- Email: [email protected]
benefit-risk assessment of Rosuvastatin 10 to 40 milligrams
Benefit-Risk Assessment of Rosuvastatin 10 to 40 Milligrams H. Bryan Brewer, Jr.,
MD
The aim of this article is to examine the benefit-risk profile of rosuvastatin at doses of 10 to 40 mg. In dyslipidemic patients, rosuvastatin produced markedly greater reductions in low-density lipoprotein (LDL) cholesterol and equivalent or greater improvements in various lipid measures, including high-density lipoprotein (HDL) cholesterol, non-HDL cholesterol, and triglycerides when compared with atorvastatin, simvastatin, and pravastatin. In addition, rosuvastatin is more effective than these statins in allowing patients to reach National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III and Joint European Societies LDL cholesterol goals. The safety profile of rosuvastatin was reviewed (as of April 2003) in 12,569 patients, representing 14,231 patient-years of treatment at doses up to 80 mg. In controlled trials, rosuvastatin 10 to 40 mg dem-
onstrated a similar adverse event profile to those for atorvastatin 10 to 80 mg, simvastatin 10 to 80 mg, and pravastatin 10 to 40 mg. Myopathy (defined as muscle symptoms plus serum creatine kinase levels >10 times the upper limit of normal) attributed to rosuvastatin occurred in <0.03% of patients receiving rosuvastatin 10 to 40 mg. No cases of rhabdomyolysis occurred in patients receiving rosuvastatin 10 to 40 mg. Clinically significant alanine aminotransferase elevations occurred in 0.2% of patients receiving rosuvastatin and those receiving atorvastatin, simvastatin, and pravastatin. Compared with other widely used statins, the benefitrisk profile of rosuvastatin 10 to 40 mg appears to be very favorable. 䊚2003 by Excerpta Medica, Inc. Am J Cardiol 2003;92(suppl):23K–29K
osuvastatin (Crestor; licensed to AstraZeneca from Shionogi & Co, Ltd, Osaka, Japan) is a R 3-hydroxy-3-methylglutaryl coenzyme A reductase
of rosuvastatin reduced LDL cholesterol by up to 52%1,3–9 and by as much as 63% at 40 mg.1
inhibitor (statin) that markedly reduces low-density lipoprotein (LDL) cholesterol levels, increases highdensity lipoprotein (HDL) cholesterol levels, and improves other parameters of the atherogenic lipid profile.1 The worldwide clinical development program for rosuvastatin is the largest program ever conducted to evaluate the efficacy and safety of a new statin, including ⬎20,000 patients with a broad range of dyslipidemias (eg, Fredrickson type IIa/IIb hypercholesterolemia, heterozygous or homozygous familial hypercholesterolemia, or Fredrickson type IIb or IV hypertriglyceridemia). In addition, this program included a high percentage of elderly patients (31% aged ⱖ65 years; 7% aged ⱖ75 years), as well as patients with renal impairment (53%), hypertension (52%), cardiovascular disease (36%), and diabetes mellitus (17%).2 This article examines the benefit-risk profile of this agent at doses of 10 to 40 mg, using the efficacy, pharmacology, and safety data from this extensive clinical program.
LOW-DENSITY LIPOPROTEIN CHOLESTEROL REDUCTIONS In a variety of dose-ranging and comparative trials in patients with hypercholesterolemia, a 10-mg dose From the Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA. Crestor is a registered trademark of the AstraZeneca group of companies. Address for reprints: H. Bryan Brewer, Jr., MD, National Institutes of Health, Building 10, Magnuson CC, Room 7N115, 10 Center Drive, Bethesda, Maryland 20894. E-mail: [email protected]. ©2003 by Excerpta Medica, Inc. All rights reserved.
Dose-ranging trials and trials across the dose range of statin therapy: In a dose-ranging trial in patients
with hypercholesterolemia, rosuvastatin 10 to 40 mg (n ⫽ 63) produced statistically significant dose-dependent reductions in LDL cholesterol of 52% to 63% at 6 weeks, compared with placebo (n ⫽ 29).1 In another 6-week trial in patients with hypercholesterolemia that compared rosuvastatin and atorvastatin across a range of doses,4 rosuvastatin 10 to 40 mg (n ⫽ 129) reduced LDL cholesterol by 47% to 57%, compared with 38% to 54% with atorvastatin 10 to 80 mg (n ⫽ 165); the dose-dependent LDL cholesterol–lowering response with rosuvastatin was significantly greater than the response with atorvastatin (p ⬍0.001). In the Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin (STELLAR) study in patients with hypercholesterolemia,3 rosuvastatin 10 to 40 mg (n ⫽ 480) reduced LDL cholesterol by 46% to 55% versus 37% to 51% with atorvastatin 10 to 80 mg (n ⫽ 641), 28% to 46% with simvastatin 10 to 80 mg (n ⫽ 655), and 20% to 30% with pravastatin 10 to 40 mg (n ⫽ 492) at 6 weeks (Figure 1). In the STELLAR study, comparison of effects at milligram-equivalent doses showed that LDL cholesterol reductions were significantly greater with rosuvastatin than with all other statins (p ⬍0.002).
Statin comparator trials conducted for 12 and 52 weeks: A number of trials have provided data on the
comparative effects of rosuvastatin 10 mg and widely used doses of atorvastatin, simvastatin, and pravastatin. A total of 5 comparative trials, which were prospectively designed to be pooled, compared 12 weeks of treatment with rosuvastatin 10 mg versus atorva0002-9149/03/$ – see front matter doi:10.1016/S0002-9149(03)00779-3
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statin 10 mg (3 trials) or simvastatin 20 mg and pravastatin 20 mg (2 trials) in patients with hypercholesterolemia.9 Analysis of these data showed that rosuvastatin 10 mg (n ⫽ 389) significantly reduced LDL cholesterol by 47% versus 36% with atorvastatin 10 mg (n ⫽ 393; p ⬍0.001) and that rosuvastatin 10 mg (n ⫽ 231) reduced LDL cholesterol by 48% versus 36% with simvastatin 20 mg (n ⫽ 249) and 27% with pravastatin 20 mg (n ⫽ 252; p ⬍0.001 for both comparisons; Figure 2). In the 2 12-week trials (used in the aforementioned a priori pooled analysis), LDL cholesterol reductions of 43% were reported with rosuvastatin 10 mg (n ⫽ 129) versus 35% with atorvastatin 10 mg (n ⫽ 127; p ⬍0.001),5 and reductions of 49% were reported with rosuvastatin 10 mg (n ⫽ 111) versus 37% with simvastatin 20 mg (n ⫽ 129) and 28% with pravastatin 20 mg (n ⫽ 136; p ⬍0.001 for both comparisons).7 Patients with hypercholesterolemia were studied in 2 trials conducted for 52 weeks. These trials included 12-week, fixed-dose treatment periods at initial doses (12-week data used in the pooled analysis). Statin doses could be increased sequentially to 80 mg for rosuvastatin, atorvastatin, and simvastatin and 40 mg for pravastatin for patients to achieve their National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) II LDL cholesterol goals (which were in effect at the time the early phase III program was conducted).6,8,10 In the comparative trial with atorvastatin, at 12 weeks, rosuvastatin 10 mg (n ⫽ 132) reduced LDL cholesterol by 50% versus 39% with atorvastatin 10 mg (n ⫽ 139; p ⬍0.001).6 At 52 weeks, an a posteriori analysis showed that LDL cholesterol reductions were 53% in the rosuvastatin 10- to 40-mg group and 44% in the atorvastatin 10- to 80-mg group (p ⬍0.001).2 In a similarly designed trial comparing rosuvastatin with simvastatin and pravastatin,8 LDL cholesterol was reduced by 47% with rosuvastatin 10 mg (n ⫽ 115), compared with 35% with simvastatin 20 mg (n ⫽ 120) and 27% with pravastatin 20 mg (n ⫽ 116; p ⬍0.001 for both comparisons). At 52 weeks, an a posteriori analysis showed that LDL cholesterol was reduced by 48% in the rosuvastatin 10- to 40-mg group versus 38% in the simvastatin 20- to 80-mg group and 32% in the pravastatin 20- to 40-mg group (p ⬍0.001 for both comparisons).2
