Kristina Strutt, MBBS; Richard Caplan, PhD*; Howard Hutchison, MD*; Aaron Dane, MSc; James Blasetto, MD* Circ J 2004; 68:

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1 Circ J 2004; 68: More Western Hypercholesterolemic Patients Achieve Japan Atherosclerosis Society LDL-C Goals With Rosuvastatin Therapy Than With Atorvastatin, Pravastatin, or Simvastatin Therapy Kristina Strutt, MBBS; Richard Caplan, PhD*; Howard Hutchison, MD*; Aaron Dane, MSc; James Blasetto, MD* Background Data from Western comparative trials suggest that rosuvastatin is more effective than atorvastatin, simvastatin, and pravastatin in helping hypercholesterolemic patients achieve US and European lipid-lowering guidelines. The purpose of this analysis was to assess the comparative efficacy of rosuvastatin in reducing low-density lipoprotein cholesterol (LDL-C) to levels recommended by the Japan Atherosclerosis Society (JAS). Methods and Results A post hoc analysis of data from 6 randomized, double-blind, active-controlled trials was conducted to evaluate the relative efficacy of rosuvastatin and comparator statins in helping patients achieve the LDL-C goals established by the JAS. The first 5 trials, prospectively designed for pooling, were originally conducted to compare the effects of rosuvastatin with either atorvastatin, simvastatin, or pravastatin in reducing lipid levels and helping patients achieve the LDL-C goals established by the National Cholesterol Education Program. The 6th trial was conducted with similar objectives, but in patients with heterozygous familial hypercholesterolemia (HeFH). Data from 2,139 hypercholesterolemic patients in the first 5 trials were pooled for analysis: rosuvastatin 5mg (n=390) or 10mg (n=389) vs atorvastatin 10mg (n=393); rosuvastatin 5mg (n=240) or 10mg (n=226) vs simvastatin 20mg (n=249) or pravastatin 20mg (n=252). In the studies with atorvastatin as the comparator, JAS-defined LDL-C goals were reached by 67.2% of the rosuvastatin 5-mg group, 82.3% of the rosuvastatin 10-mg group, and 58.0% of the atorvastatin 10-mg group (p<0.001 for both rosuvastatin groups vs atorvastatin) at 12 weeks. Similarly, in the trials with pravastatin and simvastatin as comparators, the JAS LDL- C goals were reached by 77.5% of the rosuvastatin 5-mg group, 86.7% of the rosuvastatin 10-mg group, 45.2% of the pravastatin 20-mg group and 65.5% of the simvastatin 20-mg group (p<0.001 for both rosuvastatin groups vs pravastatin and simvastatin). In the trial of HeFH patients (n=433 for rosuvastatin, n=187 for atorvastatin), 31.9% of patients treated with rosuvastatin 20 mg achieved JAS LDL-C goals, compared with 17.6% of patients treated with atorvastatin 20mg (p<0.001). Conclusions Rosuvastatin has demonstrated clinical superiority over atorvastatin, pravastatin, and simvastatin in reducing LDL-C levels and in enabling patients to reach goals established by the JAS. (Circ J 2004; 68: ) Key Words: Atherosclerosis; HMG-CoA reductase inhibitors; Hypercholesterolemia treatment; Guidelines In Japan, as in Western countries, hypercholesterolemia is an important risk factor for coronary artery disease (CAD). 1 Over the past 50 years, the prevalence of hypercholesterolemia has risen as Japanese people have adopted an increasingly Westernized lifestyle, including a high-fat diet, although cardiovascular mortality remains lower in Japan than in Western countries. Nonetheless, the relationship between serum total cholesterol concentration and the risk of CAD is similar across both populations. 1 As with Western populations, the risk for Japanese people increases with the presence of hypertension, obesity, abnormal glucose tolerance, a history of smoking, age, and family history. (Received July 11, 2003; revised manuscript received October 30, 2003; accepted November 7, 2003) AstraZeneca, Alderley Park, Cheshire, UK and *AstraZeneca, Wilmington, Delaware, USA Mailing address: Kristina Strutt, MBBS, AstraZeneca, Parklands, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom. kristina.strutt@astrazeneca.com Concerns over the increasing incidence of cardiovascular morbidity and mortality prompted the Japan Atherosclerosis Society (JAS) to develop evidence-based guidelines for the diagnosis and treatment of hyperlipidemia, 2 similar to those developed in North America and Europe. 