Efficacy and safety of rosuvastatin alone and in combination with cholestyramine in patients with severe hypercholesterolemia: A randomized, open-label, multicenter trial

CtINICAL THERAPEUIICS®/VoL. 2 6 , NO. 11, 2 0 0 4

Efficacy and Safety of Rosuvastatin Alone and in Combination with Cholestyramine in Patients with Severe Hypercholesterolemia: A Randomized, Open-Label, Plulticenter Trial Christie M. Ballantyne, MD, 1,2 Elinor Miller, MD, 3 and Rohini Chitra, PhD 3 ~Method~st DeEakey Heart Center, 2Eaylor College of Medicine, Houston, Texas, and 3AstraZeneca LE Wilmington, Delaware

ABSTRACT

Background: Patients with severe hypercholesterolemia may need greater cholesterol reductions than can be achieved with statin therapy alone. Objective: The primary objective of this trial was to compare the efficacy of a combination of rosuvastatin plus cholestyramine with that of rosuvastatin alone for reducing low-density lipoprotdn cholesterol (LDL-C) levels after 6 weeks of treatment. Methods: In this open-label, multicenter, randomized, parallel-group, comparator trial, adult patients with severe hypercholesterolemia (LDL-C level, 190--400 mg/dL) received rosuvastatin 40 mg/d for 6 weeks after a &week dietary lead-in period and were then randomized to 6 weeks of treatment with rosuvastatin 80 mg/d alone or rosuvastatin 80 mg/d plus cholestyramine 16 g/d (8 g BID with meals). Results: Of 153 eligible patients, 147 (83 men, 64 women; mean [SD] age, 54.5 [13.7] years; mean [SD] body weight, 81.3 [14.4] kg) received randomized treatment, and 144 had postbaseline measurements and were included in the analysis. The mean (SD) reduction in LDL-C was 522% (13.0%) after treatment with rosuvastatin 40 rag, and the least squares mean (SE) reductions in LDL-C were 56.4% (1.8%) and 60.5% (1.8%) after treatment with rosuvastatin 80 mg alone (n = 69) and rosuvastatin 80 mg plus cholestyramine (n = 75), respectively. No significant differences between treatments were found for these or other lipid measurements. Incremental LDL-C reductions >30% were obtained in 29% (22/75) of patients receiving combination therapy and 4% (3/69) of patients receiving rosuvastatin alone. The combination therapy was less well tolerated, primarily due to gastrointestinal symptoms; otherwise, the treatments were generally well tolerated. Conclusion: In this group of patients with severe hypercholesterolemia, the combination of rosuvastatin 80 mg with cholestyramine 16 g/d did not provide a significantly greater efficacy benefit than rosuvastatin alone. (Cltn Ther. 2004126:1855-1864) Copyright © 2004 Excerpta Medica, Inc. Key words: rosuvastatin, cholestyramine, hypercholesterolemia, low-density lipoprotdn cholesterol, lipids. This work was presented in part at the XIV International Symposqum on Drags Affecting Lipid Metabolism, September 9 12, 2001, NewYork, New York.

Accepted2or Fublicatior~A%ctst 24, 2004. Pnnted in tee USA. Reprodu.ction in whole or part is not peiTrtitted.

Copyright @ 2004 Excerpta Medica,Inc.

doi:l 01016.*'j.clinthera.200411.001 0149 291 W04/$1900

] 85 5

CLINICAL THERAPEUTICS®

INTRODUCTION

Much evidence supports the association between a reduction in plasma low-density lipoprotein cholesterol (LDL-C) and a reduction in the risk of atherogenie disease and related adverse clinical events in patients with hypercholesterolemia. 1 A variety of drug therapies are used to treat hyperlipidemia, usually after dietary and lifestyle modifications alone have been unsuccessful in reducing LDL-C levels. Of the available lipid-lowering medications, the 3hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are most effective in producing and maintaining large reductions in LDL-C. Such reductions have been associated with decreases in the risk of cardiovascular mortality, as well as all-cause mortality, in both primary and secondary prevention settings. 24 However, some patients may not achieve the recommended lipid levels with statin treatment alone. Bile acid sequestrant resins such as cholestyrarnine have been used as cholesterol-lowering agents for many years and are often used in combination with statins. ~-9 Rosuvastatin has been shown to be highly efficacious for significantly reducing plasma LDL-C levels and for increasing high-density lipoprotein cholesterol (HDL-C) levels across the currently approved dose range of 5 to 40 rag.l° 12 Because patients with severe hypercholesterolemia who are treated with rosuvastatin might also receive bile acid sequestrants,

