Comparison of Efficacy and Safety of Rosuvastatin Versus Atorvastatin in African-American Patients in a Six-Week Trial

Comparison of Efficacy and Safety of Rosuvastatin Versus Atorvastatin in African-American Patients in a Six-Week Trial Keith C. Ferdinand, MD,a,* Luther T. Clark, MD,b Karol E. Watson, MD, PhD,c Ryan C. Neal, MD,d Clinton D. Brown, MD,b B. Waine Kong, PhD, JD,e Boisey O. Barnes, MD,f William R. Cox, MD,g Franklin J. Zieve, MD, PhD,h Jonathan Isaacsohn, MD,i Joseph Ycˇas, PhD,j Philip T. Sager, MD,j and Alex Gold, MD,j for the ARIES Study Group† The lipid-modifying effects of statin therapy in hypercholesterolemic African-Americans have not been well characterized. This study compared the efficacy and safety of rosuvastatin and atorvastatin treatment for 6 weeks in hypercholesterolemic African-American adults. In the African American Rosuvastatin Investigation of Efficacy and Safety (ARIES) trial (4522US/0002), 774 adult African-Americans with low-density lipoprotein cholesterol >160 and <300 mg/dl and triglycerides <400 mg/dl were randomized to receive open-label rosuvastatin 10 or 20 mg or atorvastatin 10 or 20 mg for 6 weeks. At week 6, significantly greater reductions in low-density lipoprotein cholesterol, total cholesterol, non– high-density lipoprotein cholesterol, and apolipoprotein B concentrations, as well as lipoprotein and apolipoprotein ratios, were seen with rosuvastatin versus milligram-equivalent atorvastatin doses (analysis of variance with Bonferroni-adjusted critical p <0.017 for all comparisons). Rosuvastatin 10 mg also increased high-density lipoprotein cholesterol significantly more than atorvastatin 20 mg (p <0.017). Although statistical comparisons were not performed, larger proportions of rosuvastatin-treated patients than atorvastatintreated patients achieved National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol goals. The median high-sensitivity Creactive protein levels were significantly reduced statistically from baseline with rosuvastatin 20 mg and atorvastatin 20 mg among all patients and with rosuvastatin 10 and 20 mg and atorvastatin 20 mg in those patients with a baseline C-reactive protein level >2.0 mg/L. The 2 study medications were well tolerated during the 6-week study period. In conclusion, rosuvastatin 10 and 20 mg improved the overall lipid profile of hypercholesterolemic African-Americans better than did milligramequivalent doses of atorvastatin. © 2006 Elsevier Inc. All rights reserved. (Am J Cardiol 2006;97:229 –235)

African-Americans have a higher prevalence of coronary heart disease and a higher coronary heart disease mortality rate than white Americans.1,2 Despite the promulgation of

a

Heartbeats Life Center and Xavier University College of Pharmacy, New Orleans, Louisiana; bState University of New York Downstate Medical Center, Brooklyn, New York; cUniversity of California, Los Angeles, Geffen School of Medicine, Los Angeles, California; dBaylor College of Medicine, Houston, Texas; eAssociation of Black Cardiologists, Atlanta, Georgia; fPrivate Practice, Washington, DC; gCFP Research, Incorporated, Cincinnati, Ohio; hHunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia; iMedpace, Cincinnati, Ohio; and jAstraZeneca, Wilmington, Delaware. Manuscript received May 4, 2005; revised manuscript received and accepted August 12, 2005. This research was supported by AstraZeneca LP, Wilmington, Delaware. *Corresponding author: Tel: 800-753-9222; fax: 678-302-4223. E-mail address: [email protected] (K.C. Ferdinand). †

A complete list of investigators appears in the Appendix.

0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.08.026

the national cholesterol management guidelines,2,3 in clinical practice, African-Americans are undertreated with lipidmodifying therapy, both in receiving recommended therapy and in achieving recommended lipid goals.4 – 6 The need to reduce cardiovascular risk in African-Americans, combined with a paucity of data from controlled trials in hypercholesterolemic African-Americans, is a strong indication for a trial of lipid-modifying therapy in this population.7 The African American Rosuvastatin Investigation of Efficacy and Safety (ARIES) trial is the first prospective, large-scale, comparative trial of statin therapy in an exclusively AfricanAmerican population. This trial compared the efficacy and safety of rosuvastatin and atorvastatin during 6 weeks of treatment in hypercholesterolemic African-American adults.