3,4 These guidelines have now been updated to more closely reflect data obtained from recent epidemiologic studies undertaken in Japan as well as in Western countries. 1 As with the previous guidelines, the new JAS guidelines define hypercholesterolemia as total serum cholesterol 220 mg/dl and emphasize the need to reduce low-density lipoprotein cholesterol (LDL-C) to target levels. However, the new guidelines place an increased emphasis on risk factors other than hyperlipidemia and now include a new system for patient categorization that incorporates multiple risk factors (Table 1). Category A includes patients with no coronary heart disease (CHD) or risk factors other than LDL-C; categories B1 B4 include patients with no CHD, but with one or more other risk factors; and category C includes patients with existing CHD in whom secondary prevention is

2 108 STRUTT K et al. Table 1 JAS Guideline Recommendations for Target TC and LDL-C Concentrations According to Patient Category Category of patients Target TC Target LDL-C CHD* Major risk factors (mg/dl) (mg/dl) A No 0 <240 <160 B1 1 <220 <140 B2 2 B3 3 <200 <120 B4 4 C Yes <180 <100 TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; CHD, cardiovascular heart disease. *CHD is defined as definitely diagnosed myocardial infarction and angina pectoris. Major coronary risk factors other than LCL-C: age (male: 45, female: 55), hypertension, diabetes mellitus (including impaired glucose tolerance), smoking, family history of CHD, and low HDL-C (<40 mg/dl). Adapted from Reference 1. required. Throughout the world, hypercholesterolemia is most often treated with one of the 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitors, or statins. 5 Initial data to support the use of rosuvastatin (Crestor ) for treatment of hypercholesterolemia in Japanese patients has come from a phase II dose response study, which showed that rosuvastatin reduces LDL-C in a dose-dependent fashion (up to 58% with 20mg) in patients with hypercholesterolemia. 6 A dose-ranging study in Western patients showed similar efficacy. 7,8 These dose-ranging studies were consistent with an earlier study that showed that hypercholesterolemic patients receiving rosuvastatin at a dose range of 1 4 mg achieved reductions in LDL-C levels ranging from 32% to 42%. 9 As part of the rosuvastatin phase III program, 5 randomized comparative trials of rosuvastatin vs atorvastatin or vs simvastatin and pravastatin were conducted in Western hypercholesterolemic patients. Together, the 5 comparative trials established that rosuvastatin at daily doses of 5 mg or 10 mg is clinically superior to atorvastatin 10 mg, simvastatin 20mg, and pravastatin 20 mg in reducing LDL-C and in enabling more patients to reach the LDL-C goals established by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) and the European Atherosclerosis Society (EAS) A 6th trial showed that rosuvastatin was also more effective than atorvastatin in helping Western patients with heterozygous familial hypercholesterolemia (HeFH) achieve treatment goals. 14 This paper reports on a reanalysis of the pooled data of the first 5 trials, as well as data from the HeFH trial, to assess the comparative efficacy of rosuvastatin in reducing LDL-C to the levels recommended by the JAS (Table 1). Methods The efficacy of rosuvastatin in reducing LDL-C and other lipid parameters compared with other widely used statins was assessed in 6 randomized, multicenter, doubleblind, comparative trials conducted in Europe and North America Five of these trials were prospectively designed to include a 12-week fixed-dose phase that permitted pooling of data: 3 of them 10,11,15 compared rosuvastatin with atorvastatin and 2 12,13 compared rosuvastatin