A Randomised Study Comparing the Efficacy and Safety of Rosuvastatin With Atorvastatin for Achieving Lipid Goals in Clinical Practice in Asian Patients at High Risk of Cardiovascular Disease (DISCOVERY- Asia Study)

By Zhu, Jun-ren Tomlinson, Brian; Ro, Young Moo; Sim, Kui-Hian; Lee, Yuan-Teh; Sriratanasathavorn, Charn

Key words: Asian – Atorvastatin – Cardiovascular disease – Low- density-lipoprotein cholesterol (LDL-C) – Rosuvastatin ABSTRACT

Background: Most studies investigating the benefits of statins have focused on North American and European populations. This study focuses on evaluating the lipid-lowering effects of rosuvastatin and atorvastatin In Asian patients.

Objectives: The Direct Statin Comparison of LDL-C Values: an Evaluation of Rosuvastatin therapY (DISCOVERY)-Asia study is one of nine independently powered studies assessing the efficacy of starting doses of statins in achieving target lipid levels in different countries worldwide. DISCOVERY-Asia was a 12-week, randomised, open-label, parallel-group study conducted in China, Hong Kong, Korea, Malaysia, Taiwan, and Thailand.

Results: A total of 1482 adults with primary hypercholesterolaemia and high cardiovascular risk (>20%/ 10 years, type 2 diabetes, or a history of coronary heart disease) were randomised in a 2:1 ratio to receive rosuvastatin 10 mg once daily (o.d.) or atorvastatin 10 mg o.d. The percentage of patients achieving the 1998 European Joint Task Force low-density lipoprotein cholesterol (LDL-C) goal of <3.0 mmol/L at 12 weeks was Significantly higher in the rosuvastatin group (n = 950) compared with the atorvastatin group (n = 471) (79.5 vs. 69.4%, respectively; p < 0.0001). Similar results were observed for 1998 European goals for total cholesterol (TC), and the 2003 European goals for LDL-C and TC. LDL-C and TC levels were reduced significantly more with rosuvastatin compared with atorvastatin. Both drugs were well- tolerated and the incidence and type of adverse events were similar in each group.

Trials registration: The trial registry summary is available at http://www.clinicaltrials.gov/; ClinicalTrials.gov Identifier: NCT00241488

Conclusions: This 12-week study showed that the starting dose of rosuvastatin 10 mg o.d. was significantly more effective than the starting dose of atorvastatin 10 mg o.d. at enabling patients with primary hypercholesterolaemia to achieve European goals for LDL-C and TC in a largely Asian population in real-life clinical practice. The safety profile of rosuvastatin 10 mg is similar to that of atorvastatin 10 mg in the Asian population studied here, and is consistent with the known safety profile of rosuvastatin in the white population.

Introduction

Atherothrombosis is the leading cause of cardiovascular morbidity and mortality, regardless of region as shown in the INTERHEART and REduction of Atherothrombosis for Continued Health (REACH) worldwide studies on cardiovascular risk factors1,2. Studies from individual countries in Asia, including China3,4, India5, Korea6, Malaysia7, Taiwan8, and Thailand9,10, have identified dyslipidaemia as an important risk factor for cardiovascular events. A cross-sectional survey of 15 540 Chinese adults, carried out by the InterASIA Collaborative Group, found that about 32% had at least borderline high total cholesterol (TC) levels (>/=5.2 mmol/L [200 mg/dL]) and 25% had at least borderline high low-density lipoprotein cholesterol (LDL-C) levels (>/=3.4 mmol/L [130 mg/dL])4. Further evidence from China suggests that the dramatic increases in coronary heart disease (CHD) mortality observed in Beijing between 1984 and 1999 may be explained by rises in cholesterol, reflecting an increasingly Western diet3. Reduced levels of physical activity and a more sedentary lifestyle may also contribute to the rapidly growing prevalence of obesity in China, with an associated increase in cardiovascular risk11. In a study of Thai labour workers, undesirable cholesterol levels were also linked to lifestyle, with higher cholesterol levels observed in the more affluent and those who lived in municipalities versus the less well-off and those in rural regions10.

Despite the increasing prevalence of dyslipidaemia, under- treatment with statins remains a problem. A large study carried out recently in China calculated that 35 million Chinese adults should be considered for lifestyle changes and lipid-lowering therapy (LLT) according to National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III guidelines, but that the majority of Chinese adults receive no treatment at all12.

