Once-a-Week Rosuvastatin (2.5 to 20 mg) in Patients With a Previous Statin Intolerance
Article Outline
The purpose of this study was to determine the efficacy of rosuvastatin dosed once a week in patients with a previous statin adverse event. Rosuvastatin once a week was tolerated by 37 (74%) of the 50 study participants, with doses ranging from 2.5 mg to 20 mg a week (mean 10 ± 4 mg). Patients tolerating the once-a-week regimen experienced a 17% reduction in total cholesterol, 23% reduction in low-density lipoprotein cholesterol, 12% reduction in triglycerides, and a 5% increase in high-density lipoprotein cholesterol (all p <0.001), during a mean follow-up of 4 months ± 2. Although this alternative dosing regimen has not been proven to reduce cardiovascular events, it may provide a therapeutic option for patients who may otherwise go without the proven benefits of statin therapy. In conclusion, this dosing strategy was well tolerated in patients with a history of an adverse event to 1 or more statins and led to significant lipoprotein changes.
Previous data indicate that using alternative rosuvastatin dosing (every other day, three times a week, and twice a week) in patients with previous statin adverse events can improve patient tolerability and significantly lower total cholesterol and low-density lipoprotein cholesterol (LDL-C).1, 2, 3 The present study demonstrates the efficacy of rosuvastatin dosed once a week in patients with a previous statin adverse event.
We manually reviewed approximately 1,300 medical records in the Atherosclerosis and LDL-Apheresis Center at the University of Kansas Medical Center to identify patients with previous statin adverse events who received rosuvastatin once a week. Patients were excluded if other significant changes were made to their lipid regimen or the length of once-a-week rosuvastatin therapy was <4 weeks.
Continuous variables are expressed as mean ± SD. Data analysis was performed using SPSS version 14.0 (SPSS, Inc., Chicago, Illinois). Paired Student's t tests were used to compare lipid levels before and after rosuvastatin therapy. Results were considered significant at p <0.05.
Fifty patients met study criteria, and overall most (37/50; 74%) tolerated the once-a-week regimen (Table 1). Among those who experienced myalgias from previous statins, 71% (25/35) tolerated once-a-week rosuvastatin. Also, 5 of 6 patients (83%) with a history of elevated creatine kinase levels from previous statins experienced lower levels with the new regimen, and 1 (17%) had no changes in creatine kinase values. Finally, most patients with elevated hepatic transaminases, gastrointestinal complaints, and other complaints tolerated once-a-week rosuvastatin (7/7, 100%; 2/4, 50%; and 3/4, 75% respectively). The mean rosuvastatin dose was 10 ± 4 mg (Table 1), and post-treatment lipid levels were drawn approximately 4 months (mean 4 ± 2) after initiating rosuvastatin. Nearly all patients (46; 92%) were taking rosuvastatin in combination with other lipid-altering agents, including ezetimibe, nicotinic acid, fibrates, bile acid sequestrants, and/or omega-3 fatty acids, throughout the study.
Table 1. Baseline characteristics of patients with previous statin intolerance (n = 50)
| Men | 19 (38%) |
| Women | 31(62%) |
| Age (yrs) (mean ± SD) | 61±10 |
| Black | 7(14%) |
| White | 40(80%) |
| Other | 3(6%) |
| Body mass index (kg/m2) (mean ± SD) | 29.3±4.6 |
| Waist circumference (inches) (mean ± SD) | 37.5±5.5 |
| Family history⁎ | 25(50%) |
| Hypertension | 39(78%) |
| Smoking (current/past) | 5(10%)/13(30%) |
| HDL-C < 40 (mg/dL) | 15(30%) |
| Metabolic syndrome | 21(42%) |
| Coronary heart disease | 11(22%) |
| Diabetes mellitus | 12(24%) |
| Peripheral vascular disease | 1(2%) |
| Previous number of intolerable statins (mean) | 2 |
| 1 | 15(30%) |
| 2 | 19(38%) |
| 3 | 10(20%) |
| 4 | 5(10%) |
| 5 | 1(2%) |
| Previous statin adverse effects | |
| Myalgias | 35(70%) |
| Elevated creatine kinase | 6(12%) |
| Elevated hepatic transaminases | 7(14%) |
| Gastrointestinal complaints | 4(8%) |
| Other | 4(8%) |
| Weekly dose of rosuvastatin† (mg) | |
| 2.5 | 2(5%) |
| 5 | 7(19%) |
| 10 | 25(68%) |
| 20 | 3(8%) |
⁎Family history of premature coronary heart disease in male first-degree relative <55 yrs of age or female first-degree relative <65 yrs of age. |
†n = 37. |
Patients tolerating the once-a-week rosuvastatin experienced significant alterations in lipoproteins (Figure 1 and Table 2), enabling 10/37 patients (27%) to achieve their National Cholesterol Education Program Adult Treatment Panel III LDL-C goal.4 Lastly, there was no significant difference (p = 0.714) between groups in LDL-C reduction among 34 patients who had follow-up lipid levels drawn 1 to 3 days (–24% ± 13) or 4 to 7 days (–23% ± 17) after their last dose. Mean rosuvastatin doses were similar between these groups, 9.7 mg and 9.1 mg respectively.