Week

we compared the efficacy and safety profile of rosuvastatin 80 mg alone with that of a combination of rosuvastatin 80 mg plus cholestyrarnine 16 g/d. The primary objective was to assess the effects of these treatments on LDL-C after 6 weeks of treatment. Secondary objectives included assessing the effects of these treatments and rosuvastatin 40 mg on other lipid levels, lipoprotein fractions, and inflammatory markers. The safety profile was assessed, including an assessment of adrenal function in a subset of patients. PATIENTS AND METHODS Trial Design

This open-label, rnulticenter, randomized, parallelgroup, cornparator trial (4522IL/0031)was conducted in 15 clinical research centers in the United States from October 1999 to September 2000. The trial consisted of three 6-week periods (Figure 1). After the dietary lead-in period, during which patients were instructed to follow the National Cholesterol Education Program Step I diet, those who had 2 fasting plasma LDL-C levels that were 190 to 400 rng/dL and within 15% of each other during the lead-in period, as well as an Eating Pattern Assessment Tool Section 113 score <28 (demonstrating compliance with the Step I diet), were treated with rosuvastatin calcium* 40 mg PO QD for 6 weeks. During the final *Tredemark: Crestor® (AstraZeneca LE Wilmington, Delaware). Licensed to A~traZeneca [rom Shionogt Co., Ltd., Osaka,Japan.

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Rosuvastatin 80 mg QD + cholestyramine 8 g BID*

Rosuvastatin 40 mg QD

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Baseline

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Figure I. Trial design. * Patients who did not tolerate cholestyramine 8 g BID (I 6 $/d) may have had their dose of cholestyramine reduced to 4 g BID (8 g/d); once reduced, doses could not be increased.

1856

C.M. Ballantyne et al.

6-week period, patients were randomized to treatment with either rosuvastatin 80 mg QD or rosuvastatin 80 mg QD plus cholestyramine* 16 g/d (8 g BID). Rosuvastatin was taken -3 hours after the evening meal, and cholestyramine was taken as two 4-g packets with meals. Patients who could not tolerate 16 g/d of cholestyramine were allowed to decrease the dosage to one 4-g packet BID (8 g/d). An interactive voice response system was used for randomized allocation of patient numbers and allocation to treatment in balanced blocks at each center. Dietary intakes were monitored, and dietary advice was reinforced throughout the trial. Patients Men and women aged _>18 years who had severe hypercholesterolemia (fasting LDL-C, 190-400 mg/dL [4.9-10.3 rnrnol/L]) and fasting triglyceride (TG) level <400 mg/dL (4.5 retool/L) and who had discontinued lipid-lowering therapy were enrolled in the trial. Patients were excluded if they had active hepatic disease or dysfunction, active arterial disease, a history of malignancy, uncontrolled hypertension or hypothyroidism, a history of homozygous familial hypercholesterolemia or familial dysbetalipoproteinemia, or serum creatine kinase (CK) level >3 times the upper limit of normal (ULN). Other exclusion criteria included the presence of conditions or the use of medications known to affect lipid measurements, present a safety concern, or interfere with trial participation. All participants gave their informed consent before undergoing any trial procedure. The trial protocol was approved by the institutional review boards of each trial center and was conducted in accordance with the version of the Declaration of Helsinki amended by the 48th World Medical Association Congress in October 1996. Efficacy and Safety End Points The primary end point was percentage change in plasma LDL-C level from baseline to the end of treatment (at 12 weeks). Secondary efficacy end points included percentage change from baseline in LDL-C level after 6 weeks of treatment with rosuvastatin 40 mg and percentage changes from baseline in other *Trademark: Que~tranTM Light (Bristol Laboratories, Bristol Myers Squibb Compan?; Pnnceton, New Jersey).

