Canadian Journal of Cardiology 30 (2014) 1392e1395

Brief Rapid Report

The Effect of Infrequent Low-Dose Rosuvastatin on the Lipid Profile Christine Ibrahim, MD, Matthew R. Ban, BSc, and Robert A. Hegele, MD Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada

ABSTRACT

  RESUM E

We retrospectively studied 21 patients who had difficulty tolerating daily or alternating-day statins. Patients received rosuvastatin at a mean frequency of 1.7 doses per week, and a mean dose of 11.7 mg per week. We assessed lipid profiles at baseline and after at least 3 months of therapy. We found that total and low-density lipoprotein cholesterol were reduced by 2.03  2.04 and 1.31  0.83 mmol/L (27.9% and 31.5%), respectively, from baseline (both P < 0.001). Thus, in patients with statin intolerance, infrequent low-dose rosuvastatin significantly improved low-density lipoprotein cholesterol and was well tolerated over the long term.

tudie  de façon re trospective 21 patients qui tole raient Nous avons e mal la prise quotidienne de statines ou la prise en alternance un jour quence sur deux. Les patients ont reçu la rosuvastatine selon une fre moyenne de 1,7 dose par semaine et une dose moyenne de 11,7 mg value  les bilans lipidiques initiaux et après par semaine. Nous avons e  que le choleste rol au moins 3 mois de traitement. Nous avons observe rol à lipoprote ines de faible densite  avaient total et le choleste  de 2,03  2,04 et 1,31  0,83 mmol/l (27,9 % respectivement diminue but (P < 0,001 pour les deux). Par conet 31,5 %) depuis le de quent, chez les patients intole rants aux statines, la prise occase liore  sionnelle de rosuvastatine à faible dose a significativement ame rol à lipoprote ines de faible densite  et a bien e t e  tole r e e à le choleste long terme.

Increased plasma concentrations of low-density lipoprotein (LDL) cholesterol (C) increase cardiovascular disease (CVD) risk.1 Thus, reducing LDL-C is a cornerstone of primary and secondary CVD prevention.1 Statins might reduce LDL-C by as much as 55%.1 The Cholesterol Treatment Trialists’ Collaboration meta-analysis showed that a 1.0 mmol/L reduction in LDL-C decreases the risk of major CVD events by one-fifth.1,2 A reduction of LDL-C by 2-3 mmol/L reduces CVD risk by up to 50%.1,2 However, not everyone can tolerate statin therapy. Statin intolerance encompasses a range of clinical features, including myopathy, myalgia, myositis, and rhabdomyolysis.3 Mylagias are quite common and is sometimes accompanied by an increased serum creatine kinase.3 These symptoms pose a major impediment to compliance, attenuating the potential life-saving benefits of statin therapy. Rosuvastatin has a longer half-life than the other statins (approximately18-20 hours),4 and nondaily dosing of rosuvastatin in patients with statin

intolerance has been recently evaluated.5,6 Using rosuvastatin as infrequently as 3 times a week (approximately 30 mg/wk), helped achieve approximately a 34% reduction in LDL-C.6 However, some patients cannot tolerate even this reduced dose, which prompted us to evaluate the efficacy and adverse effects of even less frequent, lower-dose regimens of rosuvastatin.

Received for publication June 27, 2014. Accepted July 3, 2014. Corresponding author: Dr Robert A. Hegele, Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, University of Western Ontario, London, Ontario N6A 5K8, Canada. Tel.: þ1-519-931-5271; fax: þ1-519-931-5218. E-mail: [email protected] See page 1394 for disclosure information.

