Uses
Rosuvastatin is used as an adjunct to nondrug therapies (i.e., lifestyle modifications) for prevention of cardiovascular events and for the management of dyslipidemias.
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Prevention of Cardiovascular Events
The American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol management guideline recommends statins as first-line therapy for prevention of atherosclerotic cardiovascular disease (ASCVD) in adults. There is extensive evidence demonstrating that statins can substantially reduce ASCVD risk when used for secondary prevention or primary prevention (in high-risk patients). Because the relative reduction in ASCVD risk is correlated with the degree of low-density lipoprotein (LDL)-cholesterol lowering, the maximum tolerated statin intensity should be used to achieve optimum ASCVD benefits. According to the ACC/AHA guidelines, rosuvastatin may be used for primary or secondary prevention in adults when moderate- or high-intensity statin therapy is indicated.
(See Prevention of Cardiovascular Events under Dosage and Administration: Dosage.) Nonstatin therapies do not provide acceptable ASCVD risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD. and also consult the most recent ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (available at http://www.cardiosource.org or http://my.americanheart.org).-
Primary Prevention
Rosuvastatin is used as an adjunct to nondrug therapies (i.e., lifestyle modifications) in patients without clinical evidence of coronary heart disease (CHD) who have an increased risk of cardiovascular disease based on age (men 50 years of age or older, women 60 years of age or older), high-sensitivity C-reactive protein (hsCRP) concentrations of 2 mg/L or greater, and at least one additional cardiovascular disease risk factor (e.g., hypertension, low high-density lipoprotein [HDL]-cholesterol concentrations, smoking, family history of premature CHD) to reduce the risk of stroke or myocardial infarction (MI) and to reduce the risk of undergoing arterial revascularization procedures.
The ACC/AHA cholesterol management guideline recommends statins as first-line therapy for primary prevention in patients 21 years of age and older without clinical ASCVD who have primary, severe elevations in LDL-cholesterol concentration (190 mg/dL or greater); patients 40-75 years of age with type 1 or 2 diabetes mellitus; and patients 40-75 years of age with LDL-cholesterol concentrations of 70-189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher. Before initiating statin therapy for primary prevention in patients without clinical ASCVD or diabetes mellitus, it is reasonable for clinicians and patients to discuss the potential for ASCVD risk reduction benefits, adverse effects, and drug interactions, as well as patient preferences for treatment.
In the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study in 17,802 patients (men 50 years of age or older and women 60 years of age or older) without clinical evidence of cardiovascular disease who had LDL-cholesterol concentrations of less than 130 mg/dL and hsCRP concentrations of 2 mg/L or greater, therapy with rosuvastatin (20 mg daily) for a mean of 2 years reduced the risk of major cardiovascular events (i.e., composite of cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for unstable angina or an arterial revascularization procedure) by 44% compared with placebo. Aside from reducing the risk of the primary composite end point, rosuvastatin also substantially reduced the risk of certain individual components of the primary end point (i.e., nonfatal MI, nonfatal stroke, arterial revascularization procedure), as well as the risk of any (fatal and nonfatal) MI and stroke. However, there were no treatment differences among the rosuvastatin and placebo groups for death secondary to cardiovascular causes or hospitalization for unstable angina. At one year, rosuvastatin increased HDL-cholesterol concentrations and reduced LDL-cholesterol, hsCRP, total cholesterol, and serum triglyceride concentrations compared with placebo. In a post hoc subgroup analysis of 1405 patients with hsCRP concentrations of 2 mg/L or greater and no other traditional risk factors (smoking, blood pressure of at least 140/90 mmHg or taking antihypertensives, low HDL-cholesterol concentrations) other than age, there was no substantial treatment benefit associated with rosuvastatin after adjustment for high HDL-cholesterol concentrations.
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Reducing Progression of Coronary Atherosclerosis
Rosuvastatin is used as an adjunct to dietary therapy to slow the progression of atherosclerosis as part of a treatment strategy to lower total and LDL-cholesterol concentrations to target levels.
In the Measuring Effects on Intima Media Thickness: an Evaluation of Rosuvastatin (METEOR) study in 984 patients with elevated LDL-cholesterol concentrations and subclinical atherosclerosis (as determined by carotid intimal-medial thickness [cIMT]) who were at low risk (Framingham risk less than 10% over 10 years) for symptomatic coronary artery disease, therapy with rosuvastatin (40 mg daily) for 2 years slowed progression of atherosclerosis (as determined by B-mode ultrasound of the rate of change in mean maximum cIMT) compared with placebo. However, rosuvastatin did not induce disease regression.