Methods Trial design: This 6-week, randomized, open-label trial (4522US/0002) was conducted from March 2002 to Decemwww.AJConline.org

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ber 2003 at 76 academic and clinical research centers in the United States. After successfully completing a 6-week dietary lead-in period, eligible patients were randomized (1: 1:1:1) to receive once daily 10- or 20-mg doses of rosuvastatin (Crestor, AstraZeneca, Wilmington, Delaware; licensed from Shionogi, Osaka, Japan) or atorvastatin (Lipitor, Pfizer, New York, New York) for 6 weeks. Patients randomized to rosuvastatin treatment were given a 6-week supply of rosuvastatin 10- or 20-mg tablets by their physician. Patients randomized to atorvastatin treatment were given a prescription for a 6-week supply of atorvastatin 10or 20-mg tablets and asked to obtain the assigned treatment supply at their local pharmacy. Ethical considerations: This trial was designed and conducted in accordance with the Declaration of Helsinki (version amended October 2000) and in compliance with the ethical principles of good clinical practice. Appropriate ethics committees or institutional review boards approved the research protocol. All patients gave their written, informed consent before initiation of any trial procedure. Patients: Eligible patients were African-American men and women (self-reported for race) aged ⱖ18 years who were diagnosed with type IIa or IIb hypercholesterolemia.8 Patients entered the dietary lead-in period in which all cholesterol-lowering drugs were discontinued and a therapeutic lifestyle changes diet was initiated.2 Patients were eligible for the randomized treatment period if they had fasting low-density lipoprotein (LDL) cholesterol ⱖ160 mg/dl and ⱕ300 mg/dl and triglycerides ⬍400 mg/dl. Exclusion criteria included the following: history of homozygous familial hypercholesterolemia or known type I, III, or V hyperlipoproteinemia; active arterial disease (e.g., unstable angina, myocardial infarction, transient ischemic attack, cerebrovascular accident, coronary artery bypass graft surgery, or angioplasty within 3 months of trial entry); uncontrolled hypertension; poorly controlled diabetes (glycosylated hemoglobin ⱖ9% or fasting glucose ⱖ180 mg/dl); active liver disease or dysfunction indicated by hepatic transaminases or bilirubin levels ⱖ2 times the upper limit of normal (ULN); unexplained serum creatine kinase levels ⬎3 times the ULN; and serum creatinine 2.0 mg/dl (⬎177 ␮mol/L). Laboratory methods: Analyses of all laboratory samples were performed at a central laboratory (Medical Research Laboratories, Highland Heights, Kentucky), which maintains Centers for Disease Control and Prevention and National Heart, Lung, and Blood Institute part III lipid standardization.9 Blood samples were obtained after a 12hour fast. Baseline fasting lipid levels were the mean of ⱕ3 measurements taken during the dietary lead-in period and at week 0. Baseline fasting lipid and apolipoprotein values were measured at the week 0 visit. Lipid and apolipoprotein values were measured again after 6 weeks of study treatment. LDL cholesterol was calculated using the Friedewald

