Fast track — ArticlesEffect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial
Introduction
Despite advances in immunosuppressive therapy and long-term graft survival, renal transplant recipients have a notably shortened life expectancy.1 This effect is due largely to premature cardiovascular disease, which is the leading cause of death in patients with a functioning renal graft.1, 2 Many transplant recipients have pre-existing cardiovascular disease at the time of transplantation.1, 2, 3 and immunosuppressive therapy may aggravate existing risk factors or promote development of new risk factors, notably hyperlipidaemia and hypertension.1, 3
Lipid-lowering treatment with statins reduces cardiovascular events in a wide range of patients at increased risk of cardiovascular disease, including those with normal cholesterol concentrations.4, 5, 6, 7, 8, 9, 10, 11, 12 In renal transplant recipients the relation between lipid concentrations and cardiovascular events is less clear than in other populations.1, 3, 13 Although findings from observational studies suggest a potential benefit of statin therapy,14 this benefit has not been shown in prospective controlled trials.
The Assessment of LEscol in Renal Transplantation (ALERT) trial is an investigator-initiated and investigator-led study designed to investigate the effects of fluvastatin on cardiac and renal endpoints in renal transplant recipients. We believed a large-scale interventional trial was necessary before recommending the widespread use of statins in transplant recipients, who require lifelong therapy with immunosuppressive and other drugs, and are at increased risk of drug interactions, malignant diseases, and infections.15, 16
Section snippets
Methods
The ALERT study design and baseline data have been previously described.17 Briefly, we recruited 2102 renal transplant recipients from nephrology and transplant clinics in Belgium, Denmark, Finland, Germany, Norway, Sweden, Switzerland, the UK, and Canada.
Participants
We recruited men and women aged 30–75 years who had received renal or combined renal and pancreas transplants more than 6 months before randomisation and who had stable graft function. All patients were receiving immunosuppressive therapy with ciclosporin and had total serum cholesterol concentrations of 4·0–9·0 mmol/L, to exclude recent myocardial infarction (MI). Patients who had had MI more than 6 months before randomisation could be enrolled if total cholesterol concentration was 4·0–7·0
Trial procedure
Patients were randomly assigned fluvastatin 40 mg daily or matching placebo (figure 1). Treatment was assigned at each centre separately, according to medication-pack numbers, with use of fixed-block randomisation. After around 2 years, the dose of study drug was doubled in both groups after obtaining written informed consent from patients. The dose increase was implemented on the recommendation of the independent data safety monitoring board on the basis of emerging safety data and clinical
Statistical analysis
In the original sample-size calculation we assumed a 25% placebo event rate after 5 years of follow-up, based on a survey of the renal transplant population in the participating countries19 and a 25% size effect. By use of the χ2 test statistic for a difference between two proportions, we calculated that a sample size of 1476 patients (738 per group) would give 80% power to detect a difference between groups for the primary endpoint (α=0·05, two-tailed). We increased this number to 1800
Role of the funding source
The study sponsor, Novartis Pharma AG, which had one non-voting representative on the steering committee, had no role in the study design, data analysis, data interpretation, writing of the paper, or the decision to submit the paper for publication. The sponsor did collect the data.
Results
Between June, 1996, and October, 1997, 2102 patients were recruited; 1050 were randomly assigned fluvastatin and 1052 placebo (figure 1). The number of patients screened and recruitment strategy in individual centres were not recorded. All eligible patients were randomised. Follow-up was sought for all patients who discontinued treatment early and was achieved for all except seven.
Overall, 66% of patients were male, and the mean age was 50 years. The major causes of renal failure among all
Discussion
In the ALERT study the net reduction of LDL-cholesterol was generally 1·0 mmol/L lower in the fluvastatin group than in the placebo group and was associated with a lower cardiac event rate than placebo. However, the observed cardiac event rate was lower than predicted at the outset, and the trial had insufficient power to detect a significant reduction in the chosen primary endpoint. The 35% reduction in the secondary endpoint of cardiac death and non-fatal MI, with fluvastatin use are
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