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Intensity of Statin Therapy
The ACC/AHA cholesterol management guideline states that the appropriate intensity of a statin should be used to reduce the risk of ASCVD in patients most likely to benefit. Based on the average LDL-cholesterol response observed with specific statins and dosages used in the randomized controlled studies evaluated by the guideline expert panel, ACC/AHA considers rosuvastatin 5-10 mg daily to be a moderate-intensity statin (producing approximate LDL-cholesterol reductions of 30% to less than 50%) and rosuvastatin 20-40 mg daily to be a high-intensity statin (producing average LDL-cholesterol reductions of at least 50%). However, individual response may vary in clinical practice.
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Combination Antilipemic Therapy
The ACC/AHA cholesterol management guideline states that nonstatin drugs may be useful adjuncts to statin therapy in certain high-risk patients (e.g., patients with ASCVD, LDL-cholesterol concentrations of at least 190 mg/dL, or diabetes mellitus) who have a less-than-anticipated response to statins, are unable to tolerate a less-than-recommended intensity of a statin, or are completely intolerant to statin therapy, particularly if there is evidence from randomized controlled studies suggesting that the addition of the nonstatin drug further reduces ASCVD events. If combination therapy is necessary, selection of the nonstatin drug should be based on the risk and benefit profile (i.e., reduction in ASCVD risk outweighs the drug's potential for adverse effects and drug interactions) and patient preferences.
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Patients with Chronic Kidney Disease
The potential benefits of rosuvastatin in patients with chronic kidney disease, a population at high risk of cardiovascular disease, were evaluated in the Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis (AURORA), a randomized, double-blind study in 2776 patients undergoing hemodialysis. In this study, therapy with rosuvastatin 10 mg daily for a median duration of 3.8 years did not substantially reduce the primary composite end point of cardiovascular death, nonfatal MI, or nonfatal stroke compared with placebo.
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Dyslipidemias
Rosuvastatin is used as an adjunct to dietary therapy for the management of primary hyperlipidemia or mixed dyslipidemia, hypertriglyceridemia, primary dysbetalipoproteinemia, and/or homozygous familial hypercholesterolemia. Efficacy of rosuvastatin in patients with Fredrickson type I or V dyslipidemia has not been established.
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Primary Hyperlipidemia or Mixed Dyslipidemia
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Adults
Rosuvastatin is used as an adjunct to nondrug therapies (e.g., dietary management) in adults to reduce elevated total cholesterol, LDL-cholesterol, apolipoprotein B (apo B), non-HDL-cholesterol, and triglyceride concentrations, and to increase HDL-cholesterol concentrations in the management of primary hyperlipidemia or mixed dyslipidemia. Efficacy of rosuvastatin in patients with hyperlipidemia or mixed dyslipidemia has been established in placebo-controlled studies and in comparative studies with other statins (e.g., atorvastatin, pravastatin, simvastatin). Statins such as rosuvastatin also are used in combination with fenofibrate to decrease triglyceride concentrations and increase HDL-cholesterol concentrations in patients with mixed dyslipidemia and CHD (or CHD risk equivalents) who are receiving optimal statin therapy; however, no additional benefit on cardiovascular morbidity and mortality has been demonstrated with such combination therapy beyond that already established with statin monotherapy.
Reductions in total cholesterol and LDL-cholesterol concentrations achieved with usual dosages of rosuvastatin substantially exceed those with placebo or compared with baseline values. In a dose-ranging study in patients with primary hyperlipidemia, mean reductions in total cholesterol averaged 33, 36, 40, or 46% with rosuvastatin dosages of 5, 10, 20, or 40 mg, respectively, compared with 5% with placebo; corresponding reductions in LDL-cholesterol concentrations were 45, 52, 55, or 63%, respectively, versus 7% with placebo, while increases in HDL-cholesterol averaged 13, 14, 8, or 10%, respectively, versus 3% with placebo.
