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Assessment of Lescol in Renal Transplantation - ALERT
Description:
The goal of the Assessment of Lescol in Renal Transplantation (ALERT) trial was to evaluate the effects of fluvastatin on cardiac and renal endpoints in renal transplant recipients during a five- to six-year follow-up.
Hypothesis:
Treatment of renal transplant patients with fluvastatin would result in a reduction in major adverse cardiac events (MACE) over placebo during a five- to six-year follow-up.
Study Design
Study Design:
Patients Enrolled: 2102
Mean Follow Up: 5-6 years
Mean Patient Age: Mean age 50 years
Female: 34%
Patient Populations:
Age 30-75 years; received renal or combined renal and pancreas transplants >6 months prior to randomization and had stable graft function; receiving immunosuppressive therapy with ciclosporin and had total serum cholesterol of 4.0-9.0 mmol/l if no MI within six months or 4.0-7.0 mmol/l if MI within six months
Exclusions:
Statin use; familial hypercholesterolemia; acute rejection episodes in prior three months; or predicted life expectancy <1 year
Primary Endpoints:
MACE, defined as cardiac death, nonfatal MI, or coronary intervention procedure
Secondary Endpoints:
Individual components of composite endpoint, combined cardiac death or nonfatal MI, cerebrovascular events, noncardiovascular death, all-cause mortality, and graft loss or doubling of serum creatinine
Drug/Procedures Used:
Renal transplant recipient patients with total cholesterol 4.0-9.0 mmol/l were randomized to fluvastatin (40 mg/d, n=1050) or placebo (n=1052). After two years, the study drug dose was doubled at the recommendation of the independent Data Safety Monitoring Board, due to clinical trial data published after the initial design of the trial.
Every six months, laboratory measures were assessed by a central lab, including fasting lipids (serum total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides), serum creatinine, creatine kinase, and hepatic enzymes. Investigators were only informed of patient lipid data if values exceeded predefined thresholds.
Concomitant Medications:
All patients received ciclosporin, and 81% also received steroids.
Principal Findings:
LDL-C was significantly reduced in the fluvastatin arm by six weeks (mean -25%, 95% confidence interval [CI] -26 to -24) compared with placebo (0.4%, 95% CI 0.9 to 1.8) and throughout the study (-32%, 95% CI -33 to -30 in the fluvastatin arm vs. -7.9%, 95% CI -10.0 to -5.7 in the placebo arm at the end of the study). Both total cholesterol and triglycerides also decreased significantly in the fluvastatin arm versus placebo, but there was no difference in HDL-C.
The primary endpoint of MACE did not differ significantly in the fluvastatin arm versus placebo (10.7% vs. 12.7%, risk ratio [RR] 0.83, 95% CI 0.64-1.06; p=0.139). However, risk of cardiac death was lower in the fluvastatin arm (3.4% vs. 5.1%, RR 0.62, 95% CI 0.40-0.96; p=0.031) as was nonfatal myocardial infarction (MI; 4.4% vs. 6.3%, RR 0.68, 95% CI 0.47-1.00; p=0.050) and the composite of death or MI (6.7% vs. 9.9%, RR 0.65, 95% CI 0.48-0.88; p=0.005). There was no difference in the need for CABG (2.4% vs. 2.3%, p=0.932), coronary intervention procedure (2.8% vs. 3.5%, p=0.357), or the frequency of cerebrovascular events (7.0% vs. 6.0%, p=0.391), all-cause mortality (13.6% vs. 13.1%, p=0.848), or graft loss or doubling of serum creatinine (17.4% vs. 15.7%, p=0.369). The rate of cancer (28.3% vs. 30.1%) or infection (64.9% vs. 64.0%) did not differ by treatment group.
Interpretation:
Among renal transplant patients, treatment with fluvastatin was not associated with a reduction in the primary composite endpoint of cardiac death, nonfatal MI, or coronary intervention procedure during 5-6 years of follow-up, but was associated with a reduction in the secondary endpoints of cardiac death and nonfatal MI and was associated with an average 1.0 mmol/l reduction in LDL-C.
Cardiovascular disease is the leading cause of death in renal transplant patients with a functioning graft. The trial was designed and powered to detect a difference based on a 22.5-25.0% event rate in the placebo arm. The actual event rate in the placebo arm was only 12.7%, limiting the ability to detect a treatment effect difference. Despite being underpowered, a treatment difference did occur for the secondary endpoints of cardiac death and nonfatal MI.
The rate of cancer was not increased in the fluvastatin arm, a concern, given the trend toward higher cancer rates in the statin arm in the recent PROSPER trial. A preplanned two-year extension of the ALERT trial, in which all patients receive active therapy, is currently underway.
References:
Holdaas H, Fellstrom B, Jardine AG, et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 2003;361:2024–31.
Keywords: Cyclosporine, Myocardial Infarction, Kidney Transplantation, Neoplasms, Creatine Kinase, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Fatty Acids, Monounsaturated, Lipids, Clinical Trials Data Monitoring Committees, Creatinine, Cholesterol, Cause of Death, Pancreas Transplantation, Indoles, Triglycerides, Fasting
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