Choice of statin may also be important in terms of achieving lipid goals. Rosuvastatin at an initial dose of 10 mg once daily (o.d.) has been shown to achieve greater reductions in LDL-C and enable more patients to achieve lipid goals compared with commonly prescribed doses of other currently marketed statins13-17. There is some debate concerning the dose of rosuvastatin which might be required in Asian compared with white populations because of differences in pharmacokinetic and pharmacodynamic profiles. In a study of healthy, dyslipidaemic, or renal-impaired Japanese subjects, systemic exposure to rosuvastatin was found to be approximately two-fold higher compared with matched white subjects in western Europe or the USA18. Rosuvastatin pharmacokinetics were not altered in the Japanese subjects with mild or moderate renal impairment compared with those without. Potential environmental and dietary influences were largely ruled out by a study conducted in healthy volunteers living in Singapore, which also showed that Chinese, Malay, and Asian-Indian subjects had 1.6 to 2.3-fold greater exposures to rosuvastatin compared with white patients19. It has been suggested that genetic variations, possibly in membrane transporters or other pathways involved in rosuvastatin disposition, may account for these differences but further research is warranted19,20. To date, ethnicity-determined variations in exposure have not been reported for other statins; however, some trials suggest altered efficacy on cholesterol metabolism by some statins in East Asian patients21,22, and most statins are approved for lower maximal doses in Japan compared with the USA. However, despite the observed difference in plasma exposure between Asian and white patients, clinical studies have shown that the efficacy of rosuvastatin in Asian patients is similar to that observed in white patients23″25. In addition, rosuvastatin has been shown to be well- tolerated by Asian patients and to have a safety profile similar to that in white patients23,25,26.

The majority of clinical studies investigating the benefits of statins have focused on North American and European populations. Large-scale studies to confirm the efficacy of these agents in routine clinical practice and in previously under-represented populations are required. Further evidence of the efficacy of rosuvastatin in achieving lipid goals in a ‘real-life’ setting has been investigated in the Direct Statin Comparison of LDL-C Values: an Evaluation of Rosuvastatin therapY (DISCOVERY) Programme, which began in 2002. The DISCOVERY Programme consists of nine independently powered studies carried out in different countries and regions worldwide: (1) the Netherlands; (2) Triple Country (Iceland, Ireland, and Finland); (3) Asia; (4) Alpha (Eastern Europe, Central and South America, and the Middle East); (5) Belux (Belgium and Luxemburg); (6) Canada; (7) PENTA (Latin America and Portugal); (8) Beta (Estonia); and (9) the UK. The objective was to compare the efficacy of rosuvastatin at a starting dose of lOmg o.d. versus other statins (at their respective starting doses) in achieving target lipid levels in the clinical setting in Asian patients with primary hypercholesterolaemia and at high risk of cardiovascular diseases. The aim of this report is to present the results of the DISCOVERY-Asia study.

Patients and methods

Study design

DISCOVERY-Asia was a 12-week, randomised, multi-national, open- label, parallel-group, comparative study conducted at 70 centres in China, Hong Kong, Korea, Malaysia, Taiwan, and Thailand. Dietary counselling for ~6 weeks was provided for LLT-nai’ve patients before the study, whereas patients switching from a starting dose of other LLT could enter the study immediately after they were determined eligible, with no dietary run-in period.

Eligible Asian patients were randomised sequentially in a 2:1 ratio to open-label treatment with either rosuvastatin 10 mg o.d. or atorvastatin 10 mg o.d. for 12 weeks, after which there was an optional extension period. Treatment given to patients was determined by country-specific randomisation lists, generated using SAS version 8.2. During the extension phase, patients who reached the 1998 European LDL-C goal (<3.0 mmol/L [115 mg/dL])27 on rosuvastatin lOmg o.d. could continue on this dose, and those who did not could be titrated up to rosuvastatin 20 mg o.d. and then reviewed at 12-week intervals. Patients who did not reach the LDL-C goal on atorvastatin 10 mg o.d. could be treated with rosuvastatin at the starting dose of 10 mg o.d. and then reviewed at 12-week intervals. In both groups during the extension period, rosuvastatin could be titrated up to a maximum of 40 mg o.d. as needed, until local rosuvastatin launch or for 6 months from their first study visit. Patients who had achieved the LDL-C goal on atorvastatin 10 mg o.d. during the 12-week study period did not have the option to continue into the extension phase and were returned to normal clinical practice, with treatment at the discretion of the investigator. The findings from this optional extension period are not reported here and will be presented separately at a later date. The study was performed in accordance with the ethical principles in the Declaration of Helsinki, and was consistent with the International Conference on Harmonisation/Good Clinical Practice and applicable regulatory requirements. The study protocol was approved by the ethics committee at each institution, and all patients gave written informed consent to participate before any study procedures were undertaken.

Patients

Men and women aged >/=18 years with primary hyper- cholesterolaemia were eligible for inclusion in the study if they were either LLT-naive or had been receiving starting doses of LLT that had proved ineffective. Hypercholesterolaemia was defined as LDL-C >3.5 mmol/L (135 mg/dL) if LLT-naive, or >3.1 mmol/L (120 mg/ dL) if switching. Patients were also required to have triglycerides (TG) 20%, or diabetes mellitus). Clinical evidence of atherosclerotic disease was defined as:

(1) Patients with a history of transient ischaemic attacks or ischaemic stroke; carotid artery disease as evidenced by a history of carotid endarterectomy, angioplasty, or other cerebral revascularisation; or those patients with advanced (at least 60% stenosis) atherosclerosis in the common or internal carotid artery (documented by angiography or ultrasound);

(2) Patients with coronary artery disease, defined by a history of myocardial infarction or hospitalisation for treatment of unstable angina, angina pectoris corroborated by objective evidence of myocardial ischaemia, coronary revascularisation, or angiographic evidence of stenosis >50% in one or more major epicardial coronary artery;

(3) Patients with peripheral arterial disease defined by a history of aortic aneurysm repair, aortoiliac, femoral, or other arterial surgery or angioplasty performed to relieve lower limb ischaemia, lower limb amputation performed due to complications of atherosclerotic arterial disease, or intermittent claudication with an ankle-brachial pressure index (ABI) <0.9.