LOW-DENSITY LIPOPROTEIN CHOLESTEROL GOAL ACHIEVEMENT Rosuvastatin has been shown to be more effective than several widely used statins in enabling patients to reach NCEP ATP III11 and Joint European Societies12 LDL cholesterol goals. In a pooled analysis of data from 3 trials comparing rosuvastatin and atorvastatin,13 ATP III LDL cholesterol goals were achieved at 12 weeks in 76% of patients receiving rosuvastatin 10 mg versus 53% of patients receiving atorvastatin 10 mg (p ⬍0.001). In these trials, the most stringent LDL 24K THE AMERICAN JOURNAL OF CARDIOLOGY姞
cholesterol goal of ⬍100 mg/dL was achieved in 60% (120 of 199) of rosuvastatin-treated patients versus 19% (35 of 189) of atorvastatin-treated patients (p ⬍0.001). In a pooled analysis of 2 trials comparing rosuvastatin with pravastatin and simvastatin,13 goals were achieved at 12 weeks in 86% of patients receiving rosuvastatin 10 mg versus 64% of patients receiving simvastatin 20 mg and 49% of patients receiving pravastatin 20 mg (p ⬍0.001 for both comparisons). The goal of ⬍100 mg/dL was achieved in 63% (41 of 65) of rosuvastatin-treated patients versus 22% (18 of 80) of simvastatin-treated patients and 5% (4 of 75) of pravastatin-treated patients (p ⬍0.001 for both comparisons). In the pooled data analysis, the European LDL cholesterol goal (⬍116 mg/dL) was achieved at 12 weeks in 82% of patients receiving rosuvastatin 10 mg and 51% of those receiving atorvastatin 10 mg (p ⬍0.001). In the comparative trials with pravastatin and simvastatin, the European LDL cholesterol goal was reached in 80% of the rosuvastatin 10-mg group versus 48% of the simvastatin 20-mg group and 16% of the pravastatin 20-mg group (p ⬍0.001 for all). Compared with other statins at initial doses and with dose titration, rosuvastatin was shown to also improve achievement of NCEP ATP II LDL cholesterol goals during early phase 3 studies.10 In the 52week trial comparing rosuvastatin and atorvastatin,6 ATP II goals were achieved at a 10-mg starting dose in 82% of patients in the rosuvastatin 10- to 40-mg group versus 59% of patients in the atorvastatin 10- to 80-mg group at the end of the 40-week dose-titration period. Overall, ATP II goals were achieved in 96% (102 of 106) of patients receiving rosuvastatin 10 to 40 mg during dose titration versus 87% (101 of 116) of patients receiving atorvastatin 10 to 80 mg (p ⫽ 0.006 using an a posteriori analysis).2 In the 52-week trial comparing rosuvastatin with pravastatin and simvastatin,8 ATP II goals were achieved at week 52 at starting doses in 79% of the rosuvastatin 10- to 40-mg group, 50% of the simvastatin 20- to 80-mg group, and 31% of the pravastatin 20- to 40-mg group among those patients completing 52 weeks of treatment. Overall, ATP II goals were reached by 88% (84 of 96) of patients receiving rosuvastatin 10 to 40 mg, 73% (74 of 102) of patients receiving simvastatin 20 to 80 mg, and 60% (57 of 95) of those receiving pravastatin 20 to 40 mg (p ⬍0.05 versus simvastatin and p ⬍0.001 versus pravastatin using an a posteriori analysis).2
EFFECTS ON HIGH-DENSITY LIPOPROTEIN CHOLESTEROL Data from comparative trials also indicate greater effectiveness of rosuvastatin treatment in increasing HDL cholesterol. In the STELLAR study,3 rosuvastatin 10 to 40 mg consistently increased HDL cholesterol by 7.7% to 9.6%, compared with increases of 5.2% to 6.8% with simvastatin 10 to 80 mg and 3.2% to 5.6% with pravastatin 10 to 40 mg, whereas in-
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FIGURE 1. Low-density lipoprotein cholesterol (LDL-C) reductions with rosuvastatin 10 to 40 mg, atorvastatin 10 to 80 mg, simvastatin 10 to 80 mg, and pravastatin 10 to 40 mg at 6 weeks in the Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin (STELLAR) trial. Pairwise comparisons were performed with rosuvastatin doses and equivalent or higher doses of comparators with the significance level set at p <0.002 to adjust for multiple comparisons. LS ⴝ least squares. (Data are from Am J Cardiol.3)
FIGURE 2. Low-density lipoprotein cholesterol (LDL-C) reductions with rosuvastatin (RSV) 10 mg versus atorvastatin (ATV) 10 mg (left) and RSV 10 mg versus pravastatin (PRA) 20 mg and simvastatin (SIM) 20 mg (right) at 12 weeks in pooled data analysis. LDL-C changes are least squares (LS) mean percent changes from baseline. (Adapted with permission from Am J Cardiol.9)
creasing doses of atorvastatin produced elevations in HDL cholesterol ranging from 5.7% (10 mg) to 2.1% (80 mg). In the pooled data analysis discussed above,9 HDL cholesterol was elevated by 8.9% with rosuva-
statin 10 mg versus 5.5% with atorvastatin 10 mg (p ⬍0.001) and by 9.1% with rosuvastatin 10 mg versus 6.2% with simvastatin 20 mg and 6.2% with pravastatin 20 mg (p ⬍0.05 for both comparisons). A SYMPOSIUM: DYSLIPIDEMIA MANAGEMENT
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EFFECTS ON NON–HIGH-DENSITY LIPOPROTEIN CHOLESTEROL In patients with elevated triglycerides (ⱖ200 mg/ dL), NCEP ATP III identifies non-HDL cholesterol (total cholesterol minus HDL cholesterol) as a secondary target after LDL cholesterol, with a goal set at 30 mg/dL higher than that for LDL cholesterol.11 In the pooled analysis of 12-week trials, rosuvastatin 10 mg produced significantly greater reductions in non-HDL cholesterol (⫺43%) than atorvastatin 10 mg (⫺34%; p ⬍0.001), with similarly greater results seen for rosuvastatin 10 mg versus simvastatin 20 mg and pravastatin 20 mg (⫺44% versus ⫺33% and ⫺25%; p ⬍0.001 for both comparisons).9 In the 6-week trial comparing the effects of rosuvastatin and atorvastatin across their dose ranges,4 rosuvastatin 10 to 40 mg reduced non-HDL cholesterol by 43% to 52%, compared with 36% to 50% with atorvastatin 10 to 80 mg. Comparison of effects across the dose ranges studied showed that non-HDL cholesterol reductions were significantly greater with rosuvastatin than with atorvastatin (p ⬍0.001).
