James W. Blasetto

Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial).

The primary objective of this 6-week, parallel-group, open-label, randomized, multicenter trial was to compare rosuvastatin with atorvastatin, pravastatin, and simvastatin across dose ranges for reduction of low-density lipoprotein (LDL) cholesterol. Secondary objectives included comparing rosuvastatin with comparators for other lipid modifications and achievement of National Cholesterol Education Program Adult Treatment Panel III and Joint European Task Force LDL cholesterol goals. After a dietary lead-in period, 2,431 adults with hypercholesterolemia (LDL cholesterol > or =160 and <250 mg/dl; triglycerides <400 mg/dl) were randomized to treatment with rosuvastatin 10, 20, 40, or 80 mg; atorvastatin 10, 20, 40, or 80 mg; simvastatin 10, 20, 40, or 80 mg; or pravastatin 10, 20, or 40 mg. At 6 weeks, across-dose analyses showed that rosuvastatin 10 to 80 mg reduced LDL cholesterol by a mean of 8.2% more than atorvastatin 10 to 80 mg, 26% more than pravastatin 10 to 40 mg, and 12% to 18% more than simvastatin 10 to 80 mg (all p <0.001). Mean percent changes in high-density lipoprotein cholesterol in the rosuvastatin groups were +7.7% to +9.6% compared with +2.1% to +6.8% in all other groups. Across dose ranges, rosuvastatin reduced total cholesterol significantly more (p <0.001) than all comparators and triglycerides significantly more (p <0.001) than simvastatin and pravastatin. Adult Treatment Panel III LDL cholesterol goals were achieved by 82% to 89% of patients treated with rosuvastatin 10 to 40 mg compared with 69% to 85% of patients treated with atorvastatin 10 to 80 mg; the European LDL cholesterol goal of <3.0 mmol/L was achieved by 79% to 92% in rosuvastatin groups compared with 52% to 81% in atorvastatin groups. Drug tolerability was similar across treatments.

Comparison of the efficacy of rosuvastatin versus atorvastatin, simvastatin, and pravastatin in achieving lipid goals: results from the STELLAR trial

SUMMARY In the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial, the efficacy of rosuvastatin calcium (Crestor*) was compared with that of atorvastatin (Lipitor †), simvastatin (Zocor‡), and pravastatin (Pravachol§) for lowering plasma low-density lipoprotein cholesterol (LDL-C) after 6 weeks of treatment. In this multicenter, parallel-group, open-label trial, adults with hypercholesterolemia were randomized to treatments with rosuvastatin 10, 20,40, or 80u2009mg, atorvastatin 10, 20,40, or 80u2009mg, simvastatin 10,20,40, or 80u2009mg, or pravastatin 10, 20, or 40u2009mg. Efficacy and safety results from this trial have been previously published. The additional analyses included in this report show that 53% (83/156) to 80% (125/157) of patients in the rosuvastatin 10- to 40-mg groups achieved LDL-C levels <100u2009mgu2009dl−1 (<2.6u2009mmolu2009l−1), compared with 18% (28/158) to 70% (115/165) of patients who received atorvastatin, 8% (13/165) to 53% (86/163) of patients who received simvastatin, and 1% (1/160) to 8% (13/161) of patients who received pravastatin. Other additional analyses showed that more patients in the rosuvastatin 10- to 40-mg groups than in the comparator groups who were at high risk of coronary heart disease according to National Cholesterol Education Program Adult Treatment Panel (ATP) III, Joint European Societies, or Canadian guidelines achieved the LDL-C goals of <100u2009mgu2009dl−1 (<2.6u2009mmolu2009l−1) (55% to 77% compared with 0 to 64%), <3.0u2009mmolu2009l−1 (<116u2009mgu2009dl−1) (76% to 94% compared with 6% to 81%), and <2.5u2009mmolu2009l−1 (<97mgu2009dl−1) (47% to 69% compared with 0 to 53%), respectively. Results favoring rosuvastatin versus the comparators were also reported for patients: (a) who had triglycerides >200u2009mgu2009dl−1 (>2.3u2009mmolu2009l−1), and achieved both ATP III LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) goals (80% to 84% versus 15% to 84%); (b) overall who achieved the Canadian LDL-C goals of <2.5 (<97u2009mgu2009dl−1) to <5.0u2009mmolu2009l−1 (< 193mg/dl) (85% to 91% versus 44% to 86%); and (c) who achieved all 3 Canadian goals for LDL-C, triglycerides (<3.0u2009mmolu2009l−1 [< 266u2009mgu2009dl−1] to < 2.0u2009mmolu2009l−1 [<177u2009gu2009dl−1]), and the total cholesterol/high-density lipoprotein-cholesterol ratio (<4 to <7) (70% to 83% versus 35% to 79%). * Crestor is a registered trademark of the AstraZeneca group of companies and is licensed to AstraZeneca from Shionogi & Co, Ltd, Osaka, Japan. † Lipitor is a registered trademark of Pfizer Inc. ‡ Zocor is a registered trademark of Merck & Co., Inc. § Pravachol is a registered trademark of Bristol-Myers Squibb Company.