with pravastatin and simvastatin. One of these trials also included a placebo control group; another differed from the other studies in that patients were required to have documented atherosclerosis or diabetes mellitus. These 5 trials involved male and female patients who were 18 years of age with hypercholesterolemia (Fredrickson type IIa/IIb dyslipidemia). During a 6-week dietary lead-in period, patients discontinued all cholesterollowering medication and started an NCEP step I diet. Patients were seen at weeks 6, 2 and 1. To be randomized, patients were required to have a fasting LDL-C of 160 mg/dl and <250 mg/dl (within a 15% variation as determined on 2 measurements) and a fasting triglyceride (TG) of 400 mg/dl. Patients were also required to demonstrate compliance with the step I diet, as evidenced by a score of <28 on the Eating Pattern Assessment Tool. During weeks 0, 2, 6, 10, and 12, lipid concentrations were measured and compliance with the NCEP step I diet was assessed via the Eating Pattern Assessment Tool. The 6th trial 14 was also a randomized, double-blind comparison of rosuvastatin and atorvastatin, but was conducted with HeFH patients and included forced titration of the study drugs. Entry criteria included patients ( 18 years) with HeFH (based on clinical and/or genetic criteria), mean fasting LDL-C concentrations of 220 mg/dl, but <500 mg/dl, and fasting TG concentrations of 400 mg/dl. Following a 6-week dietary run-in period, patients were randomized to once-daily treatment with 20 mg of rosuvastatin or atorvastatin. The study drugs were then forcetitrated at 6-week intervals to 40 mg/day and then to 80mg/day (total treatment time of 18 weeks). The primary end-point for the post hoc analysis was achievement of JAS LDL-C goals at week 12 for the first 5 trials and at week 6 for the HeFH study. Patients were stratified according to JAS categories (Table 1), with categories B1 and B2 combined to assess LDL-C target concentrations of <140mg/dl and categories B3 and B4 combined to assess target concentrations of <120 mg/dl. In the pooled analysis of the first 5 trials, the proportion of patients achieving JAS goals at week 12 was assessed with a logistic regression analysis using the last observation carried forward (LOCF) in intent-to-treat (ITT) populations, with factors being fitted for treatment and baseline LDL-C fitted as a covariate. Statistical comparisons were performed for each rosuvastatin dose vs each comparator statin, whereas comparisons were not done between rosuvastatin doses. In the individual studies and in the pooled analysis, changes in lipid measures from baseline at week 12 were assessed from an analysis of variance (ANOVA) using LOCF in ITT populations. Least-squares means and standard errors (SE) from ANOVA were used for pairwise comparisons. As in the analysis of JAS LDL-C goals, statistical comparisons of changes in lipid measures were performed for each rosuvastatin dose vs each comparator statin, but not between

3 Achievement of JAS LDL-C Goals 109 Table 2 Demographic Characteristics of Patients in Pooled Studies of Rosuvastatin vs Atorvastatin Rosuvastatin 5 mg Rosuvastatin 10 mg Atorvastatin 10 mg (n=394) (n=392) (n=396) Mean age, years (SD) 59 (11) 59 (10) 59 (12) Gender: male: n (%) 205 (52%) 221 (56%) 211 (53%) Mean BMI, kg/m 2 (SD) 28 (4.5) 28 (4.1) 28 (5.3) Race, % White Black Other JAS risk category (n)* A B1/B B3/B C *10 patients excluded from final analysis. Adapted from Reference 15. Table 3 Demographic Characteristics of Patients in Pooled Studies of Rosuvastatin vs Pravastatin and Simvastatin Rosuvastatin 5 mg Rosuvastatin 10 mg Pravastatin 20 mg Simvastatin 20 mg (n=243) (n=231) (n=255) (n=250) Mean age, years (SD) 57 (11) 59 (10) 59 (11) 59 (12) Gender: male: n (%) 110 (45%) 92 (40%) 113 (44%) 109 (44%) Mean BMI, kg/m 2 (SD) 28 (4.9) 29 (5.8) 27 (4.1) 28 (4.9) Race, % White Black Other JAS risk category (n)* A B1/B B3/B C *12 patients excluded from final analysis. Adapted from Reference 15. rosuvastatin