equation.10 Other lipid and apolipoprotein measures were determined by the following methods: total cholesterol and triglycerides were determined by colorimetric enzymatic assay11; high-density lipoprotein (HDL) cholesterol was measured by colorimetric enzymatic assay and precipitation12; non-HDL cholesterol was calculated as total cholesterol minus HDL cholesterol; and apolipoprotein (apo) B and apo A-I were measured by immunonephelometry.13 High-sensitivity C-reactive protein (hs-CRP) levels were measured using a latex-enhanced immunoassay at baseline (week 0) and after 6 weeks.14 Trial assessments: The primary efficacy measure was the change from baseline in LDL cholesterol to that measured at 6 weeks. Secondary efficacy measures included changes from baseline in other lipids, apolipoproteins, and various ratios. Patients were classified at baseline according to the National Cholesterol Education Program’s Adult Treatment Panel (ATP) III risk categories, and proportions of patients observed to achieve ATP III LDL cholesterol goals according to risk category were determined.2 Statistical analysis: An analysis of variance model was used for all lipid measures, with pairwise comparisons between the rosuvastatin 10-mg group and atorvastatin 10and 20-mg groups and between the rosuvastatin 20-mg group and atorvastatin 20-mg group. A Bonferroni correction with a significance level of p ⬍0.017 was applied to each lipid measure to correct for the multiplicity of the 3 treatment comparisons.15 Before testing for superiority, a noninferiority test was performed with a 6% limit.16 Efficacy analyses were performed for the intention-to-treat population (i.e., patients with ⱖ1 dose of study drug and ⱖ1 baseline and 1 post-baseline lipid evaluation), with the last observation carried forward. A total of 12 patients (3.1%) randomized to the atorvastatin treatment arms received an inadequate supply of medication from their pharmacies. To avoid obvious bias in the efficacy analyses, these patients were excluded from the intention-to-treat population. Because the trial was not powered to evaluate categorical responses, lipid goal-attainment data were summarized by observed frequency, and no formal statistical treatment comparisons were performed. An exploratory analysis evaluated the within-treatment change in hs-CRP, using the Wilcoxon sign-rank test. The evaluation of safety included review of adverse effects, clinical chemistry and hematology evaluation, urinalysis, assessment of vital signs, and physical examination. Adverse events were summarized with MedDRA preferred terms. The safety population included all patients receiving ⱖ1 dose of study drug. Descriptive statistics were used to evaluate the safety data.

Results Of a total of 2,385 patients who entered the screening phase, 774 patients were randomized to the study treatment and

Preventive Cardiology/Comparing Statin Therapies in African-Americans

Dietary lead-in (n = 2,385) Failed screening (n = 1,611) Randomized (n = 774)

RSV

ATV

391

383

RSV 10

RSV 20

ATV 1 0

195

196

191

Discontinued 16

13

Completed 179

183

A TV 2 0 192

Discontinued 13

10

Completed 178

182

Figure 1. Patient disposition. RSV ⫽ rosuvastatin; ATV ⫽ atorvastatin.

722 (93.3%) completed the 6-week trial (Figure 1). The treatment groups were similar with regard to baseline characteristics (Table 1) and baseline lipid levels (Table 2). Patients were a mean age of approximately 55 years, and almost 2/3 were women. Nearly 1/4 of the patients had a family history of cardiovascular disease (23.9%) or diabetes mellitus (24.3%), and ⬎1/2 had hypertension (52.8%). Although patients with serum creatinine levels ⬎2.0 mg/dl (177 ␮mol/L) were excluded from the study, 304 (39.3%) of enrolled patients had mild or moderate renal impairment and 6 (0.8%) had severe impairment according to the calculated creatinine clearance at baseline.17 Randomized treatment was discontinued in 52 patients as follows: adverse events (rosuvastatin 13 [3.3%], atorvastatin 5 [1.3%]); lost to follow-up (rosuvastatin 8 [2.0%], atorvastatin 5 [1.3%]); protocol noncompliance or deviation (rosuvastatin 2 [0.5%], atorvastatin 10 [2.6%]); withdrawn consent (rosuvastatin 5 [1.3%], atorvastatin 3 [0.8%]); and investigator discretion (rosuvastatin 1 [0.3%], atorvastatin 0). A total of 732 patients were included in the intentionto-treat efficacy analysis population, and 765 patients were included in the safety analysis. Lipid changes at 6 weeks: LDL cholesterol was reduced significantly more by rosuvastatin than by milligramequivalent doses of atorvastatin (p ⬍0.01). The reduction with rosuvastatin 10 mg was not significantly different statistically from that seen with atorvastatin 20 mg (Table 2 and Figure 2). The reductions in total cholesterol, non-HDL cholesterol, and apo B, and LDL cholesterol/HDL cholesterol, total cholesterol/HDL cholesterol, non-HDL cholesterol/HDL cholesterol, and apo B/apo A-I ratios were significantly greater statistically with rosuvastatin than with milligram-equivalent doses of atorvastatin. In these measures, the reductions with rosuvastatin 10 mg and those with atorvastatin 20 mg were not statistically significant. The increase in HDL cholesterol was significantly greater statistically with rosuvastatin 10 mg than with atorvastatin 20 mg (Figure 2), and increases in apo A-I were significantly greater statistically with rosuvastatin 10 and 20 mg than

