AURORA

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

Among patients undergoing maintenance hemodialysis, does rosuvastatin reduce the incidence of cardiovascular events?

Bottom Line

There is no significant effect on the incidence of cardiovascular events in hemodialysis patients taking rosuvastatin.

Major Points

Statins have been shown to reduce cardiovascular events in the general population at high-risk for cardiovascular events . Previous observational studies have also suggested a benefit in statin therapy in patients on hemodialysis. The 4D Study investigated this issue by randomizing patients with type 2 diabetes undergoing hemodialysis to either statin therapy or placebo, and found no benefit to pharmacotherapy[1].

The AURORA trial was conducted in order to investigate whether statins would demonstrate a reduction in cardiovascular events in a more diverse hemodialysis population. Patients were randomized to either rosuvastatin 10mg daily or placebo. The group receiving pharmacotherapy had 42.9% lower LDL compared to baseline, compared to the placebo group experiencing only a 1.9% reduction. Despite this difference in lipid levels, there was no significant difference in the primary outcome (a composite endpoint of death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke) or any secondary outcomes.

A subsequent trial, SHARP, found the combined use of simvastatin and ezetimibe reduced atherosclerotic events in the general CKD population. However, subgroup analysis of only the patients on dialysis did not reveal the same finding[2]. A meta-analysis of hemodialysis patients receiving statin therapy in the 4D, AURORA, and SHARP trials did not come to a definitive conclusion on the utility of statin therapy, as results did not reach statistical significance[3].

Guidelines

KDIGO Clinical Practice Guidelines for Lipid Management in Chronic Kidney Disease (2013, adapted)[4] In adults with dialysis-dependent CKD, we suggest that statins or statin/ezetimibe combination not be initiated (Grade 2A).

In patients already receiving statins or statin/ezetimibe combination at the time of dialysis initiation, we suggest that these agents be continued (Grade 2C).

Design

  • International, multicenter, randomized, double-blind, prospective trial
  • N=2,776
    • Rosuvastatin 10mg once daily(n=1,389)
    • Placebo (n=1,384)
  • Setting: 280 centers in 25 countries
  • Follow-up: Mean 3.2 years (Max: 5.6 years)
  • Analysis: Intention-to-treat
  • Primary outcome:
    • Time to a major cardiovascular event (Nonfatal myocardial infarction, nonfatal stroke, death from cardiovascular causes)

Population

Inclusion Criteria

  • Ages 50-80 years
  • End stage renal disease
  • Regular hemodialysis or hemofiltration for >3 months

Exclusion Criteria

  • Statin therapy within past six months
  • Expected kidney transplantation within 1 year
  • Serious hematologic, neoplastic, gastrointestinal, infectious, or metabolic disease (excluding diabetes) that limited predicted life expectancy to less than 1 year
  • Malignancy, active liver disease (ALT > 3x upper limit of normal), uncontrolled hypothyroidism, unexplained CK elevation (>3x upper limit of normal)

Baseline Characteristics

From the rosuvastatin group.

  • Demographics: Age 64.1 years, female 38.7%
  • Baseline health data: BMI 25.4, BP 137/76, Smokers 14.5%
  • Cholesterol: Total 176 mg/dL, LDL 100mg/dL, HDL 45 mg/dL, Triglycerides 157 mg/dL
  • hsCRP: 4.8 mg/L (median)
  • Duration of dialysis treatment: 3.5 years
  • Duration of dialysis sessions: 11.9h/week
  • Cause of ESRD
    • Nephrosclerosis 19.7%
    • Glomerulonephritis or vasculitis 18.0%
    • Diabetes 20.6%
    • Tubulointerstitial disease 14.8%
    • Hereditary 12.3%
    • Other 14.6%
  • Clinical History
    • Diabetes 27.0%
    • Cardiovascular disease 39.5%
    • Myocardial infarciton 10.5%
    • Coronary revascularization 5.9%
    • Peripheral vascular disease 15.3%
  • Drug Therapy
    • ACE or ARB: 35.8%
    • CCB: 34.6%
    • B-blocker: 38.4%
    • Diuretic: 30.8%
    • Platelet inhibitor: 42.7%
    • Vitamin D: 46.3%
    • Calcium substitution: 74.3%
    • Sevelamer:28.7%
    • Erythropoietin: 86.7%

Interventions

  • Randomization in 1:1 ratio in blocks of four:
    • Rosuvastatin: rosuvastatin 10mg daily
    • Matching placebo
  • Patients were treated on average 2.9 years (longest 5.6 years)
  • 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.

Primary Outcome

Time to Major Cardiovascular Event

Defined as nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes.

9.2 vs. 9.5 events/100 patient-years (HR: 0.96; P=NS)

Secondary Outcomes

All-Cause Mortality
13.5 vs. 14.0 per 100 patient-years (p=NS)
Noncardiovascular Deaths
p=NS

Additional Analyses

Relationship between Lipid Levels and Reaching Cardiovascular Endpoints
LDL vs. Primary Outcome: HR 1.00 (p=NS)
Subgroup Analysis: Cardiovascular Events in Subgroups with Different Co-Morbidities
Diabetes, pre-existing cardiovascular disease, hypertension, high LDL, high hsCRP: all p = NS

Other Data

Medication Compliance (Tablets)
91.7% vs 89.5%
Adverse Events
96.3% vs 96.7%
Serious Adverse Events
82.1% vs 84.1%

Criticisms

  • Patients using statins in the last six months were excluded, despite being the ones most likely with cardiovascular disease that may benefit from lipid lowering therapy
  • Younger patients (<50y) were excluded, and may have benefited more due to starting therapy at an earlier age
  • High medication discontinuation rate may mask the potential benefit of therapy

Funding

AstraZenca, the manufacturer of Crestor (R), brand name for rosuvastatin.

Further Reading

  1. Wanner C, et al. "Atorvastatin in patients with type 2 diabetes undergoing hemodialysis." The New England Journal of Medicine. 2005; 353:238-248.
  2. Baigent C, et al. "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". The Lancet. 2011; 377(9784): 2181-2192.
  3. Upadhyay A, et al. "Lipid-lowering therapy in persons With chronic kidney disease: A systematic Review and meta-analysis." Ann Intern Med. 2012; 157: 251–262.
  4. Kidney Disease: Improving Global Outcomes (KDIGO) Lipid Work Group. KDIGO Clinical Practice Guide[1]line for Lipid Management in Chronic Kidney Disease. Kidney inter., Suppl. 2013; 3: 259–305.