Safety of rosuvastatin

doi:10.1016/j.amjcard.2004.06.049

The American Journal of Cardiology

Volume 94, Issue 7, 1 October 2004, Pages 882-888

https://doi.org/10.1016/j.amjcard.2004.06.049 Get rights and content

The safety and tolerability of rosuvastatin were assessed (as of August 2003) using data from 12,400 patients who received 5 to 40 mg of rosuvastatin in a multinational phase II/III program, which represented 12,212 patient-years of continuous exposure to rosuvastatin. An integrated database was used to examine adverse events and laboratory data. In placebo-controlled trials, adverse events, irrespective of causality assessment, occurred in 57.4% of patients who received 5 to 40 mg of rosuvastatin (n = 744) and 56.8% of patients who received placebo (n = 382). In fixed-dose trials with comparator statins, 5 to 40 mg of rosuvastatin showed an adverse event profile similar to those for 10 to 80 mg of atorvastatin, 10 to 80 mg of simvastatin, and 10 to 40 mg of pravastatin. Clinically significant elevations in alanine aminotransferase (>3 times the upper limit of normal) and creatine kinase (>10 times the upper limit of normal) were uncommon (≤0.2%) in the groups that received rosuvastatin and comparator statins. Myopathy (creatine kinase >10 times the upper limit of normal with muscle symptoms) that was possibly related to treatment occurred in ≤0.03% of patients who took rosuvastatin at doses ≤40 mg. A positive finding of proteinuria with dipstick testing at rosuvastatin doses ≤40 mg was comparable to that seen with other statins, and the development of proteinuria was not predictive of acute or progressive renal disease. No deaths in the program were attributed to rosuvastatin, and no rhabdomyolysis occurred in patients who received 5 to 40 mg of rosuvastatin. Rosuvastatin was well tolerated by a broad range of patients who had dyslipidemia, and its safety profile was similar to those of the comparator statins investigated in this extensive clinical program.

Section snippets

Ethical considerations

The trials in the rosuvastatin clinical development program were designed and conducted in accordance with the Declaration of Helsinki (versions amended October 1996 and October 2000) and in compliance with the ethical principles of good clinical practice. Appropriate ethics committees or institutional review boards approved the research protocols; all patients (or their parents or guardians) gave their written, informed consent before initiation of any trial procedure.

Patient population

The patients studied had

Demographic and baseline characteristics

Demographic and baseline characteristics of the 12,400 patients who received 5 to 40 mg of rosuvastatin in the phase II/III program are listed in Table 1. This population included large numbers of patients ≥65 years old, women, and patients who had cardiovascular disease, diabetes mellitus, hypertension, and renal impairment. The 8 patients who were <18 years of age were included in a trial in patients with homozygous familial hypercholesterolemia. No major differences in demographic or

Discussion

The rosuvastatin phase II/III program was designed to study a patient population that had dyslipidemia and was representative of the patients who should receive statin therapy in clinical practice, particularly those patients characterized as “high risk” according to international cholesterol guidelines.12, 13 Altogether, 12,400 patients received 5 to 40 mg of rosuvastatin, representing >12,000 patient-years of continuous exposure in clinical trials. In this program, rosuvastatin was well

Acknowledgment

We gratefully acknowledge the investigators, their co-investigators and study coordinators, and the patients who participated in the rosuvastatin clinical development program. In addition, we thank Eric Justice, MA, and Gregg Truitt, BS, for assistance in the preparation of this report.