EFFECTS ON TRIGLYCERIDES Data from comparative trials of rosuvastatin and other statins also indicate equivalent or greater effects of rosuvastatin in reducing triglycerides. For example, in the pooled data analysis,9 rosuvastatin 10 mg reduced triglycerides by 19% versus 18% with atorvastatin 10 mg (p ⫽ not significant) and by 20% versus 12% with simvastatin 20 mg and 12% with pravastatin 20 mg (p ⬍0.01 for both comparisons). In a 6-week, dose-ranging trial in patients with hypertriglyceridemia, rosuvastatin 10 to 40 mg compared with placebo produced significant mean reductions from baseline in triglycerides (p ⬍0.001), ranging from ⫺37% to ⫺40% (median changes, ⫺37% to ⫺43%).14
PHARMACOLOGIC PROPERTIES Rosuvastatin exhibits a number of desirable pharmacologic characteristics, including greater inhibition of the 3-hydroxy-3-methylglutaryl coenzyme A reductase enzyme, compared with other statins, as well as relative hydrophilicity and selectivity for uptake into and activity in hepatic cells.1,15 Preclinical studies have also shown that rosuvastatin undergoes minimal metabolism by the cytochrome P450 system and, in particular, no significant metabolism by the cytochrome 3A4 system, suggesting a low potential for drug-drug interactions with many co-prescribed medications.1,15,16 These findings have been borne out in clinical pharmacology studies, in which rosuvastatin was administered in combination with erythromycin, azole antifungals, fenofibrate, and digoxin, without evidence of clinically significant drug interactions.17–22 In clinical trials in patients with hypercholesterolemia, there has been no evidence of adverse reactions when rosuvastatin was coadministered with antihypertensive agents, antidiabetic agents, or hormone replacement therapy. In addition, there are no apparent differences in the pharmacologic effects of rosuvastatin 26K THE AMERICAN JOURNAL OF CARDIOLOGY姞
in relation to morning or evening dosing, age, sex, or food intake.2,23,24
SAFETY Overall, the statin class is very well tolerated, and serious adverse events with statin therapy are rare.25 Consistent with their mechanism of action and the alleged effects of altering lipid metabolism, the safety assessment of statin drugs has focused primarily on peripheral muscle and the liver. Myalgia, apparently dose related, is a common side effect of statin therapy, occurring in about 5% to 7% of treated patients.26,27 The risk for myopathy with statin therapy is low (approximately 1 in 1,000 patients treated), appears to be dose related, and is increased when these agents are administered with other drugs that use common metabolic pathways.26 Similarly, the risk for liver toxicity with statin therapy, as evidenced by elevated hepatic transaminases, is low, occurring in approximately 1% to 2% of patients treated with statins.26 As with any new agent, it is important to evaluate the safety and tolerability of rosuvastatin. The safety profile of rosuvastatin was reviewed (as of April 2003) in 12,569 patients, representing 14,231 patient-years of treatment at doses up to 80 mg.2 Data on adverse events and laboratory measures from completed trials and ongoing extension trials, reflecting a broad patient population with regard to demographics and patient lipid profiles, were pooled by trial type and, where possible, are presented for the 10- to 40-mg dose range. In controlled trials (with fixed doses), rosuvastatin 10 to 40 mg was well tolerated and had an adverse event profile similar to those of atorvastatin 10 to 80 mg, simvastatin 10 to 80 mg, and pravastatin 10 to 40 mg, with adverse events leading to treatment withdrawal occurring in 2.9% of patients receiving rosuvastatin 10 to 40 mg (n ⫽ 3,074), 3.2% of atorvastatin patients (n ⫽ 2,899), 2.5% of simvastatin patients (n ⫽ 1,457), and 2.5% of pravastatin patients (n ⫽ 1,278).2 The most common adverse events attributed to rosuvastatin were myalgia, asthenia, nausea, and abdominal pain; these were generally mild and transient. Moreover, no deaths in the clinical trial program were attributed to rosuvastatin treatment. In the clinical trial program of rosuvastatin 10 to 40 mg, myopathy (defined as muscle symptoms plus serum creatine kinase levels ⬎10 times the upper limit of normal [ULN]) attributed to rosuvastatin occurred in ⱕ0.03% of patients. No cases of rhabdomyolysis occurred in patients receiving rosuvastatin 10 to 40 mg. In all controlled trials with ongoing laboratory assessments, clinically significant alanine aminotransferase elevations (defined as levels ⬎3 times ULN at ⱖ2 consecutive measurements) occurred in 0.2% of patients receiving rosuvastatin up to 80 mg (n ⫽ 8,190), atorvastatin up to 80 mg (n ⫽ 3,749), simvastatin up to 80 mg (n ⫽ 2,398), and pravastatin up to 40 mg (n ⫽ 1,260). In controlled trials with ongoing laboratory assessments, proteinuria was observed in a small number of patients receiving statin therapy. At final visit, dipstick
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FIGURE 3. Low-density lipoprotein cholesterol (LDL-C) reductions versus creatine kinase (CK) elevations >10 times upper limit of normal (ULN) for cerivastatin, pravastatin, simvastatin, atorvastatin, and rosuvastatin. (Data are from prescribing information29,31,33,34 and summary basis for approval35,36,39,40 [atorvastatin, cerivastatin, pravastatin, simvastatin]; Lancet41 [simvastatin]; and Cardiovasc Drug Rev1 and AstraZeneca2 [rosuvastatin].)
testing detected shifts in urine protein from none or trace at baseline to ⱖ2⫹ at the last urinalysis assessment in ⬍1.0% of patients receiving rosuvastatin 10 or 20 mg and those patients receiving atorvastatin, simvastatin, or pravastatin across the dose ranges studied; this finding occurred in ⬍1.5% of patients receiving rosuvastatin 40 mg. Notably, the proteinuria was mostly transient and tubular in origin and was not associated with acute or progressive renal impairment. Evaluation of serum creatinine data showed that mean serum creatinine levels either remained the same or decreased from baseline values in patients receiving rosuvastatin 10 to 40 mg, including patients receiving long-term treatment (ⱖ48 or ⱖ96 weeks) and those with mild-to-moderate renal impairment, as defined by creatinine clearance.2 Data from the 52-week trials provide an assessment of safety with longer-term administration of rosuvastatin.6,8 In these trials, rosuvastatin treatment was well tolerated and had an adverse event profile similar to that of the comparator statins. No cases of myopathy were observed in either trial. Overall, extensive assessment and analysis of the safety of rosuvastatin 10 to 40 mg indicate that this agent has a favorable safety profile and good tolerability.
BENEFIT-RISK EVALUATION Rosuvastatin 10 to 40 mg improves LDL cholesterol lowering and LDL cholesterol goal achievement compared with widely used doses of atorvastatin, simvastatin, and pravastatin. In comparative trials, the effects of rosuvastatin on LDL cholesterol have been accompanied by beneficial changes in a number of important lipid measures in addition to LDL cholesterol, including levels of HDL cholesterol, triglycerides, total cholesterol, non-HDL cholesterol, apo-
lipoprotein B, and ratios of atherogenic to nonatherogenic lipoproteins.1,9,28 Subgroup analyses from the pooled 10 – 40 mg efficacy data showed consistent efficacy across patient subpopulations defined by age (ⱖ65 years), sex (female), postmenopausal status, hypertension (blood pressure ⱖ140/90 mm Hg or taking antihypertensive medication at baseline), atherosclerotic disease, diabetes, and obesity (body mass index ⱖ30).9 Additionally, rosuvastatin exhibits a desirable pharmacologic profile. Moreover, the safety profile of rosuvastatin 10 to 40 mg is comparable to that observed with the statins studied in this clinical development program. With respect to the primary concerns of adverse effects on muscle and liver function, Figures 3 and 4 illustrate the benefit-risk assessment for statin treatment in which the occurrence of creatine kinase elevations ⬎10 times ULN (Figure 3) and alanine aminotransferase elevations ⬎3 times ULN (Figure 4) are plotted against the percent LDL cholesterol reductions for various statins by dose.2,29 – 41 This assessment provides some suggestion of an increasing occurrence of clinically relevant creatine kinase or alanine aminotransferase levels with increasing LDL cholesterol reduction as the statin dose is increased for most of the statins examined. However, the occurrence of creatine kinase or alanine aminotransferase elevations with increasing LDL cholesterol reductions remained low in patients receiving rosuvastatin 10 to 40 mg, with minimal change as the dose increases. These data indicate a very favorable benefit-risk profile across the dose range of rosuvastatin.