doses. A similar analysis was performed for the HeFH population, but using observed rather than LOCF data. Results Five Comparative Trials of Hypercholesterolemic Patients A total of 1,182 patients were randomized to rosuvastatin vs atorvastatin, and 979 patients were randomized to rosuvastatin vs pravastatin and simvastatin ,15 The final efficacy analysis included 1,172 and 967 patients, respectively, owing to patient exclusion for 1 or more of the following reasons: failure to receive study medication, absence of a baseline reading, or absence of at least 1 postbaseline reading for all lipid measures. The vast majority of patients were categorized as medium risk (categories B1 B4) or high risk (category C) according to JAS guidelines. Treatment groups were well matched for age, gender, body mass index (BMI), and race (Tables2,3). The 1,172 patients in the pooled rosuvastatin vs atorvastatin studies included 390 who received rosuvastatin 5 mg, 389 who received rosuvastatin 10 mg, and 393 who received atorvastatin 10 mg. At 12 weeks, rosuvastatin 5mg and 10 mg produced significantly greater reductions in LDL-C vs atorvastatin (41.9% and 46.7% vs 36.4%, p<0.001 for both rosuvastatin groups vs atorvastatin), and significantly greater increases in high-density lipoprotein cholesterol (HDL-C) (8.2% and 8.9% vs 5.5%, p<0.01 for rosuvastatin 5mg, p<0.001 for rosuvastatin 10 mg) (Fig 1). 15 For all risk groups combined, 67.2% of the rosuvastatin 5-mg group, 82.3% of the rosuvastatin 10-mg group, and 58.0% of the atorvastatin 10-mg group reached JAS LDL-C goals (p<0.001 for both rosuvastatin groups vs atorvastatin) (Fig 2). In category C (LDL-C goal <100 mg/dl), 32.1% and 63.9% of the rosuvastatin 5-mg and 10-mg patients, respectively, reached their goal at week 12, compared with 16.1% of atorvastatin patients (p<0.001 for both rosuvastatin groups vs atorvastatin) (Fig 2). A total of 967 patients were enrolled in pooled trials comparing rosuvastatin 5 mg (240), rosuvastatin 10 mg (226), pravastatin (252), and simvastatin (249). At 12 weeks, rosuvastatin 5 mg and 10 mg produced significantly greater reductions in LDL-C compared with both pravastatin and simvastatin (40.6% and 48.1% vs 27.1% and 35.7%, p<0.001 for both rosuvastatin groups vs comparators) (Fig 3). 15 Rosuvastatin 10 mg also produced significantly greater increases in HDL-C compared with both pravastatin and simvastatin (9.1% vs 6.2% and 6.2%, p<0.05 for both comparisons). For all risk groups combined, 77.5% of the rosuvastatin 5-mg group, 86.7% of the rosuvastatin 10-mg group, 45.2% of the pravastatin group, and 65.5% of the simvastatin group reached JAS LDL-C goals (p<0.001 for both rosuvastatin groups vs comparators) (Fig4). In category C, 41.7% and 64.7% of the rosuvastatin 5-mg and 10-mg patients, respectively, reached their goal at week 12, compared with 8.3% of pravastatin patients and

4 110 STRUTT K et al. Fig 1. Changes in lipids at week 12: rosuvastatin vs atorvastatin. At 12 weeks, rosuvastatin 5 mg and 10 mg produced significantly greater reductions in LDL-C vs atorvastatin and significantly greater increases in HDL-C (adapted from Reference 15). Fig 2. Achievement of LDL-C goals: rosuvastatin vs atorvastatin. Rosuvastatin was significantly more effective than atorvastatin in helping patients in categories B3/B4 and C, and all categories combined reach JAS-defined target LDL-C levels. The number of patients in category A was too small to enable meaningful interpretation, and data are not shown. 25.5% of simvastatin patients (p<0.001 for both rosuvastatin groups vs comparators, except p=0.065 for rosuvastatin 5mg vs simvastatin) (Fig4). The common design features in all of the 12-week comparator studies permitted analysis of pooled data from all 1,245 patients who received rosuvastatin in either the 5-mg dose or 10-mg dose. Pooled rosuvastatin data from the 5 trials showed that the percentage of patients who reached LDL-C goals in accordance with the JAS guidelines was approximately 13% higher in patients who received the 10-