Methods Study subjects We retrospectively reviewed charts of patients who attended the Lipid Genetics Clinic, London Health Sciences Centre (London, Ontario, Canada). Inclusion criteria included patients who: (1) received nondaily rosuvastatin < 3 times per week (total dose < 20 mg/wk) for > 3 months; (2) had a history of statin intolerance, defined primarily by the presence of myalgia with or without increased level of creatine kinase, and inability to complete at least 2 previous trials of 2 different statins; and (3) were weight-stable over the time period of study, with a stable diet and stable doses of all other medications. The primary outcomes were the absolute and relative changes in the lipid profile before and after initiation of infrequent, low-dose rosuvastatin therapy, and the percentage of patients who achieved their LDL-C target as per the 2012

http://dx.doi.org/10.1016/j.cjca.2014.07.002 0828-282X/Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Ibrahim et al. Ultra-low Dose Rosuvastatin

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Table 1. Baseline characteristics of patients Characteristic Age in years n Body mass index* Type 2 diabetes Smoking Hypertension History of coronary artery disease Total cholesterol, mmol/L Triglyceride, mmol/L HDL-C, mmol/L LDL-C, mmol/L Apolipoprotein A1, g/L Apolipoprotein B, g/L Creatine kinase, U/L Aspartate transaminase, U/L Weekly rosuvastatin dose, mg Patients taking concomitant lipid-altering drugs (%) Omega-3 fatty acid/fish oil Ezetimibe Niacin Fibrate Other supplements, n (%)

Overall

Male

Female

66.4 (47-84) 21 28.9 (21.4-38.3) 4 (19.1) 8 (38.1) 9 (42.9) 5 (23.8) 7.31  2.12 2.54  2.04 1.29  0.40 4.47  0.67 1.34  0.17 1.29  0.40 144.7  96.3 32.1  14.0 11.73  5.90 10 (47.6) 2 (9.5) 10 (47.6) 3 (14.3) 1 (4.8) 8 (38.1)

66.5 (50-84) 10 28.1 (23-38.3) 3 (30) 4 (40) 4 (40) 2 (20) 6.71  0.93 2.52  2.76 1.25  0.39 4.80  0.71 1.25  0.23 1.34  0.15 193.0  146.6 26.0  8.50 12.4  5.73 5 (50) 2 (20) 5 (50) 2 (20) 1 (10) 3 (30)

66.3 (47-80) 11 29.7 (21.4-38.3) 1 (9.1) 4 (36.4) 5 (45.5) 3 (27.3) 7.84  2.74 2.57  1.20 1.34  0.41 4.18  0.49 1.43  0.34 1.24  0.19 114.7  30.10 34.2  15.50 11.1  6.26 5 (45.5) 0 (0) 5 (45.5) 1 (9.1) 0 (0) 5 (45.5)

Except as otherwise noted, continuous variables are presented as mean (range) or  SD, and discrete variables are presented as mean (%). HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. * Calculated as weight (kg)/height (m2).

Canadian Cardiovascular Society guidelines for management of dyslipidemia.7 Secondary outcomes included baseline demographic characteristics, assessment of baseline CVD risk, and the use of additional lipid-lowering therapies. Tolerability of the nondaily regimen was determined according to the absence of clinical symptoms at follow-up appointments, normal follow-up blood work, and persistence with therapy as prescribed. Statistical analysis Statistical analysis was performed using SAS version 9.3 (SAS Institute, Cary, NC). Paired t tests were used to compare lipid levels before and after rosuvastatin therapy. Results were considered nominally significant for P < 0.05. Results Twenty-one patients who were taking infrequent, low-dose rosuvastatin met our study criteria for inclusion and analysis, and their baseline data are shown in Table 1. The mean dose of rosuvastatin was 11.7 mg/wk (range, 2.5-20 mg/wk): 6 patients took 10 mg twice weekly, 6 took 5 mg twice weekly,