Major exclusion criteria were as follows: familial hypercholesterolaemia or dysbetalipoproteinaemia; secondary hypercholesterolaemia of any cause; uncontrolled diabetes or hypertension (resting diastolic blood pressure [DBP] >95 mmHg or resting systolic blood pressure [SBP] >200 mmHg), active liver disease or hepatic dysfunction (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] >/= 1.5 x the upper limit of normal [ULN]), a history of hypersensitivity to statins, unexplained serum creatine kinase (CK) >3 x ULN, serum creatinine >220 [mu]mol/L (2.5 mg/dL) and unstable angina within 3 months of the study.

Endpoints

The primary endpoint was the percentage of patients achieving the 1998 European Joint Task Force LDL-C goal (< 3.0 mmol/L [115 mg/ dL])27 at 12 weeks. secondary efficacy endpoints included percentage of patients achieving the 1998 European TC goal (<5.0 mmol/L [190 mg/ dL]) after 12 weeks; percentage change in LDL-C, TC, high-density lipoprotein cholesterol (HDL-C), and TG from baseline to week 12. The frequency and severity of adverse events (AEs), and abnormal laboratory values were also examined.

The 2003 Joint European guidelines on cardiovascular disease prevention28 (LDL-C goals <2.5 or 3.0 mmol/L [100 or 115 mg/dL], depending on risk category; TC goals <4.5 or 5.0 mmol/L [175 or 190 mg/dL], depending on risk category) became available during the course of the study, and data were also analysed according to these guidelines.

Assessments

Fasting blood samples were collected during screening and at week 12. Lipid parameters (LDL-C, TC, HDL-C, and TG) were evaluated by site or country-certified laboratories. LDL-C levels were determined using the Friedewald formula29.

Safety was assessed by the frequency of AEs and abnormal laboratory data (e.g., hepatic biochemistry [ALT and AST], serum CK, and serum creatinine). AEs were identified by means of a standard question (‘How have you felt since the last visit?’). Each investigator was required to make a causality assessment of the relationship of the event to the study drug and whether it constituted a serious AE (SAE). Safety data were summarised by treatment actually received.

Study medication was supplied to the investigators as tablets for oral administration. Patients were asked to return all unused medication and empty containers. Compliance was assessed at week 12 by calculating the number of tablets taken during the study period as a proportion of the number of tablets returned; patients were considered non-compliant if they took < 80 or > 120% of the prescribed number of tablets.

Statistical analyses

In order to compare the efficacy of rosuvastatin lOmg with atorvastatin 10 mg by assessment of the percentage of patients achieving the 1998 European LDL-C goal, 1362 patients were required. The trial was sized to detect a difference of 10% between treatments, using a randomisation ratio of 2 : 1 (rosuvastatin: atorvastatin), with 90% power and a two-sided significance level of 5% (alpha = 0.05) and to allow for a withdrawal rate of 25%.

Efficacy was evaluated by randomised treatment in the intention- to-treat (ITT) population, which consisted of all patients with a baseline lipid measurement and at least one post-baseline lipid measurement, and who had taken at least one dose of study medication. The analyses used the last available observation carried forward approach for patients with missing data.

The number and percentage of patients attaining lipid goals with rosuvastatin and atorvastatin were compared using a logistic regression model, with factors fitted for treatment, centre, pre- dose lipid parameter covariate, subject type (LLT-nai’ve or switched), and treatment-by-patient-type interaction. If the treatment-by-patient interaction was found to be significant (p <, 0.05), this indicated different treatment effects in LLT-naive and switched patients and the nature of the interaction was therefore investigated and the treatment comparisons were presented separately for each patient type. If no significant interaction was found, the term was dropped from the final model and the results were analysed for both patient types combined.

The percentage change in LDL-C, TC, HDL-C and TG was performed separately for the LLT-nai’ve and switched patients as there was no wash-out period required for patients who had just switched from LLT. Formal treatment comparisons of percentage change from pre- dose to week 12 were performed using an analysis of covariance (ANCOVA) model, with factors fitted for treatment, centre, pre-dose lipid parameter covariate, subject type (LLT-naive or switched), and treatment-by-subject-type interaction. The results are presented in terms of least squares means and the difference between least squares means, with p-values and associated 95% confidence intervals.

Descriptive safety analyses were conducted on data from all patients who had received at least one dose of study medication. No formal treatment comparisons were performed. The case report forms used in this study captured relationship of SAEs to study drug but not that of AEs overall.

Results

Study population

Of 2159 patients enrolled in the study between June 20, 2003 and September 30, 2005, 1482 patients were randomised to treatment with rosuvastatin lOmg o.d. (n = 995) or atorvastatin 10 mg o.d. (n = 487) (Figure 1). Randomisation by country is presented in Table 1. In all, 41% of the randomised patients were from China, with the other countries contributing 7-19% of patients.