5 Achievement of JAS LDL-C Goals 111 Fig 3. Changes in lipids at week 12: rosuvastatin vs pravastatin and simvastatin. At 12 weeks, rosuvastatin 5mg and 10 mg produced significantly greater reductions in LDL-C vs both pravastatin and simvastatin. Rosuvastatin 10 mg also produced significantly greater increases in HDL-C vs both pravastatin and simvastatin (adapted from Reference 15). Fig 4. Achievement of LDL-C goals: rosuvastatin vs pravastatin and simvastatin. Both the 5-mg and 10-mg doses of rosuvastatin were significantly more effective than the comparators in helping patients in categories B1/B2, B3/B4, and C, and all categories combined reach JAS target LDL-C levels, except for rosuvastatin 5 mg compared with simvastatin in category C. The number of patients in category A was too small to enable meaningful interpretation, and data are not shown. mg dose than in those receiving the 5-mg dose (Table4). That dose-related difference was particularly apparent in those patients with the most challenging LDL-C goal of 100 mg/dl.

6 112 STRUTT K et al. Table 4 Percentage of Patients Achieving JAS Guideline LDL-C Concentrations at 12 Weeks in Patients Receiving Rosuvastatin 5 mg or 10 mg (Pooled Data From 5 Trials) JAS risk category Rosuvastatin 5 mg Rosuvastatin 10 mg patients achieving target (%) patients achieving target (%) A (target: LDL-C <160 mg/dl) 41/44 (93.2) 34/36 (94.4) B1/B2 (target: LDL-C <140 mg/dl) 258/293 (88.1) 266/286 (93.0) B3/B4 (target: LDL-C <120 mg/dl) 87/114 (76.3) 109/126 (86.5) C (target: LDL-C <100 mg/dl) 62/179 (34.6) 107/167 (64.1) Total 448/630 (71.1) 516/615 (83.9) Comparative Trial in HeFH Patients A total of 623 patients were randomized: 436 for rosuvastatin, 187 for atorvastatin. 14 Final analyses were conducted with observed data, which included 433 rosuvastatin and 187 atorvastatin patients. At week 6, rosuvastatin 20 mg produced a significantly greater reduction in LDL-C than atorvastatin 20 mg (47% vs 38%, p<0.001) and a significantly greater increase in HDL-C (12% vs 5%, p<0.001). Overall, 31.9% of patients treated with rosuvastatin 20 mg achieved JAS LDL-C goals at week 6, compared with 17.6% of patients treated with atorvastatin 20mg (p<0.001, all risk groups combined). Safety The incidence and types of adverse events were similar across treatment groups in the 5 pooled studies and the HeFH study Rosuvastatin, atorvastatin, simvastatin, and pravastatin were all well tolerated; relatively few patients in any of the treatment groups withdrew from the trials due to treatment-related adverse events. Overall, the benefit risk profile of rosuvastatin appears to be consistent with other marketed statins. Discussion Statins, the most frequently prescribed lipid-lowering medications, have ushered in a new era in the treatment of hyperlipidemia. Their efficacy in reducing primary and secondary cardiovascular morbidity and mortality has been demonstrated in patients with a spectrum of lipid abnormalities and risk levels The benefits of statin therapy have also been established in Japanese patients Given the observation from previous studies that rosuvastatin lowers LDL-C to a similar degree in both Japanese and Western patients, it is reasonable to incorporate the results of the pooled trials reported here into a coherent strategy for preventing and treating CAD in the Japanese population. This analysis demonstrated that rosuvastatin is clinically superior to the other statins tested because more patients with or without established CAD reached JASrecommended LDL-C goals. These results were observed not only in patients with Fredrickson type IIa/IIb dyslipidemia, but also in patients with HeFH. The observation that rosuvastatin effectively reduces LDL-C to JAS target levels is consistent with results demonstrating similar efficacy with regard to target levels established by societies in North America and Europe. 