Efficacy of rosuvastatin compared with other statins at selected starting doses in hypercholesterolemic patients and in special population groups.

A total of 5 randomized, double-blind trials in patients with hypercholesterolemia were prospectively designed to allow pooling of plasma lipid data after 12 weeks of treatment. The purpose was (1) to compare rosuvastatin 5 and 10 mg with atorvastatin 10 mg (data from 3 of the 5 trials); (2) to compare rosuvastatin 5 and 10 mg with simvastatin 20 mg and pravastatin 20 mg (data from 2 of the 5 trials); and (3) to summarize overall efficacy and subset analyses of rosuvastatin data from all 5 trials. Rosuvastatin 5 mg (n = 390) and 10 mg (n = 389) reduced low-density lipoprotein (LDL) cholesterol significantly more than did atorvastatin 10 mg (n = 393) (41.9% and 46.7% vs 36.4%, both p <0.001). Treatment with rosuvastatin 5 mg (n = 240) and 10 mg (n = 226) also resulted in significantly greater reductions in LDL cholesterol compared with both simvastatin 20 mg (n = 249) and pravastatin 20 mg (n = 252) (40.6% and 48.1% vs 27.1% and 35.7%, all p <0.001). Significant differences favoring rosuvastatin 10 mg were also observed for total cholesterol, high-density lipoprotein (HDL) cholesterol, non-HDL cholesterol, apolipoprotein (apo) B, and apo A-I versus atorvastatin 10 mg, and for total cholesterol, HDL cholesterol, triglycerides, non-HDL cholesterol, and apo B versus simvastatin 20 mg and pravastatin 20 mg. Analyses of all the rosuvastatin 10 mg data (n = 615) from the 5 trials in subgroups defined by age > or =65 years, female sex, postmenopausal status, hypertension, atherosclerosis, type 2 diabetes, and obesity showed that rosuvastatin had consistent efficacy across patient subgroups.

Safety of Rosuvastatin: Update on 16,876 Rosuvastatin-Treated Patients in a Multinational Clinical Trial Program

Background: The safety and tolerability of rosuvastatin were assessed using data from 16,876patients who received rosuvastatin 5–40 mg in a multinational phase II/III/IIIb/IV program, representing 25,670 patient-years of continuous exposure to rosuvastatin. Methods: An integrated database, consisting of 33 trials whose databases were locked up to and including September 16, 2005, was used to examine adverse events and laboratory data. Results: In placebo-controlled trials, adverse events irrespective of causality assessment occurred in 52.1% of patients receiving rosuvastatin 5–40 mg (n = 931) and 51.8% of patients receiving placebo (n = 483). In all controlled clinical trials with comparator statins, rosuvastatin 5–40 mg was associated with an adverse event profile similar to profiles for atorvastatin 10–80 mg, simvastatin 10–80 mg, and pravastatin 10–40 mg. Clinically significant elevations in alanine aminotransferase (>3 times the upper limit of normal [ULN] on at least 2 consecutive occasions) were uncommon (≤0.2%) in the rosuvastatin and comparator statin groups. Elevated creatine kinase >10 times ULN occurred in ≤0.3% of patients receiving rosuvastatin or other statins. Myopathy (creatine kinase >10 times ULN with muscle symptoms) possibly related to treatment occurred in 0.03% of patients taking rosuvastatin at doses ≤40 mg. The frequency of dipstick-positive proteinuria at rosuvastatin doses ≤20 mg was comparable to that seen with other statins, and the development of proteinuria was not predictive of acute or progressive renal disease. Both short- and long-term rosuvastatin treatment were associated with small increases in estimated glomerular filtration rate, with improvements appearing to be somewhat greater in those patients beginning treatment with greater renal impairment. In the phase II–IV program, no deaths were attributed to rosuvastatin; at doses of rosuvastatin ≤40 mg, 1 case of rhabdomyolysis occurred in a patient who received rosuvastatin 20 mg and concomitant gemfibrozil treatment. Conclusion: In summary, rosuvastatin was well tolerated by a broad range of patients with dyslipidemia, and its safety profile was similar to those of comparator statins investigated in the clinical program. (Nota bene: The clinical development program for rosuvastatin initially evaluated rosuvastatin doses up to 80 mg. Following completion of the phase III/IIIb program, a decision was made not to pursue marketing approval for the 80-mg dose because the additional lipid-modifying benefits of this dose did not justify the potential risks for use in the general population of patients with dyslipidemia.)