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with atorvastatin 20 mg. Triglyceride reductions were similar with both statins at milligram-equivalent doses. ATP III goal achievement: Overall, most patients (66.4%) were observed to achieve ATP III LDL cholesterol goals on the study medication. Although statistical comparisons were not performed, greater proportions of patients achieved their LDL cholesterol goals on rosuvastatin than on milligram-equivalent doses of atorvastatin within the low-, medium-, and high-risk categories (Figure 3). The observed difference was most marked among high-risk patients (ATP III LDL cholesterol goal ⬍100 mg/dl), with 62.5% of high-risk patients receiving rosuvastatin 20 mg versus 27.0% of those receiving atorvastatin 20 mg and 43.9% versus 21.8% of high-risk rosuvastatin versus atorvastatin patients overall observed to achieve this goal. High-sensitivity CRP changes at 6 weeks: A total of 708 patients in the intention-to-treat population had paired baseline and 6-week samples for the hs-CRP analysis. Most of these patients had baseline hs-CRP levels ⬎2.0 mg/L (Table 1). At 6 weeks, both rosuvastatin and atorvastatin produced reductions from baseline in median hs-CRP levels (Figure 4). Among patients with baseline hs-CRP levels ⬎2.0 mg/L, median hs-CRP levels were statistically significantly decreased with rosuvastatin 10 and 20 mg and atorvastatin 20 mg compared with baseline (Figure 4). Safety: Both open-label statins were well tolerated during the 6 weeks. No deaths occurred in this trial, and no myopathy or rhabdomyolysis occurred. Most adverse events were mild to moderate in severity and were considered unrelated to the study medication. The most commonly reported adverse events overall (regardless of causality) were myalgia (2.5%), headache (2.1%), nasopharyngitis (1.7%), constipation (1.7%), and arthralgia (1.6%). The occurrence rate of myalgia by treatment group was 2.6% and 3.6% for rosuvastatin 10 and 20 mg and 2.6% and 1.0% for atorvastatin 10 and 20 mg, respectively. The overall occurrence of adverse events was similar in the rosuvastatin and atorvastatin groups (34.4% vs 33.6%, respectively). Additionally, no serious adverse events were considered treatment related. Serious adverse events consisted of chest discomfort (unrelated to muscle pain), gastrointestinal hemorrhage, osteomyelitis, and muscular weakness in 1 rosuvastatin recipient each and atrial fibrillation and coronary artery disease in 1 and 2 atorvastatin recipients, respectively. No patients had creatine kinase elevations ⬎10 times the ULN. Changes in hepatic biochemistry measures were small, and no clinically apparent differences were found among the treatment groups. No increases in hepatic transaminases of ⬎3 times the ULN were observed, and no symptom complexes suggestive of liver disturbance were observed in any patients. No clinically meaningful changes in renal biochemistry measures were seen. No patients had a doubling of their serum creatinine levels. Three rosuva-

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Table 1 Demographics and baseline characteristics Demographic or Baseline characteristic Age (yrs) ⱖ65 yrs Women Men Weight (kg) Body mass index (kg/m2) ⬎30 kg/m2 Calculated creatinine clearance Normal (⬎80 ml/min) Mild impairment (50–ⱕ80 ml/min) Moderate impairment (30– ⬍50 ml/min) Severe impairment (⬍30 ml/min) Adult Treatment Panel III risk category* High Medium Low CRP level (mg/L) CRP ⬎2.0 mg/L†

Rosuvastatin 10 mg (n ⫽ 195)

Atorvastatin 20 mg (n ⫽ 196)

10 mg (n ⫽ 191)

20 mg (n ⫽ 192)

55.0 ⫾ 11.2 39 (20.0%) 118 (60.5%) 77 (39.5%) 91.2 ⫾ 18.6 32.3 ⫾ 6.2 116 (59.5%)

55.4 ⫾ 12.8 46 (23.5%) 133 (67.9%) 63 (32.1%) 91.9 ⫾ 20.1 32.5 ⫾ 7.6 107 (54.6%)

54.9 ⫾ 10.3 37 (19.4%) 122 (63.9%) 69 (36.1%) 90.9 ⫾ 19.0 32.7 ⫾ 6.8 114 (59.7%)