In a 6-week comparative study in more than 2200 patients (approximately 50% were women and about 30% were 65 years of age or older) with primary hyperlipidemia, reductions in LDL-cholesterol concentrations in patients receiving rosuvastatin (10 mg daily) exceeded those with atorvastatin (10 mg daily), pravastatin (10, 20, or 40 mg daily), or simvastatin (10, 20, or 40 mg daily). LDL-cholesterol reductions from baseline averaged 46, 52, or 55% with rosuvastatin 10, 20, or 40 mg, respectively, daily in these patients.
Rosuvastatin alone or combined with extended-release niacin improves the atherogenic lipid profile in patients with mixed dyslipidemia and low HDL-cholesterol concentrations. In a 24-week, randomized, double-blind study, LDL-cholesterol reductions averaged 48, 0.1, 42, or 36% in patients receiving rosuvastatin 40 mg daily, extended-release niacin 2 g daily, rosuvastatin 40 mg plus extended-release niacin 1 g daily, or rosuvastatin 10 mg plus extended-release niacin 2 g daily, respectively; HDL-cholesterol concentrations with these regimens were increased by 11, 12, 17, or 24%, respectively. Reductions in triglyceride concentrations and increases in HDL-cholesterol concentrations were similar with the highest dosage of rosuvastatin (40 mg daily) or extended-release niacin (2 g daily) given as monotherapy. Patients receiving rosuvastatin had a lower incidence of treatment-related adverse effects than those receiving niacin-containing regimens. (
See Musculoskeletal Effects under Cautions: Warnings/Precautions and alsoDrug Interactions: Niacin .)
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Pediatric Patients
Rosuvastatin is used as an adjunct to nondrug therapies (e.g., dietary management) to decrease elevated serum total cholesterol, LDL-cholesterol, and apo B concentrations in the management of heterozygous familial hypercholesterolemia in children and adolescents 8-17 years of age who, despite an adequate trial of dietary management, have a serum LDL-cholesterol concentration exceeding 190 mg/dL or a serum LDL-cholesterol concentration exceeding 160 mg/dL and either a family history of premature cardiovascular disease or 2 or more other cardiovascular risk factors. The long-term effect of rosuvastatin therapy in childhood on reducing cardiovascular morbidity and mortality in adulthood has not been established. and also consult the most recent Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents (available at http://www.nhlbi.nih.gov).
Efficacy and safety of rosuvastatin in pediatric patients with heterozygous familial hypercholesterolemia were evaluated in a double-blind, placebo-controlled study and an open-label uncontrolled study. In the controlled study (which was followed by a 40-week, open-label, dose-titration phase), 176 children and adolescents 10-17 years of age with heterozygous familial hypercholesterolemia (mean baseline LDL-cholesterol concentration of 233 mg/dL) were randomized to receive either rosuvastatin (5, 10, or 20 mg daily) or placebo for 12 weeks; after 12 weeks of the double-blind phase, all patients entered an open-label phase and received rosuvastatin for an additional 40 weeks. Treatment with rosuvastatin resulted in substantial reductions in concentrations of total cholesterol, LDL-cholesterol (primary end point), and apo B compared with placebo during the 12-week double-blind phase. Mean reductions in total cholesterol averaged 30, 34, or 39% with rosuvastatin dosages of 5, 10, or 20 mg, respectively, compared with 0% with placebo; corresponding reductions in LDL-cholesterol concentrations were 38, 45, or 50%, respectively, versus 1% with placebo, and in apo B concentrations were 32, 38, or 41%, respectively, versus 2% with placebo. Changes in concentrations of triglycerides and HDL-cholesterol were similar in patients receiving rosuvastatin and in those receiving placebo. At the end of the 12-week double-blind phase, 12, 41, or 41% of patients receiving rosuvastatin dosages of 5, 10, or 20 mg achieved the LDL-cholesterol goal of less than 110 mg/dL compared with 0% of those receiving placebo. During the 40-week open-label phase, 71% of patients were titrated to the maximum rosuvastatin dosage of 20 mg daily and 41% of the patients achieved the LDL-cholesterol goal of less than 110 mg/dL.
