Effects of Rosuvastatin on Cardiovascular Events in Patients Undergoing Hemodialysis (AURORA Trial)

Authors: Not Provided

Journal Name: New England Journal of Medicine

Year: 2009

Volume: Not Provided

Issue: Not Provided

Type of Study: Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial

DOI/PMID: ClinicalTrials.gov NCT00240331

Quick Reference Summary

Rosuvastatin, administered at 10 mg daily, significantly lowered LDL cholesterol levels by 43% in hemodialysis patients but did not reduce the incidence of major cardiovascular events compared to placebo after a median follow-up of 3.8 years.

There was no significant difference in all-cause mortality or individual components of the primary endpoint between the rosuvastatin and placebo groups (P>0.05).

Core Clinical Question

Does rosuvastatin therapy reduce cardiovascular mortality and major cardiovascular events in patients undergoing maintenance hemodialysis compared to placebo?

Background

Disease Overview:

Patients on maintenance hemodialysis have a markedly increased risk of premature cardiovascular disease, with a distinct pattern including higher incidences of sudden cardiac death and heart failure.

Prior Data:

Statins have been proven to reduce cardiovascular events in various high-risk populations.

The 4D study showed no significant cardiovascular benefit of atorvastatin in diabetic hemodialysis patients.

Current Standard of Care:

Statin therapy is endorsed by clinical guidelines in many countries for various high-risk populations, including those with diabetes, though its benefit in hemodialysis patients remains unproven.

Knowledge Gaps Addressed:

The efficacy of statin therapy in the broader population of hemodialysis patients without diabetes.

Understanding whether lipid-lowering impacts cardiovascular outcomes in this specific population.

Study Rationale:

To investigate whether rosuvastatin can reduce cardiovascular events and mortality in the general population of hemodialysis patients, beyond the diabetic subset studied in the 4D trial.

Methods Summary

Study Design:

Randomized, double-blind, placebo-controlled, multicenter trial.

Setting and Time Period:

Conducted in 280 centers across 25 countries from January 2003 through December 2004.

Population Characteristics:

2776 patients, aged 50 to 80 years, undergoing maintenance hemodialysis or hemofiltration for at least 3 months.

Inclusion/Exclusion Criteria:

Exclusions: Prior statin therapy within 6 months, expected kidney transplantation within 1 year, serious comorbid conditions limiting life expectancy, malignant conditions, active liver disease, uncontrolled hypothyroidism, elevated creatine kinase levels.

Intervention Details:

Rosuvastatin 10 mg daily.

Control/Comparison Group Details:

Matching placebo.

Primary and Secondary Outcomes:

Primary Endpoint: Time to major cardiovascular event (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes).

Secondary Endpoints: All-cause mortality, cardiovascular event-free survival, procedures for vascular access stenosis or thrombosis, coronary or peripheral revascularization, death from cardiovascular and noncardiovascular causes.

Statistical Analysis Approach:

Intention-to-treat analysis using Cox proportional-hazards models.

Subgroup analyses based on predefined criteria.

Sample Size Calculations:

Initially based on 620 major cardiovascular events; revised to 805 events considering updated assumptions.

Ethics and Funding Information:

Conducted in accordance with ethical guidelines; funded by AstraZeneca.

Detailed Results

Participant Flow and Demographics:

Total Screened: 3021

Randomized: 2776 (Rosuvastatin: 1391; Placebo: 1385)

Excluded from Intention-to-Treat: 3 patients

Final Analysis Population: 2773

Baseline Characteristics: Well-matched between groups (age, sex, race/ethnicity, concomitant therapy, duration of dialysis)

Primary Outcome Results:

Primary Endpoint Occurrence:

• Rosuvastatin: 396 patients (9.2 events per 100 patient-years)
• Placebo: 408 patients (9.5 events per 100 patient-years)
• Hazard Ratio: 0.96 (95% CI, 0.84 to 1.11; P=0.59)

Individual Components:

• Death from Cardiovascular Causes: Rosuvastatin 7.2 vs. Placebo 7.3 per 100 patient-years (P=0.97)
• Nonfatal Myocardial Infarction: Rosuvastatin 2.1 vs. Placebo 2.5 per 100 patient-years (P=0.23)
• Nonfatal Stroke: Rosuvastatin 1.2 vs. Placebo 1.1 per 100 patient-years (P=0.42)

Secondary Outcome Results:

All-Cause Mortality:

• Rosuvastatin: 636 patients (13.5 events per 100 patient-years)
• Placebo: 660 patients (14.0 events per 100 patient-years)
• Hazard Ratio: 0.96 (95% CI, 0.86 to 1.07; P=0.51)

Death from Noncardiovascular Causes: Hazard Ratio 0.92 (95% CI, 0.77 to 1.09; P=0.34)

Secondary Endpoints: No significant differences observed.