At baseline, the treatment groups were well balanced in terms of demographic, clinical, and lipid parameters, and the majority in each group were Asian patients (Table 2). As expected from the inclusion criteria (primary hypercholesterolaemia with high cardiovascular risk [>20%/10 years, type 2 diabetes, or a history of CHD]), quite a high proportion of patients in each group (45%) had diabetes and overall, patients’ mean body mass index (BMI) was also high (>25 kg/m^sup 2^), confirming a largely high-risk population. Prior to study entry, 2.3% of patients in the rosuvastatin group and 2.1% of patients in the atorvastatin group had been on fibrate therapy.

Sixty patients were excluded from the ITT population, which comprised 1422 patients (950 in the rosuvastatin group and 472 in the atorvastatin group) (Figure 1). However, one subject in the atorvastatin group was excluded from the efficacy analysis because week 12 lipid data were provided by a non-study laboratory. Nine patients did not take any study medication and were excluded from the safety population of 989 patients on rosuvastatin and 484 patients on atorvastatin. A total of 1390 patients completed the study, 930 on rosuvastatin and 460 on atorvastatin.

Table 1. Randomised patients in each country in the DISCOVERY- Asia study

Table 2. Patient characteristics at baseline (ITT population) in the DISCOVERY-Asia study

Mean compliance with treatment during the study was similar in each group (rosuvastatin, 95.7%; atorvastatin, 96.5%).

Figure 1. Patient flow through the DISCOVERY-Asia study. ITT, intention-to-treat. *One patient had lipid data recorded at week 12 by a non-study laboratory. This patient was included in the ITT population by virtue of these lipid results being present in the database. However, this patient was excluded from summaries of week 12 results, and summaries of changes from baseline to week 12, as summaries are based on data associated with a known study laboratory at both timepoints. Note: two patients randomised to atorvastatin actually received rosuvastatin and were included in the safety analysis Efficacy

Lipid goals

The percentage of patients achieving the 1998 European LDL-C goal (<3.0 mmol/L [115 mg/dL]) at 12 weeks was significantly higher in the rosuvastatin 10-mg group compared with the atorvastatin 10-mg group (79.5 vs. 69.4%, p < 0.0001; Figure 2). Rosuvastatin 10 mg also enabled significantly more patients to achieve the 1998 European TC goal (<5.0mmol/L [190mg/dL]) compared with atorvastatin (77.1 vs. 67.5%, p < 0.0001; Figure 2).

Achievement of the 2003 European lipid goals was also assessed. Overall, significantly more patients achieved the 2003 LDL-C goals (<2.5 or 3.0 mmol/L [100 or 115 mg/dL], depending on risk category) with rosuvastatin 10 mg than with atorvastatin 10 mg (65.8 vs. 49.5%, p < 0.0001; Figure 3). Significantly more patients also achieved the 2003 TC goal (<4.5 or 5.0 mmol/L [175 or 190 mg/dL], depending on risk category) with rosuvastatin 10 mg than with atorvastatin 10 mg (64.0 vs. 49.7%, p < 0.0001; Figure 3).

Improvements across the lipid profile

The percentage change from baseline in lipid levels was analysed separately in patients not receiving LLT before the study (LLT- naive), and in patients who had been receiving other LLT (switched).

Figure 2. Percentage of subjects reaching 1998 European LDL-C (< 3.0 mmol/L [115 mg/dL]) and TC (< 5.0 mmol/L [190 mg/dL]) goals (ITT population). ITT, intention-to-treat; LDL-C, low-density lipoprotein cholesterol; n = number of evaluable patients; TC, total cholesterol. *p < 0.0001 vs. atorvastatin 10 mg; [dagger] One subject in the atorvastatin treatment group was excluded from calculations related to efficacy variables because week 12 lipid data were provided by a non-study laboratory

In LLT-naive patients, rosuvastatin 10mg was shown to be significantly more effective than atorvastatin 10 mg at reducing LDL- C levels (-47.5 vs. -40.2%, p < 0.0001; Table 3). TC levels were also reduced significantly (p < 0.0001) more with rosuvastatin than with atorvastatin (Table 3). There was a minor increase in HDL-C from baseline with rosuvastatin but not atorvastatin in LLT-naive patients, but the difference was not statistically significant (Table 3). Both rosuvastatin and atorvastatin reduced TG levels to a similar extent in LLT-naive patients, and there were no significant differences between treatment groups (Table 3).

Figure 3. Percentage of subjects reaching 2003 European LDL-C (< 2.5 or 3.0 mmol/L [100 or 115 mg/dL], depending on risk) and TC (< 4.5 or 5.0 mmol/L [175 or 190 mg/dL], depending on risk category) (ITT population). ITT, intention-to-treat; LDL-C, low-density lipoprotein cholesterol; n = number of evaluable patients; TC, total cholesterol. *p < 0.0001 vs. atorvastatin 10 mg; [dagger] One subject in the atorvastatin treatment group was excluded from calculations related to efficacy variables because week 12 lipid data were provided by a non-study laboratory

As might be expected in switched patients, reductions in LDL-C and TC were typically lower than those seen in treatment-naive patients. However, rosuvastatin also reduced LDL-C and TC levels significantly (p < 0.0001) more than atorvastatin (Table 3). In switched patients, there was no significant difference between treatment groups with regard to effect on HDL-C (Table 3). In contrast to atorvastatin, rosuvastatin reduced TG levels from baseline but again differences between treatment groups were not significant.