CONCLUSION In summary, the extensive data on the lipoproteinmodifying effects, goal achievement, pharmacologic A SYMPOSIUM: DYSLIPIDEMIA MANAGEMENT
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FIGURE 4. Low-density lipoprotein cholesterol (LDL-C) reductions versus alanine aminotransferase (ALT) elevations >3 times upper limit of normal (ULN) for fluvastatin, lovastatin, simvastatin, atorvastatin, and rosuvastatin. (Data are from prescribing information30 –32,34 and summary basis for approval35,37,38,40 [atorvastatin, simvastatin, fluvastatin, lovastatin]; Lancet41 [simvastatin]; and Cardiovasc Drug Rev1 and AstraZeneca2 [rosuvastatin].)
characteristics, and safety and tolerability of the 10- to 40-mg doses of rosuvastatin indicate that this new statin will be a useful therapeutic agent for the treatment of patients at risk for the development of cardiovascular disease. 1. Olsson AG, McTaggart F, Raza A. Rosuvastatin: a highly effective new HMG-CoA reductase inhibitor. Cardiovasc Drug Rev 2003;20:303–328. 2. Data on file. AstraZeneca LP, Alderley Park, Macclesfield, Cheshire, UK; 1998 –2003. 3. Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, Cain VA, Blasetto JW. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial). Am J Cardiol 2003;92:152–160. 4. Schneck DW, Knopp RH, Ballantyne CM, McPherson R, Chitra RR, Simonson SG. Comparative effects of rosuvastatin and atorvastatin across their dose ranges in patients with hypercholesterolemia and without active arterial disease. Am J Cardiol 2003;91:33–41. 5. Davidson M, Ma P, Stein EA, Gotto AM Jr, Raza A, Chitra R, Hutchinson H. Comparison of effects on low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with rosuvastatin versus atorvastatin in patients with type IIa or IIb hypercholesterolemia. Am J Cardiol 2002;89:268 –275. 6. Olsson AG, Istad H, Luurila O, Ose L, Stender S, Tuomilehto J, Wiklund O, Southworth H, Pears J, Wilpshaar JW. Effects of rosuvastatin and atorvastatin compared over 52 weeks of treatment in patients with hypercholesterolemia. Am Heart J 2002;144:1044 –1051. 7. Paoletti R, Fahmy M, Mahla G, Mizan J, Southworth H. Rosuvastatin demonstrates greater reduction of low-density lipoprotein cholesterol compared with pravastatin and simvastatin in hypercholesterolaemic patients: a randomized, double-blind study. J Cardiovasc Risk 2001;8:383–390. 8. Brown WV, Bays HE, Hassman DR, McKenney J, Chitra R, Hutchinson H, Miller E. Efficacy and safety of rosuvastatin compared with pravastatin and simvastatin in patients with hypercholesterolemia: a randomized, double-blind, 52-week trial. Am Heart J 2002;144:1036 –1043. 9. Blasetto J, Stein E, Brown WV, Chitra R, Raza A. Efficacy of rosuvastatin compared with other statins at selected starting doses in hypercholesterolemic patients and in special population groups. Am J Cardiol 2003;91(suppl 5A):3C– 10C. 10. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treat-
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ment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA 1993;269:3015–3023. 11. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486 –2497. 12. Second Joint Task Force. Prevention of coronary heart disease in clinical practice: recommendations of the Second Joint Task Force of European and other Societies on Coronary Prevention. Eur Heart J 1998;19:1434 –1503. 13. Shepherd J, Hunninghake DB, Barter P, McKenney JM, Hutchinson HG. Guidelines for lowering lipids to reduce coronary artery disease risk: a comparison of rosuvastatin with atorvastatin, pravastatin, and simvastatin for achieving lipid-lowering goals. Am J Cardiol 2003;91(suppl):11C–19C. 14. Hunninghake DB, Chitra RR, Simonson SG, Schneck DW. Rosuvastatin markedly improved the atherogenic profile in hypertriglyceridaemic patients [abstract]. Eur Heart J 2001;22(suppl):270. 15. McTaggart F, Buckett L, Davidson R, Holdgate G, McCormick A, Schneck D, Smith G, Warwick M. Preclinical and clinical pharmacology of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Am J Cardiol 2001;87(suppl):28B–32B. 16. Michalets EL. Clinically significant cytochrome P-450 drug interactions— author’s reply. Pharmacotherapy 1998;18:892–893. 17. Cooper KJ, Martin PD, Dane AL, Warwick MJ, Raza A, Schneck DW. The effect of erythromycin on the pharmacokinetics of rosuvastatin. Eur J Clin Pharmacol 2003;59:51–56. 18. Cooper KJ, Martin PD, Dane AL, Warwick MJ, Schneck DW, Cantarini MV. Effect of itraconazole on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther 2003;73:322–329. 19. Cooper KJ, Martin PD, Dane AL, Warwick MJ, Raza A, Schneck DW. Lack of effect of ketoconazole on the pharmacokinetics of rosuvastatin in healthy subjects. Br J Clin Pharmacol 2003;55:94 –99. 20. Cooper KJ, Martin PD, Dane AL, Warwick MJ, Schneck DW, Cantarini MV. The effect of fluconazole on the pharmacokinetics of rosuvastatin. Eur J Clin Pharmacol 2002;58:527–531. 21. Martin PD, Kemp J, Dane AL, Warwick MJ, Schneck DW. No effect of rosuvastatin on the pharmacokinetics of digoxin in healthy volunteers. J Clin Pharmacol 2002;42:1352–1357. 22. Martin PD, Dane AL, Schneck DW, Warwick MJ. An open-label, randomized, three-way crossover trial of the effects of coadministration of rosuvastatin and fenofibrate on the pharmacokinetic properties of rosuvastatin and fenofibric acid in healthy male volunteers. Clin Ther 2003;25:459 –471. 23. Martin PD, Mitchell PD, Schneck DW. Pharmacodynamic effects and pharmacokinetics of a new HMG-CoA reductase inhibitor, rosuvastatin, after morning
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or evening administration in healthy volunteers. Br J Clin Pharmacol 2002;54: 472–477. 24. Martin PD, Dane AL, Nwose OM, Schneck DW, Warwick MJ. No effect of age or gender on the pharmacokinetics of rosuvastatin: a new HMG-CoA reductase inhibitor. J Clin Pharmacol 2002;42:1116 –1121. 25. Ballantyne CM, Corsini A, Davidson MH, Holdaas H, Jacobson TA, Leitersdorf E, Marz W, Reckless JP, Stein EA. Risk for myopathy with statin therapy in high-risk patients. Arch Intern Med 2003;163:553–564. 26. Black DM. A general assessment of the safety of HMG CoA reductase inhibitors (statins). Curr Atheroscler Rep 2002;4:34 –41. 27. Ucar M, Mjorndal T, Dahlqvist R. HMG-CoA reductase inhibitors and myotoxicity. Drug Saf 2000;22:441–457. 28. Schuster H. Rosuvastatin: a highly effective HMG-CoA reductase inhibitor: review of clinical trial data at 10 to 40 mg doses in dyslipidemic patients. Cardiology 2003;99:126 –139. 29. Baycol [package insert]. West Haven, CT: Bayer; 2000. 30. Lescol [package insert]. East Hanover, NJ: Novartis Pharmaceuticals; 2001. 31. Lipitor [package insert]. New York, NY: Pfizer; 2002. 32. Mevacor [package insert]. West Point, PA: Merck & Co.; 2002.