54.9 ⫾ 11.9 37 (19.3%) 128 (66.7%) 64 (33.3%) 90.8 ⫾ 18.7 32.4 ⫾ 5.9 112 (58.3%)

108 (55.4%) 71 (36.4%)

114 (58.2%) 65 (33.2%)

115 (60.2%) 67 (35.1%)

115 (59.9%) 65 (33.9%)

11 (5.6%)

10 (5.1%)

6 (3.1%)

9 (4.7%)

2 (1.0%)

2 (1.0%)

1 (0.5%)

1 (0.5%)

61 (31.3%) 70 (35.9%) 64 (32.8%) 3.40 (1.5–7.2) 118/177 (66.7%)

67 (34.2%) 47 (24.0%) 82 (41.8%) 4.55 (2.3–8.1) 143/184 (77.7%)

61 (31.9%) 53 (27.7%) 77 (40.3%) 3.90 (1.8–6.9) 124/172 (72.1%)

68 (35.4%) 56 (29.2%) 68 (35.4%) 3.60 (3.6–7.8) 117/175 (66.9%)

Data are presented as number (percentages), mean ⫾ SD, and median (interquartile ranges). * High risk ⫽ coronary heart disease (CHD), CHD risk equivalent (other clinical atherosclerosis, diabetes), or ⱖ2 risk factors and 10-year CHD risk ⬎20%. Medium risk ⫽ ⱖ2 risk factors and 10-year CHD risk ⱕ20%. Low risk ⫽ 0 or 1 risk factor. † A total of 708 patients in the intention-to-treat population had paired samples for the hs-CRP analysis.

statin-treated patients and 5 atorvastatin-treated patients had an increase in urine dipstick protein from none or trace at baseline to 2⫹ at week 6; no patients had an increase that exceeded 2⫹ proteinuria. Six rosuvastatin-treated patients and 8 atorvastatin-treated patients had an increase in urine dipstick blood from none or trace to ⱖ2⫹, with 2 rosuvastatin-treated patients and 4 atorvastatin-treated patients having a 3⫹ increase. None of the patients with a 2⫹ shift in urine dipstick protein had an increase in urine dipstick blood detected.

Discussion The ARIES trial demonstrated that, in self-identified African-Americans with hypercholesterolemia, rosuvastatin reduced LDL cholesterol more than atorvastatin did at milligram-equivalent doses of 10 and 20 mg. Although statistical comparisons were not performed, greater proportions of patients were observed to reach currently recommended LDL cholesterol goals2 with rosuvastatin than with atorvastatin, particularly among patients at greatest coronary heart disease risk. LDL cholesterol reductions and goal attainment with the 10-mg dose of rosuvastatin were similar to those seen with the 20-mg dose of atorvastatin, but HDL cholesterol levels increased significantly more with the 10-mg dose of rosuvastatin than with the 20-mg dose of

atorvastatin. The ability to achieve LDL cholesterol goals at lower doses may be an advantage in this population, which is likely to include many patients at high risk due to a high prevalence of type 2 diabetes and clustering of other cardiovascular risk factors.18,19 Moreover, at milligramequivalent doses, rosuvastatin produced greater beneficial changes in other lipid measures, including non-HDL cholesterol, apo B, apo A-I, and lipoprotein and apolipoprotein ratios. In this 6-week trial, both treatments were well tolerated in this patient population, with no cases of liver or kidney dysfunction or myopathy. The ARIES trial compared the effects of rosuvastatin and atorvastatin exclusively in African-Americans and, therefore, comparisons with other similarly designed trials in heterogeneous patient populations should be undertaken with caution. Nevertheless, in ARIES, the mean LDL cholesterol reductions seen with both rosuvastatin and atorvastatin were somewhat smaller than those observed previously in United States-based, 6-week trials comparing these 2 statins across their dose ranges in largely white hypercholesterolemic populations.20,21 In ARIES, a subset of patients receiving either rosuvastatin or atorvastatin showed relatively small decreases and, occasionally, increases in LDL cholesterol from baseline, with the result that the overall mean response in all treatment groups was reduced. Additional investigation showed that low compliance with the randomized study medication was more prevalent in this

Preventive Cardiology/Comparing Statin Therapies in African-Americans

233

Table 2 Baseline lipid parameters and least-squares mean percent change at six weeks Lipid Measure