Safety

Overall, both study drugs were well-tolerated and the incidence and type of AEs were similar between treatment groups. AEs were reported in 20.7% of patients receiving rosuvastatin 10 mg and 16.9% of those receiving atorvastatin 10 mg (Table 4). Upper respiratory tract infection and dizziness were the most frequently reported AEs in the rosuvastatin and atorvastatin groups, respectively (Table 5). The frequency of muscle, liver, and renal AEs was low in both treatment groups. A total of 12 patients experienced treatment- emergent myalgia: eight (0.8%) in the rosuvastatin group and four (0.8%) in the atorvastatin group (Table 5).

Treatment was discontinued because of an AE in 20 patients (2.0%) in the rosuvastatin group and ten patients (2.1%) in the atorvastatin group. No new safety issues were identified and the majority of AEs leading to discontinuation in each group were either known AEs, such as myalgia or headache, or events that were not unexpected in this patient population, such as acute coronary syndrome and hypertension.

The frequency of treatment-emergent SAEs was also low at 2.7% in the rosuvastatin group and 2.1% in the atorvastatin group (Table 4). Only one SAE was considered by the investigator to be related to study drug. This was a case of chronic hepatitis, in a 49-year old male in the rosuvastatin group. The AE was reported as serious 83 days after the start of treatment, and rosuvastatin was discontinued. However, the assessment was confounded by positive serology for hepatitis B surface antigen. Alcohol was excluded as a possible cause since the patient had reduced his alcohol consumption over the previous 10 months. Anti-hepatitis C virus antibody was negative. A ‘healdiy herbal tea’ taken two days prior to the tests was confirmed as a drink and not a medication and excluded as a possible cause.

Four deaths occurred during the study: two (0.2%) in the rosuvastatin group (one sudden cardiac death and one acute cerebral infarction with septicaemia) and two (0.4%) in the atorvastatin group (one death due to hypertensive heart disease and one due to multiple organ failure). None of these were considered by the investigator to be related to study drug.

Changes in clinical laboratory values from baseline were minimal and similar in both treatment groups. A serum creatinine at week 12, more than double that at baseline, was recorded in 2/956 patients (0.2%) in the rosuvastatin group. One patient increased from 26 [mu]mol/L (0.3 mg/dL) to 80 [mu]mol/L (0.9 mg/dL) and was still within the normal reference range of 44-133 [mu]mol/L (0.5-1.5 mg/ dL); the other increased from 71 [mu]mol/L (0.8mg/dL) to 159 [mu]mol/ L (1.8 mg/dL) and serum creatinine levels returned to normal within days. Both patients remained on rosuvastatin and were asymptomatic.

There were no reported cases of myopathy, myositis or rhabdomyolysis, and no treatment-related renal insufficiency with either treatment. One patient receiving atorvastatin developed acute renal failure, which was not considered related to study medication. The following individual AEs relating to the renal-urinary system were reported: proteinuria in one (0.1%) patient receiving rosuvastatin (none receiving atorvastatin); haematuria in one (0.1%) patient receiving rosuvastatin and one (0.2%) patient receiving atorvastatin. Vital signs, weight, and BMI were essentially unchanged in both treatment groups, although slight decreases in SBP (from 136.3 to 132.8 mmHg [-3.5%] in the atorvastatin group and from 135.9 to 131.1 mmHg [-4.7%] in the rosuvastatin group) and DBP (from 80.7 to 79.1 mmHg [-1.7%] in the atorvastatin group and from 80.5 to 78.2 mmHg [-2.2%] in the rosuvastatin group) were observed. Concomitant medication included calcium channel blockers (34% of patients), selective beta-blockers (33% of patients), and angiotensin-converting enzyme inhibitors (31% of patients).

Table 3. Change from baseline in serum lipid levels at 12 weeks in the DISCOVERY-Asia study

Table 4. Number of patients with adverse events (safety population) in the DISCOVERY-Asia study

Table 5. Most commonly reported adverse events (those experienced by >/= 0.8% of patients in either treatment group): number (%) of patients in the DISCOVERY-Asia study

Discussion

The results of the DISCOVERY-Asia study show that recommended starting dose of rosuvastatin 10 mg o.d. was significantly more effective than atorvastatin 10 mg o.d. at enabling high-risk patients to achieve European LDL-C and TC goals after 12 weeks of treatment. This was true both for the 1998 European guidelines and for the more stringent 2003 European guidelines. Reductions in LDL- C and TC were significantly greater with rosuvastatin compared with atorvastatin in both LLT-naive patients and those switched from the starting dose of other statins or fibrates. The results indicate that, at its recognised starting dose of 10 mg o.d.30,31, rosuvastatin could significantly improve the proportion of Asian patients achieving goals for both LDL-C and TC compared with atorvastatin at its recognised starting dose of 10 mg o.d32. Starting doses of rosuvastatin and atorvastatin of 10mg were chosen with the commonly used starting dose in certain Asian countries in mind23.