plasma lipid measurements (total cholesterol [TC], HDL-C, TG, apolipoprotem [apo] A-I, arid apo B), lipid ratios, arid inflammatory markers (C-reactive protein [CRP], mterleukm-6 [IL-6], arid E-selectin) after 6 and 12 weeks of rosuvastatin treatment. Baseline for all measurements was the level measured at the beginning of treatment with rosuvastatin 40 rag. Blood samples for lipid assays were collected from patients who had fasted for _>12 hours. All lipid and lipoprotein analyses were performed at a central laboratory (Medical Research Laboratories International, Highland Heights, Kentucky), which was certified for standardization of lipid analyses as specified by the Standardization Program of the Centers for Disease Control and Prevention (Atlanta, Georgia) and the National Heart, Lung, and Blood Institute (Bethesda, Maryland). :4 LDL-C levels were calculated using the Friedewald equation :5 in patients whose TG levels were _<400 mg/dL and were measured using preparative ultracentrifugation if sample TG levels were >400 rng/dL Compliance was assessed by comparing the number of capsules and packets of trial medication returned to the investigator with the number dispensed. Patients taking 80% to 120% of the prescribed trial medications were considered compliant. Safety profile was assessed by using adverse-event reports, clinical laboratory values, vital signs, electrocardiograms, and physical examinations. Because cholesterol is a precursor of steroid hormones, including cortisol, the adrenal reserve of a subset of study patients was measured at baseline and after 12 weeks of treatment with rosuvastatin. Adrenocorticotropic hormone (ACTH) stimulation tests were performed in several centers before any trial medication was administered and at the end of treatment. After a blood sample was collected for basal serum cortisol measurement, ACTH (cosyntropin) 250 lag was injected intravenously, and venous samples were then collected from the opposite arm at 30 and 60 minutes for determination of the serum cortisol response.~6 Statistical Analysis A total of 98 patients who completed treatment were required for a 90% power of detecting a 10°/0 difference between groups in percentage change in LDL-C level from baseline based on a 2-sided significance level of 5°/0 and a standard deviation of ]5°/0.

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An analysis of variance (ANOVA) model (SAS version 6.12, SAS Institute Inc., Cary, North Carolina) that included terms for treatment, center, and centerby-treatment interaction was used to analyze percentage change from baseline in lipid data for all patients who received ___1dose of medication and had ___1baseline and 1 postbaseline measurement (intent-to-treat analysis). Because the primary and secondary end points were analyzed using ANOVA, the results were given as least squares mean (SE). An additional analysis (per-protocol analysis) with patients who did not violate or deviate from the protocol in a major way was done to check the robustness of the intent-totreat analysis. All testing was done at a 2-sided o~ = 0.05 level. Results compared statistically were presented as least squares mean values and included the last observation carried forward for patients who withdrew or had missing values. Safety data were summarized descriptively without statistical analysis. RESULTS O f the 372 patients who were enrolled in the dietary

lead-in period, 153 (41%) were eligible for study treatment. Six of the 153 patients (4%) were withdrawn during treatment with rosuvastatin 40 mg because of adverse events (2 patients had adverse events considered unrelated to treatment ]nausea and pruritus (1 patient) and lymphoma-like reaction (1 patient)] and 1 patient had paresthesia considered possibly related to treatment), withdrawal of informed consent (1 patient), protocol noncompliance (1 patient), and LDL-C <50 mg/dL (1 patient). Three patients in each group withdrew during randornized treatment, including 2 in the combination group because of adverse events (constipation and rnyalgia) and 4 who withdrew infomled consent or were lost to follow-up. Three patients were not included in efficacy analyses because of the lack of a postbaseline measurement. Thirty-eight patients in each group (52% overall) were reported to have heterozygous familial hypercholesterolemia, according to medical and family history, but this assessment was not confirmed by genetic testing. Patient characteristics were similar in both treatment groups (Table I), and the overall characteristics of the patients who received rosuvastatin 40 mg were similar to those of patients who were randomized to the 2 treatment groups. 1858