10 Davidson et al demonstrated that patients receiving rosuvastatin 5mg or 10mg had an 84% and 82% success rate, respectively, in reaching NCEP ATP III LDL-C goals, compared with 72% of atorvastatin 10 mg patients. In a subset of patients with CHD or CHD risk equivalents and an LDL-C target concentration of <100mg/dl, 50% of rosuvastatin 5 mg patients and 42% of rosuvastatin 10 mg patients achieved NCEP ATP III LDL-C goals, compared with 27% of atorvastatin patients. When assessed by EAS guidelines, which recommend an LDL-C goal of <116mg/dl (3mmol/L), 59% of rosuvastatin 5mg patients and 75% of rosuvastatin 10 mg patients were found to have achieved this LDL-C goal, compared with 53% of atorvastatin 10 mg patients. 10 Of particular interest is the finding that the majority of patients (65%) in JAS category C (LDL-C target level <100 mg/dl) were able to reach recommended LDL-C targets with the 10-mg dose of rosuvastatin, which suggests that rosuvastatin treatment may reduce the need for dose titration. In contrast, the percentage of category C patients reaching target concentrations with comparator statins ranged from 8.3% with pravastatin 20mg to 25.5% with simvastatin 20 mg. It should be emphasized that these comparisons were made in Western patients using starting doses studied in North America and Europe; in Japan, the starting doses are lower for both pravastatin (10 mg) and simvastatin (5 mg). The difference in treatment efficacy between rosuvastatin and comparator statins has important implications in light of recent research suggesting that more effective lowering of LDL-C provides greater clinical benefits, 20,27 29 as well as in light of an analysis showing that the number of patients eligible for primary prevention lipid-lowering therapy has increased from 15 million under NCEP ATP II criteria to 35 million under NCEP ATP III criteria. 30 Of those eligible for treatment under NCEP ATP III criteria, 25% are targeted for LDL-C lowering to <100mg/dl. According to a recent survey of 4,888 North American patients receiving lipid-lowering therapy, only 38% reached the LDL-C concentration recommended by NCEP ATP II. 31 Success rates ranged from 68% among patients with 0 or 1 risk factor, 37% among patients with 2 or more risk factors without CHD, and 18% among patients with CHD. Failure to achieve NCEP goals appears to be related in large part to inadequate dosages; 31,32 in fact, most patients who begin treatment with a statin remain at the initial dose. 33,34 Therefore, a statin such as rosuvastatin, which has been shown to increase patient success in achieving JAS goals even at starting doses, may provide significant clinical advantages, including a reduced need for dose titration and additional clinical visits. Conclusions In summary, the results presented here suggest that rosuvastatin in daily doses of 5 and 10 mg is clinically superior to atorvastatin 10 mg, pravastatin 20 mg, and simvastatin 20 mg for improving the lipid profile and helping patients reach target LDL-C concentrations in accordance with JAS guidelines. Of all the regimens tested, rosuvastatin 10 mg was the most effective in helping patients achieve JAS

7 Achievement of JAS LDL-C Goals goals, particularly in those patients for whom the LDL-C targets were more challenging (<100 mg/dl). The reduced titration requirements for rosuvastatin may offer benefits in terms of efficacy and patient compliance. Because treatment response does not differ significantly between Japanese and Western subjects, it is reasonable to incorporate rosuvastatin into a comprehensive therapeutic strategy designed to minimize cardiovascular morbidity and mortality in Japanese people. References 1. Japan Atherosclerosis Society. Japan Atherosclerosis Society (JAS) guidelines for diagnosis and treatment of atherosclerotic cardiovascular disease. Tokyo: JAS, Investigating Committee of Guidelines for Diagnosis and Treatment of Hyperlipidemia in Adults. Guideline for diagnosis and treatment of hyperlipidemia. J Jpn Atheroscler Soc 1997; 25: Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. 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