Subgroup Analyses:

No significant treatment effect across all predefined subgroups, including:

• Patients with diabetes
• Preexisting cardiovascular disease
• Hypertension
• High LDL cholesterol levels
• Elevated high-sensitivity C-reactive protein levels

Adverse Events/Safety Data:

Adverse Events Reported:

• Rosuvastatin: 1338 patients (96.3%)
• Placebo: 1332 patients (96.7%)

Serious Adverse Events:

• Rosuvastatin: 1140 patients (82.1%)
• Placebo: 1159 patients (84.1%)

Notable Findings:

• No significant increase in muscle-related adverse events, rhabdomyolysis, or liver disease with rosuvastatin.
• Marginal increase in hemorrhagic strokes in diabetic patients on rosuvastatin (P=0.03).

Lipid and C-Reactive Protein Levels:

• LDL Cholesterol Reduction: 43% with rosuvastatin vs. 1.9% with placebo (P<0.001)
• Total Cholesterol Reduction: 26.6% vs. 0.5% (P<0.001)
• Triglyceride Reduction: 16.2% vs. 0.9% (P<0.001)
• High-Density Lipoprotein Cholesterol Increase: 2.9% vs. 0.8% (P=0.045)
• High-Sensitivity C-Reactive Protein Reduction: 11.5% vs. 0.21% (P<0.001)

Results Tables

Note: pt-yrs = patient-years

Authors’ Conclusions

Primary Conclusions:

Rosuvastatin significantly reduced LDL cholesterol levels but did not decrease the composite primary endpoint of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in hemodialysis patients.

Interpretation of Results:

Lowering LDL cholesterol with rosuvastatin does not translate into reduced cardiovascular risk in patients undergoing maintenance hemodialysis.

Clinical Implications:

Statin therapy with rosuvastatin should not be routinely initiated for cardiovascular prevention in hemodialysis patients solely based on LDL cholesterol reduction.

Future Research Recommendations:

Further studies, such as the SHARP trial, are needed to evaluate the benefits of combined statin and ezetimibe therapy across different stages of renal dysfunction.

Critical Analysis

A. Strengths

• Large Sample Size: 2776 patients across 280 centers in 25 countries enhance generalizability.
• Randomized Controlled Design: Minimizes selection bias and confounding.
• Double-Blind Approach: Reduces performance and detection bias.
• Comprehensive Outcome Measures: Included both primary and multiple secondary cardiovascular endpoints.
• Long Follow-Up Period: Median of 3.8 years provides adequate time to observe outcomes.
• High Adherence Rates: Over 90% tablet adherence enhances internal validity.

B. Limitations

• Exclusion of Existing Statin Users: Potential selection bias; excluded group may have different risk profiles.
• Lower Than Predicted Event Rate: May reduce the study’s power to detect differences.
• Age Range Limitation: Only patients aged 50-80 were included, excluding younger populations.
• High Discontinuation Rate: Due to adverse events and renal transplantation, possibly masking potential benefits.
• Generalizability Issues: Findings may not apply to younger patients or those with different comorbidities.

C. Literature Context

A. Previous Studies and Meta-Analyses:

4D Study: Atorvastatin showed no significant cardiovascular benefit in diabetic hemodialysis patients.
(Die Deutsche Diabetes Dialyse Studie. N Engl J Med. 2005;352(20):2001-2012.)

JUPITER Trial: Rosuvastatin reduced cardiovascular events in patients with elevated C-reactive protein.
(Ridker PM et al. N Engl J Med. 2008;359(21):2195-2207.)

CORONA and GISSI-HF: No cardiovascular benefit of statins in heart failure patients.
(Keene D et al. N Engl J Med. 2005;353(22):2277-2286.)

B. Contrasting Methodological Quality:

AURORA vs. 4D: Similar large-scale, randomized designs but differing populations (general hemodialysis vs. diabetic hemodialysis).

SHARP Trial: Combining statin with ezetimibe in a broader renal population, potentially addressing limitations of AURORA and 4D.

C. Comparisons with Guidelines:

Clinical Guidelines: Generally endorse statins for cardiovascular risk reduction in high-risk populations, but AURORA suggests limited benefit in hemodialysis patients.
(American Heart Association. 2009; N Engl J Med. 2009.)

D. This Trial’s Contribution:

AURORA: Demonstrates that rosuvastatin does not reduce major cardiovascular events in the general hemodialysis population, expanding upon the findings of the 4D study and highlighting the unique cardiovascular risk profile in hemodialysis patients.

Clinical Application

Impact on Current Practice:

Rosuvastatin should not be routinely prescribed for cardiovascular event prevention in patients undergoing maintenance hemodialysis, as it does not confer additional benefits beyond lipid lowering.

Applicable Patient Populations:

These findings are most relevant to hemodialysis patients aged 50-80 without pre-existing statin therapy.

Implementation Considerations:

Clinicians should prioritize other cardiovascular risk mitigation strategies over initiating rosuvastatin in this patient group.

Integration with Existing Evidence:

Aligns with the 4D study, reinforcing the notion that statin therapy may have limited efficacy in advanced renal disease populations.

How To Use This Info In Practice

Practitioners should not routinely initiate rosuvastatin for cardiovascular prevention in hemodialysis patients based on the current evidence, focusing instead on comprehensive cardiovascular risk management.