The DISCOVERY-Asia findings support the results of other DISCOVERY studies that have been published to date33-37. Despite including patients from a variety of ethnicities and cultural environments, all five studies showed that rosuvastatin was significantly (p < 0.001 for all) better than atorvastatin at enabling patients to achieve European LDL-C and TC goals. DISCOVERY- UK and DISCOVERY-Netherlands also included patients randomised to the recommended starting doses of simvastatin or pravastatin; in both studies, rosuvastatin resulted in a significantly higher proportion of patients achieving European lipid goals34,37. In a meta-analysis of pooled data from 6743 patients included in these five studies, rosuvastatin 10 mg was confirmed to be significantly (p < 0.001) more effective than atorvastatin 10 mg in achieving 2003 European goals for both LDL-C and TC26.

Our findings also support the efficacy results for rosuvastatin compared with other statins in the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR)13,14, and Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY (MERCURY) I16 studies, which were conducted primarily in Europe and the USA. The results of DISCOVERY-Asia extend the results of other trials by providing evidence regarding the comparative efficacy and safety of statins in Asian populations, which have been largely under-represented in prospective statin trials. Despite rosuvastatin’s documented beneficial effect on HDL levels13,26, this was not seen in this study. There was a minor increase in HDL-C from baseline with rosuvastatin but not atorvastatin, however the difference was not statistically significant. Similar results have been seen in other studies with rosuvastatin13,38,39. These results may be explained by the dose-response curves of the two statins seen in the STELLAR trial13. Results from this study showed that at low doses such as 10 mg/day, the difference in HDL response for rosuvastatin and atorvastatin was not significant. However, at higher doses such as 20-40 mg/day, HDL-C levels increased further with rosuvastatin, whereas they decreased with atorvastatin, thus making the difference in HDL-C levels between the statins significant. Nevertheless, further studies are required to explain the occurrence of these results in white as well as Asian patients.

Consistent with the greater efficacy of rosuvastatin 10mg for enabling patients to achieve goals, reductions in LDL-C and TC were also significantly (p < 0.0001) greater in both LLT-naive and switched patients compared with the atorvastatin 10-mg group.

In the absence of consolidated guidelines for the management of cardiovascular risk in largely Asian populations, the lipid goals currently recommended by the Joint European Task Force28 have been shown to be achievable using rosuvastatin 10 mg as a starting dose in two-thirds of those treated in the DISCOVERY-Asia population. Current recommended practice is to initiate statin therapy at starting doses and to titrate up if cholesterol goals are not achieved28,40,41. Titration of rosuvastatin to achieve optimal efficacy should improve the percentage achieving target goals.

There are few data on the efficacy of rosuvastatin in Asian populations. However, in an open-label study of 37 Japanese patients with heterozygous familial hypercholesterolaemia, who received rosuvastatin 10-40mg o.d., significant (p < 0.0001) reductions from baseline in LDL-C of 49.2-56.7%, and in TC of 39.4-45.4% were observed25. There were also significant reductions in TG (18.2- 25.0%, p < 0.006) and significant increases in HDL-C (9.6-13.6%, p < 0.005). Similar results were reported with a dose-response phase II trial in which 112 Japanese patients received placebo or rosuvastatin 1, 2.5, 5, 10, 20, or 40 mg o.d. for 6 weeks23. Mean percentage reductions from baseline in LDL-C ranged from 35.8-66.0% and were significantly different from placebo (p < 0.0001). Reductions in TC levels of 25.5-45.1% were also achieved with these doses. The reductions in TC and LDL-C with rosuvastatin 10 mg (35.0 and 49.7%, respectively) are consistent with data from the present study. In the sub-group of patients receiving rosuvastatin 5 mg o.d. in the study by Saito et al.23, LDL-C was reduced by a mean (SD) of 52.7% (3.1) and TC by 36.5% (2.7), both of which were statistically significant changes (p < 0.0001), and were comparable with the results in LLT-naive patients in our study. Rosuvastatin 5 mg is sometimes recommended as a starting dose in certain Asian countries since increased plasma concentrations have been observed with the 10 mg starting dose in specific Asian patient groups.

The patients included in DISCOVERY-Asia had a mean BMI exceeding 25 kg/m^sup 2^ in each treatment group, which is classified as overweight by the Working Group on Obesity in China42,43. A high proportion of patients (over 45% in each group) was also diabetic, mean baseline TG levels were > 1.7 mmol/L (150 mg/ dL) and over 70% of patients were hypertensive. It would have been interesting to compare the efficacy and safety of rosuvastatin and atorvastatin in the sub-group of those patients who qualified as having the metabolic syndrome. This scenario may be considered in another paper if the sub-analysis of these patients is performed. However, according to the International Diabetes Federation criteria for the metabolic syndrome44, waist circumference rather than BMI is as a measure of central obesity. Waist circumference is also generally considered to be more strongly correlated with cardiovascular risk in Chinese populations11.