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Although statins reduce cardiovascular morbidity and mortality, only about one-half of eligible patients receive treatment. Safe and appropriate consumer access to statins could have a significant positive public health impact.
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For the primary endpoint, participant selection for statin therapy was concordant with clinician selection in 481 (96.2%) of 500 participants (95% confidence interval: 94.1%-97.7%), of whom 23 (4.6%) were deemed appropriate and 458 (91.6%) were deemed inappropriate for treatment. Discordance was due to incorrect self-selection (“OK to use”) in 3 cases, incorrect rejection (“not right for you”) in 14 cases and an incorrect “ask a doctor” outcome in 2 cases.
The use of a technology-assisted approach to consumer self-selection for statin therapy resulted in participant self-selection that showed substantial agreement with clinician selection.
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Rosuvastatin is a fully synthetic statin wich acts by interfering with the endogenous synthesis of cholesterol through competitively inhibiting the 3-hydroxy-3-methylglutaryl coenzyme A reductase, a liver enzyme responsible of the rate-limiting step in cholesterol synthesis. When compared to other molecules of the same class, it shows high efficacy in the improvement of lipid profile, and, thanks to its non-cholesterol-lowering actions (anti-inflammatory, antioxidant and antithrombotic), represents a crucial tool for cardiovascular primary and secondary prevention.
Moreover, recent data highlight rosuvastatin beneficial effects in several other fields. In this manuscript we analyzed literature sources in order to better define rosuvastatin features and discuss some critical issues.
Renal effects of atorvastatin and rosuvastatin in patients with diabetes who have progressive renal disease (PLANET I): A randomised clinical trial
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The role of lipid-lowering treatments in renoprotection for patients with diabetes is debated. We studied the renal effects of two statins in patients with diabetes who had proteinuria.
PLANET I was a randomised, double-blind, parallel-group trial done in 147 research centres in Argentina, Brazil, Bulgaria, Canada, Denmark, France, Hungary, Italy, Mexico, Romania, and the USA. We enrolled patients with type 1 or type 2 diabetes aged 18 years or older with proteinuria (urine protein:creatinine ratio [U_PCR] 500–5000 mg/g) and taking stable angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or both. We randomly assigned participants to atorvastatin 80 mg, rosuvastatin 10 mg, or rosuvastatin 40 mg for 52 weeks. The primary endpoint was change from baseline to week 52 of mean U_PCR in each treatment group. The study is registered with ClinicalTrials.gov, number NCT00296374.
We enrolled 353 patients: 118 were assigned to rosuvastatin 10 mg, 124 to rosuvastatin 40 mg, and 111 to atorvastatin 80 mg; of these, 325 were included in the intention-to-treat population. U_PCR baseline:week 52 ratio was 0·87 (95% CI 0·77–0·99; p=0·033) with atorvastatin 80 mg, 1·02 (0·88–1·18; p=0·83) with rosuvastatin 10 mg, and 0·96 (0·83–1·11; p=0·53) with rosuvastatin 40 mg. In a post-hoc analysis to compare statins, we combined data from PLANET I with those from PLANET II (a similar randomised parallel study of 237 patients with proteinuria but without diabetes; registered with ClinicalTrials.gov, NCT00296400). In this analysis, atorvastatin 80 mg lowered U_PCR significantly more than did rosuvastatin 10 mg (−15·6%, 95% CI −28·3 to −0·5; p=0·043) and rosuvastatin 40 mg (−18·2%, −30·2 to −4·2; p=0·013). Adverse events occurred in 69 (60%) of 116 patients in the rosuvastatin 10 mg group versus 79 (64%) of 123 patients in the rosuvastatin 40 mg group versus 63 (57%) of 110 patients in the atorvastatin 80 mg group; renal events occurred in nine (7·8%) versus 12 (9·8%) versus five (4·5%).
Despite high-dose rosuvastatin lowering plasma lipid concentrations to a greater extent than did high-dose atorvastatin, atorvastatin seems to have more renoprotective effects for the studied chronic kidney disease population.
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Evidence suggesting that statins may contribute to renoprotection has been provided in experimental and clinical studies. Statins restore endothelial nitric oxide (NO) levels by mechanisms including up-regulation of endothelial NO synthase (eNOS) expression. Caveolin-1/eNOS interaction is essential preventing inadequate NO levels. Here, we evaluated whether caveolin-1 associated with eNOS/Hsp70 expression may be involved in the mechanism by which rosuvastatin exerts tubulointerstitial fibrosis protection in neonatal unilateral ureteral obstruction (UUO). Neonatal rats subjected to UUO within 2 days of birth and controls were treated daily with vehicle or rosuvastatin (10 mg/kg/day) by oral gavage for 14 days.
After UUO, morphometric evaluation of interstitial fibrosis showed increased interstitial volume (Vv) associated with reduced NO availability, increased mRNA and protein caveolin-1 expression as well as downregulation eNOS and heat shock protein 70 (Hsp70) expression. Conversely, rosuvastatin treatment attenuated the fibrotic response linked to high NO availability, decreased mRNA and protein caveolin-1 expression, and marked upregulation of eNOS and Hsp70 expression at transcriptional and posttranscriptional levels. Moreover, protein–protein interactions determined by immunoprecipitation and by immunofluorescence co-localization have shown decreased caveolin-1/eNOS as well as increased Hsp70/eNOS interaction, after rosuvastatin treatment. A dose dependent effect of rosuvastatin on decreased caveolin-1 expression was shown in control cortex.
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Renal impairment or renal failure was reported in 536 study participants during 72,488 patient-years of follow-up. Renal event rates were higher in patients with history of heart failure (n = 5011), hypertension (n = 21,864), diabetes (n = 5165), or estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m² (n = 9507) at baseline but did not differ with rosuvastatin compared with placebo or with rosuvastatin 40 mg compared with rosuvastatin 10 mg. Relative risk (RR) estimates obtained from pooled analysis of placebo-controlled trials were RR: 1.03 (95% CI: 0.86–1.23, p = 0.777) for any reported renal impairment or renal failure event, RR: 1.02 (95% CI: 0.76–1.37, p = 0.894) for serious renal AEs, and RR: 0.70 (95% CI: 0.36–1.35, p = 0.282) for renal AEs leading to death.
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: This research was supported by AstraZeneca LP, Wilmington, Delaware, and AstraZeneca, Alderley Park, United Kingdom.

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Safety of rosuvastatin

Section snippets

Ethical considerations

Patient population

Demographic and baseline characteristics

Discussion

Acknowledgment

J Am Coll Cardiol

Am Heart J

Am J Cardiol

Atherosclerosis

Am J Cardiol

Cerivastatin and reports of fatal rhabdomyolysisCorrespondence

N Engl J Med

Classification of hyperlipidaemia and hyperlipoproteinaemias

Bull World Health Organ

A comparison of simvastatin and atorvastatin up to maximal recommended doses in a large multicenter randomized clinical trial

Curr Med Res Opin

Efficacy and safety of cerivastatin 0.8 mg in patients with hypercholesterolaemia: the pivotal placebo-controlled clinical trial

J Int Med Res