Chairman, Steering Committee, and Chairman Data Safety and Monitoring Board ALERT, on behalf of the ALERT study group Email: hallvard.holdaas{at}rikshospitalet.no
Sir,
The survival benefits and safety associated with statin therapy are well established. However, statin use may be complicated by myositis and, on rare occasions, rhabdomyolysis and its sequelae. The recent voluntary withdrawal of cerivastatin from the market has prompted investigators to question the safety of statin therapy in high-risk patients or when used in combination with other agents. One patient group at particular risk is solid organ transplant recipients, who have a greatly increased cardiovascular risk, but as yet there is only very limited evidence of a survival advantage with statin therapy. A major concern is that drug interactions between calcineurin inhibitors (cyclosporine or tacrolimus) and statins may increase the risk of myositis. Calcineurin inhibitors are mainly metabolized by the microsomal enzyme cytochrome P450 (CyP) 3A4, as is cerivastatin, and several other statins [1].
ALERT (Assessment of Lescol® in Renal Transplantation) is an ongoing prospective randomized, double-blind, placebo-controlled trial designed to assess the effect of fluvastatin (4080 mg/day) in renal transplant recipients with hypercholesterolaemia (total cholesterol 4.09.0 mmol/l (166348 mg/dl)). ALERT has enrolled 2100 renal transplant patients with a planned 6-year follow-up and will conclude in autumn 2002 [2]. We reviewed blinded safety data for all adverse events reported (6500 events) for patients in this trial at a mean follow-up of 4 years. The data were assessed with particular emphasis on muscle-related symptoms and all CK levels were reviewed. In all, we noted eight incidences of CK elevation, more than five times the upper limits of normal (ULN) (only one incidence >10xULN); all of these were single visit episodes. All deaths, including those not related to major adverse cardiac events (n=154), were reviewed and there were no episodes of significant CK elevation prior to any fatal event.
This study and our findings in another major study [3] in renal transplant recipients, which assessed the immunosuppressive actions of fluvastatin in 364 patients followed for 3 months following transplantation (at a time when the highest plasma levels of cyclosporine are achieved), have established the safety of fluvastatin in renal transplant recipients receiving calcineurin inhibitors. Although there are no outcome data in this population (pending the findings of ALERT), transplant patients are often treated with statins. The minimal interactions via CyP 3A4 allow the safe use of fluvastatin in transplant recipients without dosage modification [3,4]. With the exception of pravastatin, other statins (specifically those metabolized by CyP 3A4) should be initiated at low doses with careful monitoring of lipid responses and CK levels, accepting a potential risk of adverse effects. In our experience this advice is neither widely appreciated nor applied.
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