In the open-label study (Hypercholesterolaemia in Children and Adolescents taking Rosuvastatin Open Label [CHARON]), 175 children and adolescents 8-17 years of age with heterozygous familial hypercholesterolemia (defined as a documented genetic defect in the LDL receptor or in apo B) and a mean baseline LDL-cholesterol concentration of 236 mg/dL received rosuvastatin at an initial dosage of 5 mg once daily, titrated to a maximum tolerated dosage of 10 mg daily (in patients 8-9 years of age) or 20 mg daily (in patients 10-17 years of age). The observed reductions in LDL-cholesterol concentrations from baseline were consistent across age groups and consistent with previous experience in controlled trials of adults and pediatric patients. At 24 months, LDL-cholesterol concentrations were reduced from baseline by approximately 35-43%; 48, 46, or 32% of patients receiving rosuvastatin dosages of 5, 10, or 20 mg daily, respectively, achieved the LDL-cholesterol goal of less than 110 mg/dL.
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Homozygous Familial Hypercholesterolemia
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Adults
Rosuvastatin is used as an adjunct to other lipid-lowering therapies (e.g., plasma LDL-apheresis) or alone, if such therapies are not available, to reduce elevated total cholesterol, LDL-cholesterol, and apo B concentrations in adults with homozygous familial hypercholesterolemia. In an open-label, forced-titration study in 40 patients with homozygous familial hypercholesterolemia, therapy with rosuvastatin (20-40 mg daily [titrated at a 6-week interval]) decreased LDL-cholesterol concentrations by a mean of 22%. Approximately 33% of patients achieved additional (at least 6%) LDL-cholesterol lowering with an increase in the rosuvastatin dosage from 20 to 40 mg daily. Among the 27 patients with LDL-cholesterol reductions of 15% or greater, the mean LDL-cholesterol reduction achieved was 30%; among the 13 patients with LDL-cholesterol reductions of less than 15%, 3 had no change or an increase in LDL-cholesterol concentrations. LDL-cholesterol reductions of 15% or greater were observed in 3 of 5 patients with known receptor-negative status.
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Pediatric Patients
Rosuvastatin is used alone or in combination with other lipid-lowering therapies (e.g., LDL apheresis) to decrease elevated serum LDL-cholesterol, total cholesterol, non-HDL-cholesterol, and apo B concentrations in children and adolescents 7-17 years of age with homozygous familial hypercholesterolemia as an adjunct to nondrug therapies (e.g., dietary management). In a double-blind, placebo-controlled crossover study in 14 children and adolescents 6 years of age or older with homozygous familial hypercholesterolemia (mean baseline LDL-cholesterol concentration of 416 mg/dL, 50% receiving apheresis, 57% receiving ezetimibe), treatment with rosuvastatin 20 mg daily for 6 weeks resulted in substantial reductions in concentrations of LDL-cholesterol (22.3%), total cholesterol (20.1%), non-HDL-cholesterol (22.9%), and apo B (17.1%) compared with placebo.
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Hypertriglyceridemia
Rosuvastatin is used as an adjunct to nondrug therapies (e.g., dietary management) in the treatment of hypertriglyceridemia. In a 6-week, double-blind, placebo-controlled study in patients with primary hypertriglyceridemia (baseline triglyceride concentrations of 273-817 mg/dL), triglyceride concentrations were reduced by a median of 21, 37, 37, or 43% with rosuvastatin dosages of 5, 10, 20, or 40 mg daily, respectively, and increased by a median of 1% with placebo. AHA states that although statins have consistently shown benefit in subgroups with or without high triglyceride concentrations, fibric acid derivatives have more commonly been shown to provide greater benefit in subgroups with increased triglyceride concentrations.
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Primary Dysbetalipoproteinemia
Rosuvastatin is used as an adjunct to nondrug therapies (e.g., dietary management) for the treatment of primary dysbetalipoproteinemia (Fredrickson type III).
In a double-blind, crossover study in 32 patients with primary dysbetalipoproteinemia (genotypes 27 apo E2/E2 and 4 apo-E mutation [Arg145Cys]), treatment with rosuvastatin (10 or 20 mg daily) for 6 weeks resulted in reductions in concentrations of non-HDL-cholesterol (48 or 56%, respectively), total cholesterol (43 or 48%, respectively), triglycerides (40 or 43%, respectively), combined intermediate-density lipoprotein (IDL)- and very low-density lipoprotein (VLDL)-cholesterol (47 or 56%, respectively), and circulating remnant lipoproteins.
For additional information on the role of rosuvastatin or other statins in the treatment of lipoprotein disorders, prevention of cardiovascular events, or other uses, see General Principles of Antilipemic Therapy and also Uses in the HMG-CoA Reductase Inhibitors General Statement 24:06.08.
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