33. Pravachol [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2002. 34. Zocor [package insert]. Whitehouse Station, NJ: Merck & Co.; 2002. 35. US Food and Drug Administration, Summary Basis for Approval of the
atorvastatin New Drug Application #20-702. Washington, DC, December 17, 1996. 36. US Food and Drug Administration, Summary Basis for Approval of the cerivastatin New Drug Application #20-740. Washington, DC, May 24, 1999. 37. US Food and Drug Administration, Summary Basis for Approval of the fluvastatin New Drug Application #20-261. Washington, DC, March 8, 1999. 38. US Food and Drug Administration, Summary Basis for Approval of the lovastatin New Drug Application #19-643. Washington, DC, June 25, 1997. 39. US Food and Drug Administration, Summary Basis for Approval of the pravastatin New Drug Application #19-898. Washington, DC, April 15, 1997. 40. US Food and Drug Administration, Summary Basis for Approval of the simvastatin New Drug Application #19-766/S-028. Washington, DC, July 10, 1998. 41. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22.
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MD
The aim of this article is to examine the benefit-risk profile of rosuvastatin at doses of 10 to 40 mg. In dyslipidemic patients, rosuvastatin produced markedly greater reductions in low-density lipoprotein (LDL) cholesterol and equivalent or greater improvements in various lipid measures, including high-density lipoprotein (HDL) cholesterol, non-HDL cholesterol, and triglycerides when compared with atorvastatin, simvastatin, and pravastatin. In addition, rosuvastatin is more effective than these statins in allowing patients to reach National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III and Joint European Societies LDL cholesterol goals. The safety profile of rosuvastatin was reviewed (as of April 2003) in 12,569 patients, representing 14,231 patient-years of treatment at doses up to 80 mg. In controlled trials, rosuvastatin 10 to 40 mg dem-
onstrated a similar adverse event profile to those for atorvastatin 10 to 80 mg, simvastatin 10 to 80 mg, and pravastatin 10 to 40 mg. Myopathy (defined as muscle symptoms plus serum creatine kinase levels >10 times the upper limit of normal) attributed to rosuvastatin occurred in <0.03% of patients receiving rosuvastatin 10 to 40 mg. No cases of rhabdomyolysis occurred in patients receiving rosuvastatin 10 to 40 mg. Clinically significant alanine aminotransferase elevations occurred in 0.2% of patients receiving rosuvastatin and those receiving atorvastatin, simvastatin, and pravastatin. Compared with other widely used statins, the benefitrisk profile of rosuvastatin 10 to 40 mg appears to be very favorable. 䊚2003 by Excerpta Medica, Inc. Am J Cardiol 2003;92(suppl):23K–29K
osuvastatin (Crestor; licensed to AstraZeneca from Shionogi & Co, Ltd, Osaka, Japan) is a R 3-hydroxy-3-methylglutaryl coenzyme A reductase
of rosuvastatin reduced LDL cholesterol by up to 52%1,3–9 and by as much as 63% at 40 mg.1
inhibitor (statin) that markedly reduces low-density lipoprotein (LDL) cholesterol levels, increases highdensity lipoprotein (HDL) cholesterol levels, and improves other parameters of the atherogenic lipid profile.1 The worldwide clinical development program for rosuvastatin is the largest program ever conducted to evaluate the efficacy and safety of a new statin, including ⬎20,000 patients with a broad range of dyslipidemias (eg, Fredrickson type IIa/IIb hypercholesterolemia, heterozygous or homozygous familial hypercholesterolemia, or Fredrickson type IIb or IV hypertriglyceridemia). In addition, this program included a high percentage of elderly patients (31% aged ⱖ65 years; 7% aged ⱖ75 years), as well as patients with renal impairment (53%), hypertension (52%), cardiovascular disease (36%), and diabetes mellitus (17%).2 This article examines the benefit-risk profile of this agent at doses of 10 to 40 mg, using the efficacy, pharmacology, and safety data from this extensive clinical program.
LOW-DENSITY LIPOPROTEIN CHOLESTEROL REDUCTIONS In a variety of dose-ranging and comparative trials in patients with hypercholesterolemia, a 10-mg dose From the Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA. Crestor is a registered trademark of the AstraZeneca group of companies. Address for reprints: H. Bryan Brewer, Jr., MD, National Institutes of Health, Building 10, Magnuson CC, Room 7N115, 10 Center Drive, Bethesda, Maryland 20894. E-mail: [email protected]. ©2003 by Excerpta Medica, Inc. All rights reserved.
Dose-ranging trials and trials across the dose range of statin therapy: In a dose-ranging trial in patients
with hypercholesterolemia, rosuvastatin 10 to 40 mg (n ⫽ 63) produced statistically significant dose-dependent reductions in LDL cholesterol of 52% to 63% at 6 weeks, compared with placebo (n ⫽ 29).1 In another 6-week trial in patients with hypercholesterolemia that compared rosuvastatin and atorvastatin across a range of doses,4 rosuvastatin 10 to 40 mg (n ⫽ 129) reduced LDL cholesterol by 47% to 57%, compared with 38% to 54% with atorvastatin 10 to 80 mg (n ⫽ 165); the dose-dependent LDL cholesterol–lowering response with rosuvastatin was significantly greater than the response with atorvastatin (p ⬍0.001). In the Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin (STELLAR) study in patients with hypercholesterolemia,3 rosuvastatin 10 to 40 mg (n ⫽ 480) reduced LDL cholesterol by 46% to 55% versus 37% to 51% with atorvastatin 10 to 80 mg (n ⫽ 641), 28% to 46% with simvastatin 10 to 80 mg (n ⫽ 655), and 20% to 30% with pravastatin 10 to 40 mg (n ⫽ 492) at 6 weeks (Figure 1). In the STELLAR study, comparison of effects at milligram-equivalent doses showed that LDL cholesterol reductions were significantly greater with rosuvastatin than with all other statins (p ⬍0.002).