Efficacy of Rosuvastatin 10 mg in Patients with the Metabolic Syndrome

The constellation of risk factors known as the metabolic syndrome increases the risk of coronary artery disease at any low-density lipoprotein (LDL) cholesterol level. We performed an exploratory analysis of data from 5 trials to study the effects of rosuvastatin 10 mg on lipid levels and ratios in hypercholesterolemic patients (LDL cholesterol > or =160 mg/dL and <250 mg/dL) who met a modified National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) definition of the metabolic syndrome. Of 580 patients completing 12 weeks of treatment with rosuvastatin 10 mg, 194 (33%) met the definition of the metabolic syndrome by exhibiting > or =3 of the following: body mass index >30; triglycerides > or =150 mg/dL; high-density lipoprotein (HDL) cholesterol <40 mg/dL in men and <50 mg/dL in women; blood pressure > or =130/> or =85 mm Hg or receiving current medication for hypertension; and fasting blood glucose > or =110 mg/dL. Patients with the metabolic syndrome had higher triglyceride, non-HDL cholesterol, apolipoprotein B, and lipid ratios, and lower HDL cholesterol and apolipoprotein A-I levels, at baseline compared with patients without the metabolic syndrome. In patients with the metabolic syndrome, rosuvastatin 10 mg improved LDL cholesterol (-47%), non-HDL cholesterol (-43%), non-HDL cholesterol/HDL cholesterol ratio (-47%), apolipoprotein B (-37%), apolipoprotein B/apolipoprotein A-I ratio (-40%), triglycerides (-23%), apolipoprotein A-I (+7%), and HDL cholesterol (+10%)-in a manner similar to that in hypercholesterolemic patients who did not meet these criteria. Among patients who met the metabolic syndrome criteria and who had triglycerides > or =200 mg/dL, 64% met their ATP III non-HDL goals.

Efficacy and Safety of Rosuvastatin 5 mg in Combination with Fenofibric Acid 135 mg in Patients with Mixed Dyslipidemia – A Phase 3 Study

BackgroundPatients with mixed dyslipidemia characterized by elevated low-density lipoprotein cholesterol (LDL-C), elevated triglycerides (TG), and reduced high-density lipoprotein cholesterol (HDL-C) often require combination therapy to improve multiple lipid and nonlipid parameters. This phase 3, multicenter, randomized, double-blind study evaluated the efficacy and safety of rosuvastatin 5xa0mg coadministered with fenofibric acid 135xa0mg in patients with mixed dyslipidemia.MethodsA total of 760 patients with TGu2009≥u2009150xa0mg/dL, HDL-C <40xa0mg/dL (<50xa0mg/dL for women), and LDL-Cu2009≥u2009130xa0mg/dL were randomized for a 12-week treatment period to rosuvastatin 5xa0mg, fenofibric acid 135xa0mg, or rosuvastatin 5xa0mg + fenofibric acid 135xa0mg. The primary efficacy comparisons were mean percentage changes in HDL-C and TG (rosuvastatin + fenofibric acid vs. rosuvastatin monotherapy), and LDL-C (rosuvastatin + fenofibric acid vs. fenofibric acid monotherapy).ResultsTreatment with rosuvastatin + fenofibric acid resulted in statistically significant greater improvements in HDL-C (23.0% vs. 12.4%; Pu2009<u20090.001) and TG (–40.3% vs. –17.5%; Pu2009<u20090.001), compared with rosuvastatin monotherapy; and LDL-C (–28.7% vs. –4.1%; Pu2009<u20090.001), compared with fenofibric acid monotherapy. All secondary efficacy variables improved with combination therapy. Combination therapy was generally well tolerated with a safety profile consistent with individual monotherapies. No unexpected muscle, hepatic, or renal safety signals were identified with combination therapy versus individual monotherapies.ConclusionIn conclusion, rosuvastatin 5xa0mg + fenofibric acid 135xa0mg resulted in comprehensive improvements in the lipid profile of patients with mixed dyslipidemia without unanticipated adverse events.

