Efficacy and Safety of rosuvastatin Every Other Day Compared with Once Daily in Patients with Hypercholesterolemia

Background:  There is a need to evaluate strategies that reduce cost of lipid-lowering therapy without diminishing efficacy or increasing adverse effects.  One strategy involves comparison of once daily statin therapy with every other day (EOD) therapy.  Studies have not been conducted comparing the efficacy and safety of rosuvastatin every other day with once-daily dosing.

Objective:  The objective was to compare the efficacy and safety of rosuvastatin 10mg administered EOD vs once daily. 

Methods:  This was a randomized, open-label, parallel trial.  Subjects diagnosed with hypercholesterolemia were referred to the investigators of the study to assess eligibility.  Patients were included in the study if they had primary hypercholesterolemia, were >20 years of age, met the criteria for starting statin therapy (NCEP-ATP III guidelines), signed an informed consent document, and never received statins.  Patients were excluded if they were pregnant or lactating, taking drugs known to affect lipid metabolism or to interact with rosuvastatin, had an active liver disease, severe renal impairment, elevated liver enzyme levels or creatine kinase (CK) levels >3 times normal.  A total of 80 patients, 40 in each group, were enrolled and randomly assigned to receive rosuvastatin 10 mg PO daily EOD at 20:00, for a duration of 8 weeks.  Serum lipid levels, percentage of patients who achieved their LDL goals according to NCEP-ATP III guidelines, adverse event rates, and monthly cost per percent of LDL reduction were the outcomes measured.  Subgroup analyses for the different risk categories were also performed.  Intent-to-treat was used to handle the data for four dropouts (2 from each group).  Weekly telephone communication with investigators allowed for monitoring of adverse events and other problems in participants.  One patient from the EOD group died from sepsis and the other dropped out because of headache.  Two patients from the once daily group dropped out due to malaise and myalgia.  Pill counts and scheduled follow-up visits were used to assess adherence.  Comparisons between the groups were performed using x² or Fisher’s exact tests.  Paired t-tests were used to compare variables at baseline and study end for each group and independent t-tests were used to compare the difference of variables between each group.  Power of the study was 80% with an estimated sample size of 80 patients.

Results: Significant decreases in serum total cholesterol, triglyceride, and LDL levels from baseline were observed in each group (all p values < 0.05).  HDL was significantly increased in patients who received rosuvastatin once daily (p = 0.038), but insignificantly increased in the EOD group (p = 0.114).  No significant difference in the percentage of change in serum HDL levels between the groups was found (p = 0.501).  Serum total cholesterol, triglyceride, HDL, and LDL levels at the end of the study were not significantly different between the two groups (all p > 0.05).  Both groups experienced reduced total cholesterol, triglyceride, and LDL levels with the percentage of change being significantly greater in the once-daily group versus the EOD group (all p < 0.05).  Overall, 77.5% of all patients in this study achieved their LDL goal.  There was no significant difference between the treatment and control group in reaching their LDL goals overall or in each risk category (p = 0.180 and all p>0.05, respectively).  Although the differences in the subgroup analyses were not statistical, the percent difference of patients reaching their LDL goal was considerable in each risk category.  For example, the difference in high-risk patients reaching their goal was 81.8% in the once daily group compared to 50.0% in the EOD group.  The percent differences, in combination with the insufficient sample size, suggest Type II error.  No elevations of AST or ALT > 3 times baseline or CK levels > 10 times baseline occurred during the study.  However, serum AST and ALT at week 8 for patients in the once daily group were significantly increased from baseline (no p-value provided).  The adverse event rate was not significantly different between groups (p = 0.439).  The monthly cost per percent LDL reduction for the EOD group was 38% lower than the once daily group ($0.44 and $0.72/month, respectively).  One hundred percent medication adherence was reported for the patients who completed the study and the adherence to follow-up was high for all of these patients (follow-up occurred at exactly 8 weeks).   

Strengths: Appropriate background and rationale was provided and the authors used acceptable statistical tests and data handling methods for the study results.  Adherence rates, reasons for dropout, and key limitations were provided.

Weaknesses:  This study was poorly designed and carried out.  Major weaknesses include open-label design, small sample size, lack of power to detect between group differences/considerable risk of making a Type II error, failure to evaluate the impact of lifestyle modifications in each group, and inappropriate conclusions made by the authors. 

Conclusion: The many weaknesses of the study limit its clinical usefulness and invalidate its results.  A conclusion to use EOD therapy over once daily therapy cannot be made without having an impact on efficacy.  Further research would be required using an increased sample size and a better study design to accurately interpret results and come to a valid conclusion. 

Wongwiwatthananukit S, Sansanayudh N, Dhummauppakorn R, Kitiyadisai C. Efficacy and Safety of Rosuvastatin Every Other Day Compared with Once Daily in Patients with Hypercholesterolemia. Ann Pharmacother. 2006 Sep 26; 40.

Laura K. Rhoades, Pharm D Candidate.