LDL-C Baseline (mg/dl) % change TC Baseline (mg/dl) % change HDL-C Baseline (mg/dl) % change Triglycerides Baseline (mg/dl) % change Non–HDL-C Baseline (mg/dl) % change Apo B Baseline (mg/dl) % change Apo A-I Baseline (mg/dl) % change LDL-C/HDL-C Baseline % change TC/HDL-C Baseline % change Non-HDL-C/HDL-C Baseline % change Apo B/apo A-I Baseline % change

Rosuvastatin

Atorvastatin

10 mg (n ⫽ 186)

20 mg (n ⫽ 189)

10 mg (n ⫽ 179)

20 mg (n ⫽ 178)

191.8 ⫾ 27.2 ⫺37.1 ⫾ 1.3*

189.6 ⫾ 23.4 ⫺45.7 ⫾ 1.3†

189.1 ⫾ 24.0 ⫺31.8 ⫾ 1.3

191.9 ⫾ 26.6 ⫺38.5 ⫾ 1.3

270.7 ⫾ 31.9 ⫺26.6 ⫾ 1.0*

270.9 ⫾ 29.4 ⫺33.0 ⫾ 1.0†

269.4 ⫾ 28.1 ⫺23.1 ⫾ 1.0

270.8 ⫾ 30.6 ⫺28.7 ⫾ 1.0

51.5 ⫾ 11.2 ⫹7.0 ⫾ 0.9‡

52.6 ⫾ 14.2 ⫹6.5 ⫾ 0.9

52.5 ⫾ 12.0 ⫹5.6 ⫾ 1.0

49.9 ⫾ 12.8 ⫹3.7 ⫾ 1.0

136.5 ⫾ 49.7 ⫺16.0 ⫾ 1.9

143.7 ⫾ 55.9 ⫺20.9 ⫾ 1.9

139.3 ⫾ 56.4 ⫺17.1 ⫾ 1.9

146.3 ⫾ 49.7 ⫺19.6 ⫾ 1.9

219.1 ⫾ 30.3 ⫺34.3 ⫾ 1.2*

218.3 ⫾ 26.6 ⫺42.3 ⫾ 1.2†

216.9 ⫾ 28.1 ⫺29.8 ⫾ 1.3

221.0 ⫾ 29.7 ⫺35.6 ⫾ 1.2

164.9 ⫾ 25.9 ⫺29.3 ⫾ 1.2*

165.4 ⫾ 22.7 ⫺37.2 ⫾ 1.2†

166.7 ⫾ 26.5 ⫺25.3 ⫾ 1.3

167.3 ⫾ 25.9 ⫺31.4 ⫾ 1.3

154.4 ⫾ 24.5 ⫹5.4 ⫾ 1.0‡

159.1 ⫾ 31.3 ⫹4.0 ⫾ 1.0†

158.6 ⫾ 25.4 ⫹2.7 ⫾ 1.0

153.8 ⫾ 27.5 ⫹0.7 ⫾ 1.0

3.89 ⫾ 0.95 ⫺40.9 ⫾ 1.3*

3.83 ⫾ 1.02 ⫺48.7 ⫾ 1.3†

3.80 ⫾ 0.97 ⫺35.0 ⫾ 1.4

4.06 ⫾ 1.03 ⫺40.6 ⫾ 1.4

5.46 ⫾ 1.16 ⫺30.6 ⫾ 1.1*

5.43 ⫾ 1.24 ⫺36.4 ⫾ 1.1†

5.38 ⫾ 1.22 ⫺26.5 ⫾ 1.2

5.71 ⫾ 1.25 ⫺30.5 ⫾ 1.1

4.46 ⫾ 1.16 ⫺37.6 ⫾ 1.34*

4.43 ⫾ 1.24 ⫺45.1 ⫾ 1.34†

4.38 ⫾ 1.22 ⫺32.6 ⫾ 1.39

4.71 ⫾ 1.25 ⫺37.1 ⫾ 1.37

1.10 ⫾ 0.25 ⫺32.1 ⫾ 1.3*

1.08 ⫾ 0.26 ⫺39.1 ⫾ 1.3†

1.08 ⫾ 0.24 ⫺26.8 ⫾ 1.4

1.12 ⫾ 0.25 ⫺31.3 ⫾ 1.3

Baseline data are presented as mean ⫾ SD; percent changes are presented as mean ⫾ SE. p ⬍0.017 for * rosuvastatin 10 mg versus atorvastatin 10 mg; †rosuvastatin 20 mg versus atorvastatin 20 mg, and ‡rosuvastatin 10 mg versus atorvastatin 20 mg (Bonferroni-adjusted critical p values). Comparison of least-squares mean percent change and p value from analysis of variance. Apo ⫽ apolipoprotein; HDL-C ⫽ high-density lipoprotein cholesterol; LDL-C ⫽ low-density lipoprotein cholesterol; TC ⫽ total cholesterol.