Table I, Demographic and clinical characteristics of patients randomized to treatment with either rosuvastatin (ROS) alone or ROS with cholestyramine (CHM). Treatment Group

Characteristic

ROS 80 mg (n 71)

RQS 80 mg + CHN (n 76)

Age Mean (SD),y

54.0 (I 28)

549 (I 46)

31 78 19 (27)

21 84 25 (33)

Sex, no. (%) Male Female

43 (61) 28 (39)

40 (53) 36 (47)

Pace, no. (%) White Black Other

66 (93) S (4) 2 (3)

70 (92) s (7) I (I)

Range, y _>65 y no. (%)

Body weight, mean (SD), I
825 (148)

Body mass index Mean (SD), kg/mz >30 kg/m 2, no (%)

28.1 (46) 20 (28)

277 (45) 23 (30)

Atherosclerotic disease, no. (%)

~0 (~8)

19 (~s)

Family history of premature CHD/ peripheral vascular disease, no (%)

33 (46)

37 (49)

C H D - c o r o n a r y h e a r t disease.

Compliance was lowest in the group that received the combination of rosuvastatin and cholestyrarnine, with 37 (49%) of 75 patients considered noncornpliant compared with 7 (5%) of 144 patients treated with rosuvastatin 40 rng and 6 (9%) of 69 patients treated with rosuvastatin 80 rng. Efficacy

LDL-C decreased by a mean (SD) of 52.2% (13.0%), from a mean baseline level of 257 (59) mg/dL to 125 (49) mg/dL after treatment with rosuvastatin 40 mg (Figure 2, Table II). Least squares mean (SE) decreases from baseline after rosuvastatin 80 nag and rosuvastatin 80 mg plus cholestyramine treatment were 56.4% (1.8%) and 60.5% (1.8%), respectively. Favorable changes from baseline were also observed

C.M. Ballantyne et al.

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in the other lipid and lipid ratio measurements. However, none of the changes in the lipid measurements were significantly different between groups (Table II). Because of the design of this trial, in which all patients initially received treamient with rosuvastatin 40 rag, it was also possible to calculate the percentage of further incremental reduction in LDL-C level that occurred when the regimen was changed from rosuvastatin 40 mg to rosuvastatin 80 mg alone versus rosuvastatin 80 mg plus cholestyramine. This was calculated as [(LDL-C at 40 mg - final LDL-C)/(LDL-C at 40 rag)] × 100. Three (4%) of 69 patients in the rosuvastatin 80-rag group and 22 (29%) of 75 patients in the combination-therapy group had >30% incremental reduction in LDL-C level after treatment.

The per-protocol analysis included 79% (56/71) of the patients given rosuvastatin 80 mg and 39% (30/76) of the patients given the combination therapy. The most c o m m o n reason for exclusion from this analysis was n o n c o m p l i a n c e with cholestyramine treatment. The least squares mean (SE) percentage reductions in LDL-C levels were 57.9% (1.9%) in the rosuvastatin 80-rag group and 61.9% (2.7%) in the combination-therapy group; the between-group difference was not statistically significant. Median decreases in CRP were 29% after treatment with rosuvastatin 40 rag, 42% after treatment with rosuvastatin 80 rag, and 48% after treamient with the combination of rosuvastatin 80 mg plus cholestyramine. Median baseline CRP level was 1.9 mg/L Baseline and percentage changes in IL-6 and E-selectin levels were highly variable, and no conclusions could be drawn.