Statin comparator trials conducted for 12 and 52 weeks: A number of trials have provided data on the
comparative effects of rosuvastatin 10 mg and widely used doses of atorvastatin, simvastatin, and pravastatin. A total of 5 comparative trials, which were prospectively designed to be pooled, compared 12 weeks of treatment with rosuvastatin 10 mg versus atorva0002-9149/03/$ – see front matter doi:10.1016/S0002-9149(03)00779-3
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statin 10 mg (3 trials) or simvastatin 20 mg and pravastatin 20 mg (2 trials) in patients with hypercholesterolemia.9 Analysis of these data showed that rosuvastatin 10 mg (n ⫽ 389) significantly reduced LDL cholesterol by 47% versus 36% with atorvastatin 10 mg (n ⫽ 393; p ⬍0.001) and that rosuvastatin 10 mg (n ⫽ 231) reduced LDL cholesterol by 48% versus 36% with simvastatin 20 mg (n ⫽ 249) and 27% with pravastatin 20 mg (n ⫽ 252; p ⬍0.001 for both comparisons; Figure 2). In the 2 12-week trials (used in the aforementioned a priori pooled analysis), LDL cholesterol reductions of 43% were reported with rosuvastatin 10 mg (n ⫽ 129) versus 35% with atorvastatin 10 mg (n ⫽ 127; p ⬍0.001),5 and reductions of 49% were reported with rosuvastatin 10 mg (n ⫽ 111) versus 37% with simvastatin 20 mg (n ⫽ 129) and 28% with pravastatin 20 mg (n ⫽ 136; p ⬍0.001 for both comparisons).7 Patients with hypercholesterolemia were studied in 2 trials conducted for 52 weeks. These trials included 12-week, fixed-dose treatment periods at initial doses (12-week data used in the pooled analysis). Statin doses could be increased sequentially to 80 mg for rosuvastatin, atorvastatin, and simvastatin and 40 mg for pravastatin for patients to achieve their National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) II LDL cholesterol goals (which were in effect at the time the early phase III program was conducted).6,8,10 In the comparative trial with atorvastatin, at 12 weeks, rosuvastatin 10 mg (n ⫽ 132) reduced LDL cholesterol by 50% versus 39% with atorvastatin 10 mg (n ⫽ 139; p ⬍0.001).6 At 52 weeks, an a posteriori analysis showed that LDL cholesterol reductions were 53% in the rosuvastatin 10- to 40-mg group and 44% in the atorvastatin 10- to 80-mg group (p ⬍0.001).2 In a similarly designed trial comparing rosuvastatin with simvastatin and pravastatin,8 LDL cholesterol was reduced by 47% with rosuvastatin 10 mg (n ⫽ 115), compared with 35% with simvastatin 20 mg (n ⫽ 120) and 27% with pravastatin 20 mg (n ⫽ 116; p ⬍0.001 for both comparisons). At 52 weeks, an a posteriori analysis showed that LDL cholesterol was reduced by 48% in the rosuvastatin 10- to 40-mg group versus 38% in the simvastatin 20- to 80-mg group and 32% in the pravastatin 20- to 40-mg group (p ⬍0.001 for both comparisons).2
LOW-DENSITY LIPOPROTEIN CHOLESTEROL GOAL ACHIEVEMENT Rosuvastatin has been shown to be more effective than several widely used statins in enabling patients to reach NCEP ATP III11 and Joint European Societies12 LDL cholesterol goals. In a pooled analysis of data from 3 trials comparing rosuvastatin and atorvastatin,13 ATP III LDL cholesterol goals were achieved at 12 weeks in 76% of patients receiving rosuvastatin 10 mg versus 53% of patients receiving atorvastatin 10 mg (p ⬍0.001). In these trials, the most stringent LDL 24K THE AMERICAN JOURNAL OF CARDIOLOGY姞
cholesterol goal of ⬍100 mg/dL was achieved in 60% (120 of 199) of rosuvastatin-treated patients versus 19% (35 of 189) of atorvastatin-treated patients (p ⬍0.001). In a pooled analysis of 2 trials comparing rosuvastatin with pravastatin and simvastatin,13 goals were achieved at 12 weeks in 86% of patients receiving rosuvastatin 10 mg versus 64% of patients receiving simvastatin 20 mg and 49% of patients receiving pravastatin 20 mg (p ⬍0.001 for both comparisons). The goal of ⬍100 mg/dL was achieved in 63% (41 of 65) of rosuvastatin-treated patients versus 22% (18 of 80) of simvastatin-treated patients and 5% (4 of 75) of pravastatin-treated patients (p ⬍0.001 for both comparisons). In the pooled data analysis, the European LDL cholesterol goal (⬍116 mg/dL) was achieved at 12 weeks in 82% of patients receiving rosuvastatin 10 mg and 51% of those receiving atorvastatin 10 mg (p ⬍0.001). In the comparative trials with pravastatin and simvastatin, the European LDL cholesterol goal was reached in 80% of the rosuvastatin 10-mg group versus 48% of the simvastatin 20-mg group and 16% of the pravastatin 20-mg group (p ⬍0.001 for all). Compared with other statins at initial doses and with dose titration, rosuvastatin was shown to also improve achievement of NCEP ATP II LDL cholesterol goals during early phase 3 studies.10 In the 52week trial comparing rosuvastatin and atorvastatin,6 ATP II goals were achieved at a 10-mg starting dose in 82% of patients in the rosuvastatin 10- to 40-mg group versus 59% of patients in the atorvastatin 10- to 80-mg group at the end of the 40-week dose-titration period. Overall, ATP II goals were achieved in 96% (102 of 106) of patients receiving rosuvastatin 10 to 40 mg during dose titration versus 87% (101 of 116) of patients receiving atorvastatin 10 to 80 mg (p ⫽ 0.006 using an a posteriori analysis).2 In the 52-week trial comparing rosuvastatin with pravastatin and simvastatin,8 ATP II goals were achieved at week 52 at starting doses in 79% of the rosuvastatin 10- to 40-mg group, 50% of the simvastatin 20- to 80-mg group, and 31% of the pravastatin 20- to 40-mg group among those patients completing 52 weeks of treatment. Overall, ATP II goals were reached by 88% (84 of 96) of patients receiving rosuvastatin 10 to 40 mg, 73% (74 of 102) of patients receiving simvastatin 20 to 80 mg, and 60% (57 of 95) of those receiving pravastatin 20 to 40 mg (p ⬍0.05 versus simvastatin and p ⬍0.001 versus pravastatin using an a posteriori analysis).2
EFFECTS ON HIGH-DENSITY LIPOPROTEIN CHOLESTEROL Data from comparative trials also indicate greater effectiveness of rosuvastatin treatment in increasing HDL cholesterol. In the STELLAR study,3 rosuvastatin 10 to 40 mg consistently increased HDL cholesterol by 7.7% to 9.6%, compared with increases of 5.2% to 6.8% with simvastatin 10 to 80 mg and 3.2% to 5.6% with pravastatin 10 to 40 mg, whereas in-
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FIGURE 1. Low-density lipoprotein cholesterol (LDL-C) reductions with rosuvastatin 10 to 40 mg, atorvastatin 10 to 80 mg, simvastatin 10 to 80 mg, and pravastatin 10 to 40 mg at 6 weeks in the Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin (STELLAR) trial. Pairwise comparisons were performed with rosuvastatin doses and equivalent or higher doses of comparators with the significance level set at p <0.002 to adjust for multiple comparisons. LS ⴝ least squares. (Data are from Am J Cardiol.3)
FIGURE 2. Low-density lipoprotein cholesterol (LDL-C) reductions with rosuvastatin (RSV) 10 mg versus atorvastatin (ATV) 10 mg (left) and RSV 10 mg versus pravastatin (PRA) 20 mg and simvastatin (SIM) 20 mg (right) at 12 weeks in pooled data analysis. LDL-C changes are least squares (LS) mean percent changes from baseline. (Adapted with permission from Am J Cardiol.9)
creasing doses of atorvastatin produced elevations in HDL cholesterol ranging from 5.7% (10 mg) to 2.1% (80 mg). In the pooled data analysis discussed above,9 HDL cholesterol was elevated by 8.9% with rosuva-
statin 10 mg versus 5.5% with atorvastatin 10 mg (p ⬍0.001) and by 9.1% with rosuvastatin 10 mg versus 6.2% with simvastatin 20 mg and 6.2% with pravastatin 20 mg (p ⬍0.05 for both comparisons). A SYMPOSIUM: DYSLIPIDEMIA MANAGEMENT
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EFFECTS ON NON–HIGH-DENSITY LIPOPROTEIN CHOLESTEROL In patients with elevated triglycerides (ⱖ200 mg/ dL), NCEP ATP III identifies non-HDL cholesterol (total cholesterol minus HDL cholesterol) as a secondary target after LDL cholesterol, with a goal set at 30 mg/dL higher than that for LDL cholesterol.11 In the pooled analysis of 12-week trials, rosuvastatin 10 mg produced significantly greater reductions in non-HDL cholesterol (⫺43%) than atorvastatin 10 mg (⫺34%; p ⬍0.001), with similarly greater results seen for rosuvastatin 10 mg versus simvastatin 20 mg and pravastatin 20 mg (⫺44% versus ⫺33% and ⫺25%; p ⬍0.001 for both comparisons).9 In the 6-week trial comparing the effects of rosuvastatin and atorvastatin across their dose ranges,4 rosuvastatin 10 to 40 mg reduced non-HDL cholesterol by 43% to 52%, compared with 36% to 50% with atorvastatin 10 to 80 mg. Comparison of effects across the dose ranges studied showed that non-HDL cholesterol reductions were significantly greater with rosuvastatin than with atorvastatin (p ⬍0.001).
