, does rosuvastatin reduce the incidence of cardiovascular events when compared to placebo?

Bottom Line

Among patients with ESRD on HD, rosuvastatin doesn't reduce the incidence of CVD events when compared to placebo.

Major Points

Adults with CKD experience a greater burden of CVD events that worsens with each successive stage of CKD. As such, those with ESRD on HD experience an incidence of 11 events/100 P-Y, a 10-30x increase in risk compared to the general population. Identifying strategies to reduce the burden of CVD among ESRD is essential.

Statins have been shown to reduce CVD events in the general population at high-risk for cardiovascular events in trials like HPS, WOSCOPS, TNT, LIPID, 4S, and JUPITER and observational studies have suggested a benefit in statin therapy in patients on HD. The 4D study (2005) investigated this issue by randomizing patients with T2DM undergoing HD to either statin therapy or placebo, and found no benefit with statin therapy. The role of statin therapy in the general ESRD population was unknown.

Published in 2009, the Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA) trial randomized 2,773 patients on dialysis to rosuvastatin or placebo. Patients already on statin therapy were excluded. With median follow up of 3.8 years, there was no difference in the primary endpoint of CVD mortality, non-fatal MI, or non-fatal stroke (9.2 vs. 9.5/100 P-Y; P=0.59). There were no differences in the individual CVD endpoints that comprised the primary outcome. A subsequent trial, SHARP (2011), found that the combined use of simvastatin and ezetimibe reduced atherosclerotic events in the general CKD population (N=9,270; HR 0.83; 95% CI 0.74-0.94) but not among a subgroup on dialysis (N=3,023; HR 0.90; 95% CI 0.75-1.08). Two Cochrane reviews examined the role of statins in adults with CKD by HD status. Among those with CKD not on HD, statins lower CVD events and death by 20%. Among those with CKD on HD, statins did not reduce CVD events or death. Together, there is a strong role for statin therapy in pre-ESRD CKD stages but initiation of statin therapy among patients with ESRD on HD is of little utility.

Guidelines

KDIGO Clinical Practice Guidelines for Lipid Management in Chronic Kidney Disease (2013, adapted)

• Among adults with ESRD on HD:
  • Suggest not to initiate a statin or statin/ezetimibe (grade 2A)
  • If already on statin or statin/ezetimibe when initiating HD, suggest continuing these medications (grade 2C)

Design

• International, multicenter, randomized, double-blind, prospective trial
• N=2,776
  • Rosuvastatin 10 mg once daily (n=1,389)
  • Placebo (n=1,384)
• Setting: 280 centers in 25 countries
• Median follow-up: 3.8 years
• Analysis: Intention-to-treat
• Primary outcome: CVD mortality, nonfatal MI, or nonfatal stroke

Population

Inclusion Criteria

• Ages 50-80 years
• ESRD
• HD or hemofiltration for >3 months

Exclusion Criteria

• Statin therapy within past six months
• Expected kidney transplantation within 1 year
• Other disease with short life expectancy
• Malignancy, liver disease (ALT >3x ULN), uncontrolled hypothyroidism, unexplained CK elevation (>3x ULN)

Baseline Characteristics

From the rosuvastatin group.

• Demographics: Age 64 years, female 39%
• Baseline health data: BMI 25 kg/m², BP 137/76 mm Hg, active smoker 14%
• Cholesterol: Total 176, LDL 100, HDL 45, TG 157 mg/dL
• Median hsCRP: 4.8 mg/L
• Duration of dialysis treatment: 3.5 years
• Duration of dialysis sessions: 11.9h/week
• Cause of ESRD: Nephrosclerosis 20%, glomerulonephritis or vasculitis 18%, diabetes 21%, tubulointerstitial disease 15%, hereditary condition 12%, other 15%
• Clinical History: Diabetes 27%, CVD 40%, MI 10%, coronary revascularization 6%, PVD 15%
• Drug Therapies: ACE/ARB 36%, CCB 35%, B-blocker 38%, diuretic 31%, platelet inhibitor 43%, Vitamin D 46%, calcium substitution 74%, sevelamer 29%, EPO 87%

Interventions

• Randomization in 1:1 ratio in blocks of four:
  • Rosuvastatin: rosuvastatin 10mg daily
  • Matching placebo
• Patients were evaluated at 3 months, 6 months, and every following 6 months afterwards

Outcomes

Presented as rosuvastatin vs. placebo. Statistics only given when provided by authors. P-Y is patient-years.

Primary Outcome

CVD mortality, nonfatal MI, or nonfatal stroke

9.2 vs. 9.5 events/100 P-Y (HR 0.96; 95% CI 0.84-1.11; P=0.59)

Secondary Outcomes

Nonfatal MI

2.1 vs. 2.5 events/100 P-Y (HR 0.84; 95% CI 0.64-1.11; P=0.23)

Nonfatal stroke

1.2 vs. 1.1 events/100 P-Y (HR 1.17; 95% CI 0.79-1.75; P=0.42)

All-cause mortality

13.5 vs. 14.0 per 100 patient-years (HR 0.96; 95% CI 0.86-1.07; P=0.51)

CVD mortality: 7.2 vs. 7.3 events/100 P-Y (HR 1.00; 95% CI 0.85-1.16; P=0.97)

Non-CVD mortality 5.5 vs. 6.0 events/100 P-Y (HR 0.92; 95% CI 0.77-1.09; P=0.34)

Subgroup Analyses

There was no difference for the primary outcome by sex, age, smoking status, diabetes status, prior CVD events, BMI, baseline BP, baseline LDL, or baseline HS-CRP level.

Other Data

Percentage of study tablets that were taken

91.7% vs 89.5%

Adverse Events

96.3% vs 96.7%

Serious: 82.1% vs 84.1% (P=0.80) Note: There were no differences in subtypes of these between groups.

Resulting in discontinuation of the study drug: 31.5% vs. 32.1% (P=0.78)

Criticisms

• Possibly underpowered as event rates were only 9.5%, not 11% as were incorporated in the power calculation
• High rate of discontinuation of treatment
• Exclusion of patients already on statins, who may have been more likely to benefit from the medication
• Younger patients (<50y) were excluded, and may have benefited more due to starting therapy at an earlier age
• CVD risk increases with CKD stage and it may be too late to derive benefit once in ESRD

Funding

AstraZenca, the manufacturer of Crestor, brand name for rosuvastatin. Multiple authors with reported conflicts of interest