Safety Profile Overall, 39% (60/153), 35% (25/71), and 55% ('[2/76) of patients had adverse events while treated with rosuvastatin 40 rag, rosuvastatin 80 rag, and rosuvastatin 80 mg plus cholestyramine, respectively. The most common adverse events are shown in Table III. Adverse events that were considered by the investigator to be treatment related occurred in 12% (19/153) of patients who received rosuvastatin 40 rag, 10% (7/71) of patients who received rosuvastatin 80 rag, and 43% (33/76) of patients who received rosuvastatin 80 rng plus cholestyrarnine. The most notable difference was for gastrointestinal symptoms, which occurred in 41% (31/76) of patients who received rosuvastatin 80 rng plus cholestyrarnine compared with 10% (7/71) of patients who received rosuvastatin 80 rng alone. The cholestyrarnine dosage was titrated down to 8 g/d in 9 patients (12%) because of intolerability. None of the 3 serious adverse events (pathological fracture, lyrnphorna-like reaction, hypotension) was considered to be related to treatment. In 1 patient, who had slightly elevated alanine aminotransferase (ALT) level at the end of the dietary lead-in period (1.6 x ULN), ALT level increased to >3 x ULN while the patient was receiving rosuvastatin 40 rag. ALT level returned to normal when trial medication was stopped.

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Table III. Adverse events that occurred in _>3% of patients during treatment with rosuvastatin (ROS) 40 mg, ROS 80 mg alone,or ROS 80 mg with cholestyramine (CHN).*Values are given as number (%) of patients.

Adverse Event Abdominal distention Abdominal pain Asthenia Back pain Constipation Dyspepsia Headache Hypertonia Pain Pharyngitis

ROS 40 mg ROS 80 mg ( n = 153) (n=71) I (I) 5 (3) 6 (4) 2 (I) 4 (3) 3 (2) 7 (5) 25 (2) 5 (3) 9 (6)

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*Patients may have had > I adverse event

Four patients (3%) reported myalgia during treatment with rosuvastatin 40 mg, and 1 patient (1%) reported myalgia during treatment with rosuvastatin 80 mg plus cholestyramine. One patient had an elevated CK level >10 x ULN that was associated with a musculoskeletal injury (ruptured Achilles tendon and subsequent surgical repair and physical therapy) that occurred during the dietary lead-in period. CK levels in this patient were resolving up to trial end with continued treatment with rosuvastatin 80 rag. No other clinically rneaningful changes in other laboratory values, electrocardiograms, vital signs, or physical examinations were observed. A total of 12 patients in the rosuvastatin 80-rag group and 12 in the combination-therapy group at 4 centers were included in the ACTH stimulation tests. All patients had a normal response to ACTH, and mean serum cortisol concentrations were within the normal range and increased to a similar extent before and after treatment. Mean (SD) serum cortisol concentrations with ACTH stimulation for all 24 patients before treatment initiation (ie, w e e k - 6 ) were 681 (252), 1263 (283), and 1471 (287) mmol/L at 0, 30, and 60 minutes, respectively; after treatment initiation (ie, week 6), these values were 618 (223), 1106 (241), and 1314 (266) mmol/L at 0, 30, and 60 minutes, respectively

DISCUSSION

In these patients with severe hypercholesterolemia, LDL-C reductions were 52.2% after 6 weeks of treatment with rosuvastatin 40 mg and 56.4% after an additional 6 weeks of treatment with rosuvastatin 80 rag. The group also receiving cholestyramine had a numerically greater mean reduction in LDL-C (60.5%) than the group receiving rosuvastatin 80 mg alone (56.4%), but the between-group difference was not statistically significant. Numerically but not statistically significant improvements were also observed for TC, TG, apo B, and apo A-I levels. A possible reason for the lack of a statistically significant benefit with cholestyramine combination treatment is that patients did not take sufficient cholestyramine to produce a greater effect. Approximately half (49%) of the patients in the group that received cholestyramine were considered noncompliant with the medication regimen. Previous trials have shown that the effects of cholestyramine are dependent on the dose actually received and that smaller amounts are better tolerated than larger amounts, s4z In the Pravastatin Multicenter Study, lz when cholestyramine was combined with pravastatin 40 rag/d, the LDL-C reductions varied from 43% in patients receiving <8 g/d of cholestyramine to 53% in patients receiving up to 24 g/d of cholestyramine, according to compliance assessments. Therefore, it is possible that a greater response with added cholestyramine may have been achieved in this trial if cholestyramine had been started at a lower dose and gradually titrated up to its maximal tolerated dose. Because all patients in this trial initially received treatment with rosuvastatin 40 rag, the incremental further reduction in LDL-C that occurred when the regimen was changed from rosuvastatin 40 mg to rosuvastatin 80 rng alone or rosuvastatin 80 mg plus cholestyramine could also be examined. Four percent of patients in the rosuvastatin 80-rag group and 29% in the combination-therapy group had a >30% incremental reduction in LDL-C after treatment. These results suggest that some patients may achieve clinical benefit with the addition of cholestyramine to even a high dose of rosuvastatin. -Whether this effect was related to variations in individual response or better compliance cannot be determined without a better approximation of the actual drug dose than was obtained in this trial.