EFFECTS ON TRIGLYCERIDES Data from comparative trials of rosuvastatin and other statins also indicate equivalent or greater effects of rosuvastatin in reducing triglycerides. For example, in the pooled data analysis,9 rosuvastatin 10 mg reduced triglycerides by 19% versus 18% with atorvastatin 10 mg (p ⫽ not significant) and by 20% versus 12% with simvastatin 20 mg and 12% with pravastatin 20 mg (p ⬍0.01 for both comparisons). In a 6-week, dose-ranging trial in patients with hypertriglyceridemia, rosuvastatin 10 to 40 mg compared with placebo produced significant mean reductions from baseline in triglycerides (p ⬍0.001), ranging from ⫺37% to ⫺40% (median changes, ⫺37% to ⫺43%).14
PHARMACOLOGIC PROPERTIES Rosuvastatin exhibits a number of desirable pharmacologic characteristics, including greater inhibition of the 3-hydroxy-3-methylglutaryl coenzyme A reductase enzyme, compared with other statins, as well as relative hydrophilicity and selectivity for uptake into and activity in hepatic cells.1,15 Preclinical studies have also shown that rosuvastatin undergoes minimal metabolism by the cytochrome P450 system and, in particular, no significant metabolism by the cytochrome 3A4 system, suggesting a low potential for drug-drug interactions with many co-prescribed medications.1,15,16 These findings have been borne out in clinical pharmacology studies, in which rosuvastatin was administered in combination with erythromycin, azole antifungals, fenofibrate, and digoxin, without evidence of clinically significant drug interactions.17–22 In clinical trials in patients with hypercholesterolemia, there has been no evidence of adverse reactions when rosuvastatin was coadministered with antihypertensive agents, antidiabetic agents, or hormone replacement therapy. In addition, there are no apparent differences in the pharmacologic effects of rosuvastatin 26K THE AMERICAN JOURNAL OF CARDIOLOGY姞
in relation to morning or evening dosing, age, sex, or food intake.2,23,24
SAFETY Overall, the statin class is very well tolerated, and serious adverse events with statin therapy are rare.25 Consistent with their mechanism of action and the alleged effects of altering lipid metabolism, the safety assessment of statin drugs has focused primarily on peripheral muscle and the liver. Myalgia, apparently dose related, is a common side effect of statin therapy, occurring in about 5% to 7% of treated patients.26,27 The risk for myopathy with statin therapy is low (approximately 1 in 1,000 patients treated), appears to be dose related, and is increased when these agents are administered with other drugs that use common metabolic pathways.26 Similarly, the risk for liver toxicity with statin therapy, as evidenced by elevated hepatic transaminases, is low, occurring in approximately 1% to 2% of patients treated with statins.26 As with any new agent, it is important to evaluate the safety and tolerability of rosuvastatin. The safety profile of rosuvastatin was reviewed (as of April 2003) in 12,569 patients, representing 14,231 patient-years of treatment at doses up to 80 mg.2 Data on adverse events and laboratory measures from completed trials and ongoing extension trials, reflecting a broad patient population with regard to demographics and patient lipid profiles, were pooled by trial type and, where possible, are presented for the 10- to 40-mg dose range. In controlled trials (with fixed doses), rosuvastatin 10 to 40 mg was well tolerated and had an adverse event profile similar to those of atorvastatin 10 to 80 mg, simvastatin 10 to 80 mg, and pravastatin 10 to 40 mg, with adverse events leading to treatment withdrawal occurring in 2.9% of patients receiving rosuvastatin 10 to 40 mg (n ⫽ 3,074), 3.2% of atorvastatin patients (n ⫽ 2,899), 2.5% of simvastatin patients (n ⫽ 1,457), and 2.5% of pravastatin patients (n ⫽ 1,278).2 The most common adverse events attributed to rosuvastatin were myalgia, asthenia, nausea, and abdominal pain; these were generally mild and transient. Moreover, no deaths in the clinical trial program were attributed to rosuvastatin treatment. In the clinical trial program of rosuvastatin 10 to 40 mg, myopathy (defined as muscle symptoms plus serum creatine kinase levels ⬎10 times the upper limit of normal [ULN]) attributed to rosuvastatin occurred in ⱕ0.03% of patients. No cases of rhabdomyolysis occurred in patients receiving rosuvastatin 10 to 40 mg. In all controlled trials with ongoing laboratory assessments, clinically significant alanine aminotransferase elevations (defined as levels ⬎3 times ULN at ⱖ2 consecutive measurements) occurred in 0.2% of patients receiving rosuvastatin up to 80 mg (n ⫽ 8,190), atorvastatin up to 80 mg (n ⫽ 3,749), simvastatin up to 80 mg (n ⫽ 2,398), and pravastatin up to 40 mg (n ⫽ 1,260). In controlled trials with ongoing laboratory assessments, proteinuria was observed in a small number of patients receiving statin therapy. At final visit, dipstick
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FIGURE 3. Low-density lipoprotein cholesterol (LDL-C) reductions versus creatine kinase (CK) elevations >10 times upper limit of normal (ULN) for cerivastatin, pravastatin, simvastatin, atorvastatin, and rosuvastatin. (Data are from prescribing information29,31,33,34 and summary basis for approval35,36,39,40 [atorvastatin, cerivastatin, pravastatin, simvastatin]; Lancet41 [simvastatin]; and Cardiovasc Drug Rev1 and AstraZeneca2 [rosuvastatin].)
testing detected shifts in urine protein from none or trace at baseline to ⱖ2⫹ at the last urinalysis assessment in ⬍1.0% of patients receiving rosuvastatin 10 or 20 mg and those patients receiving atorvastatin, simvastatin, or pravastatin across the dose ranges studied; this finding occurred in ⬍1.5% of patients receiving rosuvastatin 40 mg. Notably, the proteinuria was mostly transient and tubular in origin and was not associated with acute or progressive renal impairment. Evaluation of serum creatinine data showed that mean serum creatinine levels either remained the same or decreased from baseline values in patients receiving rosuvastatin 10 to 40 mg, including patients receiving long-term treatment (ⱖ48 or ⱖ96 weeks) and those with mild-to-moderate renal impairment, as defined by creatinine clearance.2 Data from the 52-week trials provide an assessment of safety with longer-term administration of rosuvastatin.6,8 In these trials, rosuvastatin treatment was well tolerated and had an adverse event profile similar to that of the comparator statins. No cases of myopathy were observed in either trial. Overall, extensive assessment and analysis of the safety of rosuvastatin 10 to 40 mg indicate that this agent has a favorable safety profile and good tolerability.