Figure 2. Mean percentage of change from baseline in LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C) at week 6. LS ⫽ least-squares; other abbreviations as in Figure 1.

subpopulation. These observations underscore the importance in clinical practice of ensuring that patients use statin therapy consistently to obtain the full therapeutic benefit. In addition, we recognize the limitation that the openlabel design used in ARIES presents. Previous trials with multiple-dose comparisons of statin therapies (e.g., Comparative Efficacy Study of Atorvastatin Versus Simvastatin, Pravastatin, Lovastatin, and Fluvastatin in Patients with Hypercholesterolemia [CURVES], Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin [STELLAR])21,22 used open-label treatments because it is logistically easier to execute an open-label trial. As with these trials, ARIES had primary and secondary lipid end points, as well as safety assessments, that were derived from laboratory data. Such data are not subjective; thus, knowledge of the treatment or dose would not be expected to affect the assessment of the various treatment groups. Additionally, the laboratory data remained blinded to the AR-

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Figure 4. Percentage of change in median CRP levels at week 6 in overall ARIES patient population and subgroup of patients with CRP ⬎2.0 mg/L at baseline. Abbreviations as in Figure 1.

ordinators, and the patients who participated in the ARIES trial. In addition, we thank Joe Hirsch, MA, of BioScience Communications, New York, New York, and Gregg Truitt, BS, of AstraZeneca, Wilmington, Delaware, for their assistance in the preparation of this manuscript..

Figure 3. Percentage of patients reaching National Cholesterol Education Program (NCEP) ATP III LDL cholesterol goals of ⬍160 mg/dl for low-risk patients (0 or 1 risk factor), ⬍130 mg/dl for medium-risk patients (ⱖ2 risk factors and 10-year coronary heart disease [CHD] risk ⱕ20%), ⬍100 mg/dl for high-risk patients (CHD, CHD risk equivalent, or ⱖ2 risk factors and 10-year CHD risk ⬎20%),2 and all categories combined for (A) patients receiving 10-mg dose of rosuvastatin (RSV) or atorvastatin (ATV) and (B) patients receiving 20-mg dose of RSV or ATV.

IES investigators and their patients until after completion of the trial. In the ARIES trial, ⬎2/3 of the patients had elevated baseline hs-CRP levels (⬎2.0 mg/L). Although this study was not designed to investigate the comparative effects of rosuvastatin and atorvastatin in reducing CRP from baseline, an exploratory within-treatment analysis suggested a trend toward decreasing CRP levels with an increasing dose of either statin. Furthermore, these reductions appeared greater in African-American patients with elevated baseline CRP. These findings, as well as the potential implications of elevated CRP levels and reducing CRP in African-Americans at risk of cardiovascular disease, require further investigation.

Acknowledgment: We gratefully acknowledge the investigators (see Appendix), their co-investigators and study co-