Despite the fact that our study was an open-label design, the overall pattern and frequency of AEs, including liver, muscle and renal AEs, and abnormal laboratory data were similar between treatment groups. No cases of myopathy or rhabdomyolysis were reported. Interestingly, there were decreases in SBP (-4.7% in the rosuvastatin group and -3.5% in the atorvastatin group) and DBP (- 2.2% in the rosuvastatin group and -1.7% in the atorvastatin group). There is evidence that, as well as their beneficial effect on lipids levels, statins may also modulate blood pressure45. In this study there were no major changes in weight, BMI, or antihypertensive medications. These changes in blood pressure, which seem to be largely independent of the lipid effects, may contribute to the overall beneficial effects of statins on cardiovascular risk46. This is one of the first studies to report a lowering of blood pressure seen with statins in an Asian population. The mechanism by which statins may decrease blood pressure still remains to be elucidated.

Increases in serum creatinine of > 100% from baseline were recorded in only two patients, both receiving rosuvastatin, but both patients were asymptomatic and there was no evidence of renal insufficiency in either patient. The effect of short-term (6-8 weeks) and long-term (up to 3.8 years) treatment with rosuvastatin 5- 40 mg on renal function, measured by glomerular filtration rate (GFR), has been assessed in patients enrolled in two studies as part of the rosuvastatin clinical development programme47,48; small but significant (p < 0.01) improvements from baseline in GFR were observed across all doses of rosuvastatin (5-40 mg). Similar improvements have been seen with atorvastatin in the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) trial with atorvastatin49 and some renal protection was seen with simvastatin in the Heart Protection Study50.

All the statins studied in the DISCOVERY Programme have been well- tolerated, with comparable safety profiles26. Rosuvastatin was shown to be well-tolerated at doses of up to 40 mg o.d. in dose-titration and phase II studies in Japanese patients23,25. However, DISCOVERY- Asia represents the first large-scale safety study of statin therapy in Asian populations. Data from the long-term extension phase of the trial will provide further information.

Data from 12 400 patients included in the multinational rosuvastatin phase Will programme have demonstrated that rosuvastatin is well-tolerated in a broad range of patients, with a similar safety profile to that of comparator statins51. A retrospective observational study using an administrative managedcare claims database including more than 470 000 patients in the USA has shown that statins as currently prescribed are safe and well-tolerated52. There were no statistically significant differences between all currently marketed statins, including rosuvastatin, in terms of incidence of hospitalisations associated with myopathy, renal events or hepatic events52.

Unlike some other statins, rosuvastatin is not significantly metabolised via the cytochrome P450 3A4 isoenzyme53, and therefore has a low potential for interactions with drugs metabolised via tins pathway. Use of lipid-lowering medication and inhibitors of CYP3A4 has been shown to lead to a significant six-fold increase in muscle disorders including rhabdomyolysis52. In persons taking simvastatin, lovastatin or atorvastatin, 60% of rhabdomyolysis cases involved drugs known to inhibit CYP3A454.

Although this study confirmed the efficacy and safety of the 10- mg dose of rosuvastatin and atorvastatin in Asian patients, the study does have limitations. The allocated trial medication was open- label, which may possibly introduce information bias. This is most likely to increase adverse event reporting for the investigational treatment compared with the control treatment. In this study similar AE rates were seen with both treatments. The measurements of achieving treatment goals are not likely to be influenced by the open-label design, as they are based on absolute laboratory lipid values. The non-equivalence of comparative treatments could be argued since rosuvastatin is considered to be twice as potent as atorvastatin30. Nevertheless, the objective of the study was to compare the efficacy of both statins at their recommended starting dose of 10 mg o.d., which is how they are, or should be used, and thus reflects daily practice. Lasdy, although this study indicates that 12 weeks of treatment with rosuvastatin 10 mg o.d. was significantly more effective than atorvastatin 10 mg o.d. with respect to reaching lipid-lowering treatment goals in Asian patients, the long-term clinical benefits, in terms of reducing cardiovascular morbidity and mortality, needs to be confirmed in clinical outcomes trials.

This study shows that the safety profile of rosuvastatin 10 mg is similar to that of atorvastatin 10 mg in Asian patients, and consistent with the known safety profile of rosuvastatin in white patients.

Conclusion

In the DISCOVERY-Asia study, 12 weeks of treatment with the 10 mg starting dose of rosuvastatin was shown to be significantly more effective than the starting dose of atorvastatin at enabling patients with primary hypercholesterolaemia to achieve European goals for LDL-C and TC, in a largely Asian population in real-life clinical practice, both in previously untreated patients and in those switched from other LLTs. As achieving lipid goals has been associated with improvements in cardiovascular outcomes49,55, treatment with rosuvastatin may be clinically beneficial. Rosuvastatin 10 mg and atorvastatin 10 mg were both well-tolerated overall, with comparable safety profiles, and consistent with the known safety profile of rosuvastatin in whites. There were no reports of renal insufficiency or rhabdomyolysis. These findings support those from five other published DISCOVERY studies in a variety of patient populations, and confirm the results of earlier studies demonstrating the efficacy and safety of rosuvastatin. Overall, the findings suggest that rosuvastatin has a favourable benefit-risk profile and a safety profile similar to other currently marketed statins when administered at their recommended starting doses in Asian populations. Moreover, this study confirms that the efficacy of rosuvastatin in Asian patients is similar to that observed in white patients, thus providing assurance for its use in Asian populations.