Figure 1.
All p values <0.001. TC = total cholesterol; TG = triglycerides.
Table 2. Change in serum lipids from baseline of patients tolerating once-a-week rosuvastatin
| Measure | Baseline (mg/dL) | Follow-up (mg/dL) | p Value |
|---|---|---|---|
| Total cholesterol | 245±55 | 199±37 | <0.001 |
| LDL-C | 167±45 | 125±31 | <0.001 |
| Triglycerides | 159±64 | 139±72 | <0.001 |
| HDL-C | 48±12 | 50±15 | <0.001 |
| Total cholesterol/HDL-C | 5.4±1.7 | 4.2±1.3 | <0.001 |
| LDL-C/HDL-C | 3.7±1.3 | 2.8±1.0 | <0.001 |
These results suggest that once-a-week rosuvastatin can significantly improve the lipid profile. We previously described 8 patients intolerant to once-a-day statin dosing who were able to tolerate once-a-week rosuvastatin (10 mg/week), with a resultant 29% reduction in LDL-C.5 Additional data using alternative rosuvastatin dosing in similar populations is comparable.1, 2, 3 For instance, we demonstrated that rosuvastatin every other day (20 mg/week) produced a 36% LDL-C reduction.1 Gadarla et al3 showed a 26% LDL-C reduction with rosuvastatin twice a week (13 mg/week). Data from the present rosuvastatin study illustrate a 23% reduction in LDL-C (10 mg/week). Rosuvastatin possesses a dose response for which doubling the dose results in an additional 5% LDL-C reduction.6 The aforementioned studies using alternate rosuvastatin dosing show a consistent and dose-dependent pattern of LDL-C reduction with increased weekly doses.
Rosuvastatin's long half-life (∼19 hours)7 and marked LDL-C reduction8 make it an attractive agent for weekly dosing. Nonetheless, there may be concern about LDL-C levels increasing before the next dose (7 days) because the drug may be cleared in 5 half-lives (∼4 days). In this study, we evaluated LDL-C reduction and days since the last dose. Patients with lipid levels measured 1 to 3 days and 4 to 7 days after receiving their last rosuvastatin dose had similar mean LDL-C reductions.
Gadarla et al3 demonstrated no change in high-density lipoprotein cholesterol (HDL-C) levels with rosuvastatin 5 mg and 10 mg twice weekly. Recently, we also showed a nonsignificant change in HDL-C with rosuvastatin every other day.1 The present study however, showed a 5% (p <0.001) increase in HDL-C levels, which is more consistent with the increases observed with once-a-day dosing. We cannot determine why HDL-C increased in our study when other alternative dosing studies have not shown significant changes.
There are several possible explanations for the overall rosuvastatin tolerability in this study. Lower plasma concentrations from the infrequent dosing are likely to cause less adverse effects. Also, simply switching to a different statin could help patients tolerate the medication. Finally, the psychological effects of taking a medication only once a week may be sufficient to improve patient tolerance.
There are several limitations to this study. It is a retrospective, observational study without placebo controls. Also, the myalgias were not objectively assessed but, rather, were patient-reported. There was no standard time for lab draws although our data imply this factor does not significantly affect lipid levels. Also, patients were not excluded if changes were made in nonpharmacologic therapies such as diet and exercise. Additionally, our patients were able to tolerate once-a-week rosuvastatin for a mean of 4 months. Long-term studies are needed to assess the continued tolerability of once-a-week rosuvastatin in this population. Finally, once-a-week rosuvastatin dosing has not proven to reduce cardiovascular events. Large randomized trials are needed to confirm our findings, but it is our theory that treating statin-intolerant patients with alternative dosing, is more desirable than no statin therapy.
References
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PII: S0002-9149(08)01713-X
doi:10.1016/j.amjcard.2008.09.095
© 2009 Elsevier Inc. All rights reserved.