BENEFIT-RISK EVALUATION Rosuvastatin 10 to 40 mg improves LDL cholesterol lowering and LDL cholesterol goal achievement compared with widely used doses of atorvastatin, simvastatin, and pravastatin. In comparative trials, the effects of rosuvastatin on LDL cholesterol have been accompanied by beneficial changes in a number of important lipid measures in addition to LDL cholesterol, including levels of HDL cholesterol, triglycerides, total cholesterol, non-HDL cholesterol, apo-
lipoprotein B, and ratios of atherogenic to nonatherogenic lipoproteins.1,9,28 Subgroup analyses from the pooled 10 – 40 mg efficacy data showed consistent efficacy across patient subpopulations defined by age (ⱖ65 years), sex (female), postmenopausal status, hypertension (blood pressure ⱖ140/90 mm Hg or taking antihypertensive medication at baseline), atherosclerotic disease, diabetes, and obesity (body mass index ⱖ30).9 Additionally, rosuvastatin exhibits a desirable pharmacologic profile. Moreover, the safety profile of rosuvastatin 10 to 40 mg is comparable to that observed with the statins studied in this clinical development program. With respect to the primary concerns of adverse effects on muscle and liver function, Figures 3 and 4 illustrate the benefit-risk assessment for statin treatment in which the occurrence of creatine kinase elevations ⬎10 times ULN (Figure 3) and alanine aminotransferase elevations ⬎3 times ULN (Figure 4) are plotted against the percent LDL cholesterol reductions for various statins by dose.2,29 – 41 This assessment provides some suggestion of an increasing occurrence of clinically relevant creatine kinase or alanine aminotransferase levels with increasing LDL cholesterol reduction as the statin dose is increased for most of the statins examined. However, the occurrence of creatine kinase or alanine aminotransferase elevations with increasing LDL cholesterol reductions remained low in patients receiving rosuvastatin 10 to 40 mg, with minimal change as the dose increases. These data indicate a very favorable benefit-risk profile across the dose range of rosuvastatin.
CONCLUSION In summary, the extensive data on the lipoproteinmodifying effects, goal achievement, pharmacologic A SYMPOSIUM: DYSLIPIDEMIA MANAGEMENT
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FIGURE 4. Low-density lipoprotein cholesterol (LDL-C) reductions versus alanine aminotransferase (ALT) elevations >3 times upper limit of normal (ULN) for fluvastatin, lovastatin, simvastatin, atorvastatin, and rosuvastatin. (Data are from prescribing information30 –32,34 and summary basis for approval35,37,38,40 [atorvastatin, simvastatin, fluvastatin, lovastatin]; Lancet41 [simvastatin]; and Cardiovasc Drug Rev1 and AstraZeneca2 [rosuvastatin].)
characteristics, and safety and tolerability of the 10- to 40-mg doses of rosuvastatin indicate that this new statin will be a useful therapeutic agent for the treatment of patients at risk for the development of cardiovascular disease. 1. Olsson AG, McTaggart F, Raza A. Rosuvastatin: a highly effective new HMG-CoA reductase inhibitor. Cardiovasc Drug Rev 2003;20:303–328. 2. Data on file. AstraZeneca LP, Alderley Park, Macclesfield, Cheshire, UK; 1998 –2003. 3. Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, Cain VA, Blasetto JW. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial). Am J Cardiol 2003;92:152–160. 4. Schneck DW, Knopp RH, Ballantyne CM, McPherson R, Chitra RR, Simonson SG. Comparative effects of rosuvastatin and atorvastatin across their dose ranges in patients with hypercholesterolemia and without active arterial disease. Am J Cardiol 2003;91:33–41. 5. Davidson M, Ma P, Stein EA, Gotto AM Jr, Raza A, Chitra R, Hutchinson H. Comparison of effects on low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with rosuvastatin versus atorvastatin in patients with type IIa or IIb hypercholesterolemia. Am J Cardiol 2002;89:268 –275. 6. Olsson AG, Istad H, Luurila O, Ose L, Stender S, Tuomilehto J, Wiklund O, Southworth H, Pears J, Wilpshaar JW. Effects of rosuvastatin and atorvastatin compared over 52 weeks of treatment in patients with hypercholesterolemia. Am Heart J 2002;144:1044 –1051. 7. Paoletti R, Fahmy M, Mahla G, Mizan J, Southworth H. Rosuvastatin demonstrates greater reduction of low-density lipoprotein cholesterol compared with pravastatin and simvastatin in hypercholesterolaemic patients: a randomized, double-blind study. J Cardiovasc Risk 2001;8:383–390. 8. Brown WV, Bays HE, Hassman DR, McKenney J, Chitra R, Hutchinson H, Miller E. Efficacy and safety of rosuvastatin compared with pravastatin and simvastatin in patients with hypercholesterolemia: a randomized, double-blind, 52-week trial. Am Heart J 2002;144:1036 –1043. 9. Blasetto J, Stein E, Brown WV, Chitra R, Raza A. Efficacy of rosuvastatin compared with other statins at selected starting doses in hypercholesterolemic patients and in special population groups. Am J Cardiol 2003;91(suppl 5A):3C– 10C. 10. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treat-
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ment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA 1993;269:3015–3023. 11. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486 –2497. 12. Second Joint Task Force. Prevention of coronary heart disease in clinical practice: recommendations of the Second Joint Task Force of European and other Societies on Coronary Prevention. Eur Heart J 1998;19:1434 –1503. 13. Shepherd J, Hunninghake DB, Barter P, McKenney JM, Hutchinson HG. Guidelines for lowering lipids to reduce coronary artery disease risk: a comparison of rosuvastatin with atorvastatin, pravastatin, and simvastatin for achieving lipid-lowering goals. Am J Cardiol 2003;91(suppl):11C–19C. 14. Hunninghake DB, Chitra RR, Simonson SG, Schneck DW. Rosuvastatin markedly improved the atherogenic profile in hypertriglyceridaemic patients [abstract]. Eur Heart J 2001;22(suppl):270. 15. McTaggart F, Buckett L, Davidson R, Holdgate G, McCormick A, Schneck D, Smith G, Warwick M. Preclinical and clinical pharmacology of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Am J Cardiol 2001;87(suppl):28B–32B. 16. Michalets EL. Clinically significant cytochrome P-450 drug interactions— author’s reply. Pharmacotherapy 1998;18:892–893. 17. Cooper KJ, Martin PD, Dane AL, Warwick MJ, Raza A, Schneck DW. The effect of erythromycin on the pharmacokinetics of rosuvastatin. Eur J Clin Pharmacol 2003;59:51–56. 18. Cooper KJ, Martin PD, Dane AL, Warwick MJ, Schneck DW, Cantarini MV. Effect of itraconazole on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther 2003;73:322–329. 19. Cooper KJ, Martin PD, Dane AL, Warwick MJ, Raza A, Schneck DW. Lack of effect of ketoconazole on the pharmacokinetics of rosuvastatin in healthy subjects. Br J Clin Pharmacol 2003;55:94 –99. 20. Cooper KJ, Martin PD, Dane AL, Warwick MJ, Schneck DW, Cantarini MV. The effect of fluconazole on the pharmacokinetics of rosuvastatin. Eur J Clin Pharmacol 2002;58:527–531. 21. Martin PD, Kemp J, Dane AL, Warwick MJ, Schneck DW. No effect of rosuvastatin on the pharmacokinetics of digoxin in healthy volunteers. J Clin Pharmacol 2002;42:1352–1357. 22. Martin PD, Dane AL, Schneck DW, Warwick MJ. An open-label, randomized, three-way crossover trial of the effects of coadministration of rosuvastatin and fenofibrate on the pharmacokinetic properties of rosuvastatin and fenofibric acid in healthy male volunteers. Clin Ther 2003;25:459 –471. 23. Martin PD, Mitchell PD, Schneck DW. Pharmacodynamic effects and pharmacokinetics of a new HMG-CoA reductase inhibitor, rosuvastatin, after morning
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