APPENDIX The following investigators participated in the ARIES trial and comprised the ARIES Study Group: Alvin Y. Abaqueta, MD, Charlotte, NC; Peter M. Abel, MD, Morgan City, LA; James R. Allison III, MD, Columbia, SC; Lawrence K. Alwine, DO, Downingtown, PA; John D. Angeloni, DO, Bala Cynwyd, PA; Peter A. Arcuri, DO, Philadelphia, PA; Jan Basile, MD, Charleston, SC; Harold E. Bays, MD, Louisville, KY; Morris L. Brown, MD, Dayton, OH; Nate Brown, MD, Cleveland, MS; Charles A. Cook, MD, Raleigh, NC; Kenneth G. Cowens, MD, Youngstown, OH; Michael H. Davidson, MD, Chicago, IL; Leon N. Davis, MD, Montgomery, AL; Philip M. Diller, MD, Cincinnati, OH; Philip B. Duncan, MD, Chester, VA; Robert S. Eads, Jr, MD, Charleston, SC; Sandra L. Ellis, MD, Southfield, MI; John C. Farmer, MD, Chicago, IL; John M. Flack, MD, Detroit, MI; Mary E. Gaffney, DO, Charlotte, NC; Michael R. Geer, MD, Chattanooga, TN; Mark J. Geller, MD, Pittsburgh, PA; David P. Gowdy, MD, Alpharetta, GA; Joe L. Hargrove, MD, Little Rock, AK; Terence T. Hart, MD, Muscle Schoals, AL; David M. Headley, MD, Port Gibson, MS; Charles B. Herring, MD, Wilmington, NC; General K. Hilliard, MD, Oakland, CA; Alan S. Hoffman, MD, Houston, TX; Jeffry A. Jacqmein, MD, Jacksonville, FL; Dean G. Karalis, MD, Philadelphia, PA; David B. Laughlin, MD, Tuscumbia, AL; Derek Lewis, MD, Little Rock, AK; Juli-

Preventive Cardiology/Comparing Statin Therapies in African-Americans

ette Lewis-Charles, DO, Elkins Park, PA; Thomas W. Littlejohn III, MD, Winston-Salem, NC; Ramon L. Lloret, MD, Miami, FL; Charles F. Lovell, MD, Norfolk, VA; Barry C. Lubin, MD, Norfolk, VA; Barry McLean, MD, Birmingham, AL; Henry Meilman, MD, Baltimore, MD; Athol W. Morgan, MD, Baltimore, MD; John M. Morgan, MD, Philadelphia, PA; Ruth D. Nurnberg, MD, Richmond, VA; John A. Pasquini, MD, Charlotte, NC; Frank S. Pettyjohn, MD, Mobile, AL; Michael Prisant, MD, Augusta, GA; George L. Raad, MD, Charlotte, NC; Pramod Raval, MD, Oak Park, MI; Efrain Reisin, MD, New Orleans, LA; Albert Reynolds, MD, Flossmoor, IL; James M. Rhyne, MD, Statesville, NC; Lisa C. Robbins, MD, Stone Mountain, GA; Jerome Robinson, MD, National City, CA; Eli M. Roth, MD, Cincinnati, OH; Sherwyn L. Schwartz, MD, San Antonio, TX; Cranford L. Scott, MD, Inglewood, CA; Jon W. Slotoroff, DO, Pleasantville, NJ; Evan A. Stein, MD, Cincinnati, OH; Cynthia B. Strout, MD, Mt. Pleasant, SC; Danny Sugimoto, MD, Chicago, IL; Malcolm Taylor, MD, Jackson, MS; Phillip D. Toth, MD, Indianapolis, IN; M. Scott Touger, MD, Birmingham, AL; Matt Turpin, MD, New Port Richey, FL; Paul L. Underwood, Jr, MD, Phoenix, AZ; Ramon Vargas, MD, New Orleans, LA; Marion R. Wofford, MD, Jackson, MS; William I. Young, MD, Los Angeles, CA. 1. American Heart Association. Heart Disease and Stroke Statistics— 2005 Update. Dallas: American Heart Association, 2004:6, 58. Available at: http://www.americanheart.org/presenter.jhtml? identifier⫽3000090. Accessed August 3, 2005. 2. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 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) final report. Circulation 2002;106:3143–3421. 3. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ, for the National Heart, Lung, and Blood Institute, American College of Cardiology Foundation, and American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004;110:227–239. 4. Nieto FJ, Alonso J, Chambless LE, Zhong M, Ceraso M, Romm FJ, Cooper L, Folsom AR, Szklo M. Population awareness and control of hypertension and hypercholesterolemia: the Atherosclerosis Risk in Communities study. Arch Intern Med 1995;155:677– 684. 5. Fonarow GC, French WJ, Parsons LS, Sun H, Malmgren JA. Use of lipid-lowering medications at discharge in patients with acute myocardial infarction: data from the National Registry of Myocardial Infarction 3. Circulation 2001;103:38 – 44. 6. Pearson TA, Laurora I, Chu H, Kafonek S. The Lipid Treatment Assessment Project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy

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