3 took 10 mg once weekly, 2 took 5 mg once weekly, and 1 each took 5 mg once every 2 weeks, 2.5 mg thrice weekly, 2.5 mg thrice every 2 weeks, and 5 mg for 5 of every 14 days. Two patients who started the infrequent, low-dose rosuvastatin regimen stopped after 10 and 14 days, because of persistent myalgias, and were not included in the final analysis. Overall, the mean  SD reduction of LDL-C was 1.43  0.83 mmol/L or 31.5% (P < 0.001) (Table 2 and Fig. 1). Furthermore, total cholesterol was significantly reduced by 2.03  2.04 mmol/L or 27.9% (P ¼ 0.0002) (Table 2 and Fig. 1). Absolute changes in triglycerides and high density lipoprotein-C were 0.55  1.49 and -0.02  0.20 mmol/L, respectively (both not significant). The Pearson correlation coefficient between percentage of LDL-C reduction and total weekly rosuvastatin dose was 0.431 (P ¼ 0.066). Thus, even at these low doses, the decrease in LDL-C tended to be correlated with total weekly rosuvastatin dose. Using this regimen, 4 patients (19%) attained the 2012 Canadian Cardiovascular Society Dyslipidemia Guidelines LDL-C target of < 2.0 mmol/L. Post hoc subgroup analyses found no difference in response to infrequent rosuvastatin therapy depending on sex or the use of concomitant medications (data not shown). Finally, there was no lower-dose threshold that provided a clear cutoff for no further statin efficacy.

Table 2. Lipid profiles after treatment

Weeks of statin therapy, mean (range) Total cholesterol, mmol/L Triglyceride, mmol/L HDL-C, mmol/L LDL-C, mmol/L Patients at LDL-C target after treatment, n (%)

Overall

Male

Female

89.2 (24-240)

86.6 (36-192)

91.6 (24-240)

5.27  0.96 1.99  0.91 1.31  0.42 3.06  1.02 4 (19.1)

5.35 1.98 1.24 3.21 2

 0.90  0.99  0.38  1.00 (20)

5.20  1.05 2.01  0.87 1.37  0.47 2.91  1.07 2 (18.1)

HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

Discussion Statin intolerance is a commonly encountered clinical challenge.8 In a small group of these patients, we found that an infrequent dosing regimen of rosuvastatin was associated with significant improvements in total cholesterol and LDL-C, which were reduced by 2.03  2.04 and 1.31  0.83 mmol/L (27.9% and 31.5%), respectively, from baseline (both P < 0.001). The total average weekly dose for patients in this study was 11.7 mg, with a mean of 1.7 tablets taken

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Canadian Journal of Cardiology Volume 30 2014

Figure 1. Mean  SD of baseline and after-treatment lipid and lipoprotein levels (mmol/L) in 21 patients given infrequent, low-dose rosuvastatin. Percent changes and P values are shown. HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NS, not significant.

weekly. Of 21 study subjects, 4 (19%) attained the LDL-C target level of < 2.0 mmol/L. For patients with difficulty tolerating daily statins, such reductions using an infrequent, low-dose rosuvastatin regimen could be seen as representing an improvement, even though hard outcomes data on such a regimen are lacking. However, assuming that some LDL-C reduction is better than no LDLC reduction, this approach might be suitable for some patients to limit symptoms of statin intolerance, while still offering a significantly improved lipid profile. Because of the variability in individual tolerance and small patient sample, a wide range of dosing was observed; in general, this was titrated to attain a dose and regimen that the patient could tolerate and was comfortable taking. This reaffirms the challenges involved in finding a single common dose for an entire population sample, and further suggests the potential need for individualized therapy. Interestingly, 2 patients not included in our final analysis stopped their infrequent, low-dose rosuvastatin regimen altogether because of persistent myalgias. Notably, in the present study, approximately half of the patients who completed the current study were later able to increase their statin dose toward a more frequent regimen (eg, 3 days per week or even daily), after having tolerated the infrequent rosuvastatin regimen for at least 3 months. Thus, infrequent low-dose statin regimens could serve as a “stepping stone” to help patients attain higher doses at more frequent intervals. The issue of muscle-related symptoms in statin users is complex and challenging. A recent N-of-1 double-blind placebo controlled study in patients with a history of statinrelated muscle symptoms found that participants reported such symptoms with equal frequency and intensity regardless of whether they were actually taking statin or placebo.9 The reasons for such observations are unclear, but infrequent, lowdose rosuvastatin therapy might represent an option for such patients that might allow them to derive some benefit from statin in the context of a treatment regimen that they might consider tolerable. There are several possible mechanisms that would explain why ultra-low statin doses given on a nondaily basis might be better tolerated by some patients.10 The current study had some limitations. First, it was a retrospective chart review. Second, we analyzed only 21 patients. Third, the sample was unbalanced with respect to sex and CVD risk. Fourth, although all subjects had to have been

