Preventive cardiology
Efficacy and Tolerability of Fluvastatin XL 80 mg Alone, Ezetimibe Alone, and the Combination of Fluvastatin XL 80 mg With Ezetimibe in Patients With a History of Muscle-Related Side Effects With Other Statins

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Although statin treatment is generally well tolerated, it is estimated that 5% to 10% of patients develop muscle-related side effects (MRSEs), resulting in less effective nonstatin alternatives or cessation of lipid-lowering therapy completely. This study was designed to assess the efficacy and tolerability of extended-release fluvastatin (fluvastatin XL) and ezetimibe alone or in combination in patients with previous MRSEs with other statins. This was a double-blinded, double-dummy trial of 199 mostly moderate- or high-risk dyslipidemic patients randomized to fluvastatin XL 80 mg/day (n = 69), ezetimibe 10 mg/day (n = 66), or fluvastatin XL 80 mg/day plus ezetimibe 10 mg/day (n = 64) for 12 weeks. Fluvastatin XL lowered low-density lipoprotein (LDL) cholesterol by 32.8% compared with 15.6% with ezetimibe (between-group difference −17.1%, 95% confidence interval −23.6 to −10.7, p <0.0001); the fluvastatin XL/ezetimibe combination lowered LDL cholesterol by 46.1% (between-group difference vs ezetimibe −30.4%, 95% confidence interval −37.0 to −23.8, p <0.0001). Proportions of patients achieving their National Cholesterol Education Program Adult Treatment Panel III target LDL cholesterol were 84% with the fluvastatin XL/ezetimibe combination, 59% with fluvastatin XL, and 29% with ezetimibe (p <0.001 for fluvastatin XL monotherapy or combination therapy vs ezetimibe monotherapy). Incidences of MRSEs were 24% in the ezetimibe group, 17% in the fluvastatin XL group, and 14% in the combination group. There were no instances of creatine kinase increases ≥10 times upper limit of normal. In conclusion, in patients with a history of statin-associated MRSEs, fluvastatin XL alone or in combination with ezetimibe offers an effective and well-tolerated lipid-lowering option.

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Methods

This randomized, double-blinded, double-dummy, parallel-group, multicenter study evaluating the efficacy and tolerability of fluvastatin XL 80 mg/day and ezetimibe 10 mg/day, alone or in combination, was conducted according to the ethical principles of the Guidelines for Good Clinical Practice and the Declaration of Helsinki of the World Medical Association. Patients were recruited in 27 centers in Germany, Greece, Norway, Russia, Turkey, and the United States from May to September 2005. Local

Results

In total 251 subjects were screened and 218 patients were randomized to treatment (Figure 1). An audit by the sponsor of 1 study center detected significant irregularities related to another study; however, there were no such findings related to this trial. As a precautionary measure, patients recruited at this center (n = 19) were excluded from the final analyses, leaving 199 patients in the intent-to-treat/safety population. Inclusion or exclusion of these 19 patients did not affect the

Discussion

The present trial demonstrates that most patients who are intolerant to other statins, due to muscular complaints without creatine kinase increases, can tolerate fluvastatin XL 80 mg/day as monotherapy or in combination with ezetimibe 10 mg/day. Fluvastatin XL 80 mg/day administered in combination with ezetimibe 10 mg/day provides substantial additional lowering of LDL cholesterol levels compared with the respective monotherapies (additional 13.3% decrease vs fluvastatin XL and additional 30.4%

Acknowledgment

The most important acknowledgement is to participants in the study and to the doctors, nurses, and administrative staff in centers throughout Europe and the United States who assisted with its conduct. The study authors acknowledge the assistance of Sajda Ghani, BSc, MSc, and Peter J. Diggle, PhD, for statistical support and of Felicity Sellers, DPhil, for collating author comments and initial editorial assistance.

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    Citation Excerpt :

    Bile acid sequestrants are not absorbed and these agents would not be expected to have adverse muscle complaints even though some patients report SAMS with bile acid sequestrants (50). Studies in patients with statin intolerance have shown that the majority of patients are able to tolerate ezetimibe (50–55). The IMPROVE-IT trial (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) evaluated the effect of ezetimibe combined with simvastatin compared with simvastatin alone in stable patients following acute coronary syndrome (55).

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The study was funded by Novartis Pharma AG, Basel, Switzerland.

The Clinical Trials.gov number is NCT00125125.

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