Lipid-modifying effects of rosuvastatin in postmenopausal women with hypercholesterolemia who are receiving hormone replacement therapy.

SUMMARY Objective: To evaluate the efficacy and safety of rosuvastatin in postmenopausal women with hypercholesterolemia who are receiving hormone replacement therapy (HRT) in a randomized, double-blind, placebo-controlled trial. Methods: After a 6-week dietary lead-in period, 135 postmenopausal women who had been taking a stable HRT regimen for at least 3 months were randomized to receive rosuvastatin 5u2009mg, 10u2009mg or placebo for 12 weeks. Fasting levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG) were assessed at weeks 0, 2, 6, 10, and 12; apolipoprotein (Apo) B and Apo A-I were measured at weeks 0 and 12. Results: Rosuvastatin 5u2009mg and 10u2009mg significantly reduced LDL-C by 38% (SE = 2.1) and 49% (SE = 2.1), respectively, compared with placebo (1% [SE = 2.1]; p < 0.001). TC, TG, Apo B, and all lipid ratios examined (LDL-C/HDL-C, TC/HDL-C, non-HDL-C/HDL-C, and Apo B/Apo A-I) were also reduced significantly by both rosuvastatin doses (u2009p < 0.001). HDL-C levels increased significantly in the rosuvastatin groups (11% and 8% for 5u2009mg and 10u2009mg, respectively, vs. –0.5% for placebo; p < 0.001), as did Apo A-I levels (u2009p < 0.05). The combination of rosuvastatin plus HRT was well tolerated with no apparent differences among treatments in the numbers or types of adverse events reported. Conclusions: Rosuvastatin 5u2009mg or 10u2009mg once daily is a well-tolerated and highly efficacious lipid-lowering therapy in postmenopausal women receiving HRT.

Effectiveness of statins in Medicare-eligible patients and patients < 65 years using clinical practice data.

Objective:u2002 This study compared effectiveness of rosuvastatin (RSV) with other statins on lowering LDL‐C and LDL‐C goal attainment among Medicare‐eligible patients (age ≥u200365u2003years) and patients with age <u200365u2003years treated in usual clinical practice to provide evidence of real‐world effectiveness of statins.

Efficacy of rosuvastatin 10 mg in patients with the metabolic syndrome. Discussions

The constellation of risk factors known as the metabolic syndrome increases the risk of coronary artery disease at any low-density lipoprotein (LDL) cholesterol level. We performed an exploratory analysis of data from 5 trials to study the effects of rosuvastatin 10 mg on lipid levels and ratios in hypercholesterolemic patients (LDL cholesterol ≥160 mg/dL and 30; triglycerides ≥150 mg/dL; high-density lipoprotein (HDL) cholesterol <40 mg/dL in men and <50 mg/dL in women; blood pressure ≥130/≥85 mm Hg or receiving current medication for hypertension; and fasting blood glucose ≥110 mg/dL. Patients with the metabolic syndrome had higher triglyceride, non-HDL cholesterol, apolipoprotein B, and lipid ratios, and lower HDL cholesterol and apolipoprotein A-1 levels, at baseline compared with patients without the metabolic syndrome. In patients with the metabolic syndrome, rosuvastatin 10 mg improved LDL cholesterol (-47%), non-HDL cholesterol (-43%), non-HDL cholesterol/HDL cholesterol ratio (-47%), apolipoprotein B (-37%), apolipoprotein B/apolipoprotein A-1 ratio (-40%), triglycerides (-23%), apolipoprotein A-1 (+7%), and HDL cholesterol (+10%) -in a manner similar to that in hypercholesterolemic patients who did not meet these criteria. Among patients who met the metabolic syndrome criteria and who had triglycerides ≥200 mg/dL, 64% met their ATP III non-HDL goals.