intolerant to at least 2 previous statins, it remains possible that they might have tolerated a third statin at a more typical dose. Fifth, a relatively wide range of rosuvastatin doses and dosing intervals made it difficult to determine or extrapolate an “ideal” dosing schedule. Finally, this study, although it showed an improvement in the lipid profile, was too short to detect any effect on hard clinical outcomes. Nonetheless, the findings support the idea that infrequent, low-dose rosuvastatin might still provide biochemical efficacy for patients who have difficultly tolerating higher doses administered at shorter intervals. In summary, we have shown that nondaily statin dosing improves the lipid profile and is tolerated by most individuals. About one-fifth of high-risk subjects attained LDL-C < 2.0 mmol/L. Of course, such treatment needs to be given in the context of continued attention to a healthy diet, physical activity, smoking cessation, and control of glycemia and blood pressure. It would be important to follow patients taking such irregular dosing regimens longitudinally to observe lasting laboratory and clinical benefits. This might be accomplished through a randomized controlled trial. Additional, nonstatin drugs (eg, cholesterol absorption inhibitors and bile acid sequestrants) could also be added, as required, to help achieve LDL-C targets. LDL-C levels also can be monitored to evaluate adherence to such a therapeutic regimen. However, the role of LDL-C targets in CVD risk reduction is currently a topic of considerable debate11 and is beyond the scope of the current report. Funding Sources R.A.H. is supported by the Jacob J. Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Canada Research Chair in Human Genetics, the Martha G. Blackburn Chair in Cardiovascular Research, and operating grants from the Canadian Institutes of Health Research (MOP-13430, MOP-79523, CTP-79853), the Heart and Stroke Foundation of Ontario (NA-6059, T-6018, PRG-4854), and Genome Canada through the Ontario Genomics Institute. Disclosures R.A.H. is on advisory boards and speaker’s bureaus for Merck, Amgen, and Valeant Pharmaceuticals. The other authors have no conflicts of interest to disclose.

Ibrahim et al. Ultra-low Dose Rosuvastatin

References 1. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376: 1670-81. 2. Cholesterol Treatment Trialists’ (CTT) Collaboration. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581-90. 3. Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med 2009;150:858-68. 4. McTaggart F, Buckett L, Davidson R, et al. Preclinical and clinical pharmacology of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Am J Cardiol 2001;87:28B-32B. 5. Joy T, Hegele RA. Alternate day dosing of rosuvastatin: potential usefulness in statin-intolerant patients. Can J Cardiol 2009;25:453. 6. Goldberg AS, DeGorter MK, Ban MR, Kim RB, Hegele RA. Efficacy and plasma drug concentrations with nondaily dosing of rosuvastatin. Can J Cardiol 2013;29:915-9.

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7. Anderson TJ, Gregoire J, Hegele RA, et al. 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol 2013;29:151-67. 8. Mancini GB, Tashakkor AY, Baker S, et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Working Group Consensus update. Can J Cardiol 2013;29:1553-68. 9. Joy TR, Monjed A, Zou GY, et al. N-of-1 (single-patient) trials for statinrelated myalgia. Ann Intern Med 2014;160:301-10. 10. Pollak PT. Nondaily statin dosing: mechanisms of a potentially important approach to dealing with statin intolerance. Can J Cardiol 2013;29: 895-8. 11. Anderson TJ, Gregoire J, Hegele RA, et al. Are the ACC/AHA guidelines on the treatment of blood cholesterol a game changer? A perspective from the Canadian Cardiovascular Society Dyslipidemia Panel. Can J Cardiol 2014;30:377-80.

The effect of infrequent low-dose rosuvastatin on the lipid profile.

We retrospectively studied 21 patients who had difficulty tolerating daily or alternating-day statins. Patients received rosuvastatin at a mean freque...
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