Acknowledgements

Declaration of interest: The DISCOVERY Asia study is sponsored by AstraZeneca; Gary Cotter, PhD, from Prime Medica, provided medical writing support on behalf of AstraZeneca.

We also thank the DISCOVERY-Asia investigators who participated in this trial. China: Jun-ren Zhu, Naisheng Cai, Zonggui Wu, Meng Wei, Guoping Lu, Jun Huang, Xinli Li, Ping Ye, Yuannan Ke, Qi Hua, Zhenzhong Guan, Zhanquan Li, Ming Zhang, Yinong Jiang, Peng Qu, Luyuan Chen, Hong Ma, Wei Wu, Yun Zhang, Yuhua Liao, Zaiying Lu, Yunzheng Chen, Shanjun Zhu. Hong Kong: Brian Tomlinson, Gary Ko. Korea: Young Moo Ro, Kwang Kon Koh, Ki Bae Seung, Wook Sung Chung, Shung Chull Chae, Kwon Bae Kim, Hong Seog Seo, Myung Yong Lee, Moo Hyun Kim, Young Woo Shin, Jong Hyun Kim, Jeong Euy Park, Ki Hoon Han, Byung II Choi, Nam Sik Chung, Hyun Seung Kim, Jung Han Yoon, Young Jo Kim, Joo Young Yang, Dong Soo Kim, Kun Joo Rhee, Won Ro Lee, Jun Kwan, Myung Ho Jeong, Kyu Hyung Ryu. Malaysia: Kui-Hian Sim, Kah Lin Khoo, Imran Zainal Abidin, Rosli Mohd Ali, Abdul Rashid Abdul Rahman, Hapizah Mohd Nawawi, Ee Ming Khoo, Mei Lin Ong, Omar Ismail, Aziz Al-Safi Ismail, Nor Azmi Kamaruddin. Taiwan: Yuan-Teh Lee, Herng-Cheng Chiou, Hung-I Yeh, Chung-Sheng Lin, Wen-Ter Lai, San-Jou Yeh, Chwen-Tzuei Chang, Cheng-Dao Tsai, Chun-Peng Liu, Kou- Yang Wang. Thailand: Cham Sriratanasathavorn, Piyamitr Sritara.

Relevant disclosures of interest by the authors: J-rZ has acted as an investigator for the DISCOVERY Asia study; BT has acted as a consultant or speaker on occasions for AstraZeneca, Bayer, Bristol- Myers Squibb, Merck KGaA, Merck Sharp and Dohme, Novartis, Pfizer, Roche, Sanofi-Aventis and Schering-Plough, and has received research funding from AstraZeneca, Merck, Merck Sharp & Dohme, Roche, Sanofi- Aventis and the Hong Kong Research Grants Council; YMR has no interests to declare; K-HS has received research grants and participated in advisory boards for AstraZeneca, B Braum Medical, Biosensors International Pte Ltd, Boston Scientific Corporation, Boehringer Ingelheim, Bristol Myers Squibb, Cordis Corporation, GE Healthcare, Merck Sharp & Dohme, Novartis, Orbus Neich Technologies, Pfizer, Phillips Medical Systems, Sanofi-Aventis, Schering-Plough, Siemens Medical, Terumo Medical Corporation, Ministry of Health Malaysia (medical research grant); Y-TL has acted as an investigator for the DISCOVERY-Asia study and has acted as a consultant and speaker for AstraZeneca; CS has acted as a consultant, speaker and chairman on occasions for AstraZeneca, Merck KGaA, Bayer, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi-Aventis and Schering- Plough.

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-4156_4, Accepted for publication: 08 October 2007

Published Online: 26 October 2007

doi:10.1185/030079907X242809

Jun-ren Zhu(a), Brian Tomlinson(b), Young Moo Ro(c), Kui-Hian Sim(d), Yuan-Teh Lee(e), Charn Sriratanasathavorn(f)

a Zhongshan Hospital, Fudan University, Shanghai, China

b The Chinese University of Hong Kong, Shatin, Hong Kong

c Korea University Anam Hospital, Seoul, Korea

d Sarawak General Hospital, Sarawak, Malaysia

e National Taiwan University Hospital, Taipei, Taiwan

f Siriraj Hospital, Mahidol University, Bangkok, Thailand

Address for correspondence: Professor Jun-ren Zhu, Department of Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shangai 200032, China. Tel.: +86 21 64041990; Fax: +86 21 64433331; jrzhu@zshospital.com

Copyright Librapharm Dec 2007

(c) 2007 Current Medical Research and Opinion. Provided by ProQuest Information and Learning. All rights Reserved.