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Overall, the differences between groups were relatively small and nonsignificant, and other possibilities besides compliance should be considered. Although statins and bile acid sequestrant resins such as cholestyramine have different mechanisms of action and are unlikely to have a pharmacokinetic interaction, the combination of these treatments appeared to be less synergistic for reduction of LDL-C levels than might have been expected. In our trial, the addition of cholestyramine to rosuvastatin 80 mg resulted in an additional incremental mean LDL-C reduction o f - 9 % beyond that obtained with rosuvastatin 40 rag, which was similar to the additive effect observed with cholestyrarnine added to atorvastatin 40 mg/d in more severely hypercholesterolemic patients. 18 To the authors' knowledge, based on a PubMed search of the literature (search terms: atorvastat~n, simvastatir~, cholestyramir~e, 80 rag), no combination studies with maximal doses (80 rag) of simvastatin or atorvastatin have been reported to date. Both statins and bile acid sequestrant resins result in increased hepatic LDL receptors, and it is possible that in some patients the liver has a near-maximal upregulation of LDL receptors, with effective inhibition of HMG-CoA reductase achieved with rosuvastatin 80 rag. Further research is needed to determine how much additional reduction in LDL-C level can be achieved when bile acid sequestrant resins are added. Cholestyramine has previously been shown to increase TG levels, which may be related to increases in hepatic cholesterol synthesis and secretion. 17,>9,?° Statins, however, reduce TG levels in these patients. >3,21 In our study, there was no significant difference in TG levels when cholestyramine was added to rosuvastatin versus rosuvastatin alone. The relationship between baseline TG levels and the effects of these treatments in severely hypercholesterolemic patients remains to be determined. In this trial, it appeared that the lipid response of these patients to rosuvastatin 40 mg was nearly as great as the response to rosuvastatin 80 rag. In another trial22 that included patients with heterozygous familial hypercholesterolemia who had a mean baseline LDL-C level of 292 mg/dL, reductions in LDL-C levels, which were 54% and 58% after forced titration to rosuvastatin 40 mg and rosuvastatin 80 rag, respectively, were similar to those observed in this trial. HDL-C level was also increased with both rosuvastatin 40 mg and rosuva1862

statin 80 mg in both this trial (12.9% and 11.3%, respectively) and the previously reported trial, 22 which included only patients with heterozygous familial hypercholesterolemia (10% and 12%, respectively). Adverse events reported were consistent with those reported previously for rosuvastatin, cholestyramine, and cholestyramine-statin combinations. 2°,23~ The most notable differences between treatments were the apparently increased prevalence of gastrointestinal symptoms (constipation, abdominal distention, and dyspepsia) in the group receiving cholestyramine. These adverse events and the unpalatability of cholestyramine are likely contributors to the high percentage of medication noncompliance observed in this study It should be noted that in this open-label trial, the assessment of these adverse events may have been affected by patients' and investigators' previous experience with bile acid sequestrant resins and rosuvastatm CONCLUSIONS

In this group of patients with severe hypercholesterolemia, the combination of rosuvastatin 80 mg with 16 g/d of cholestyramine did not have a significantly greater efficacy benefit than rosuvastatin alone, but these results do not rule out the possibility of a clinical benefit of added cholestyramine in patients needing additional LDL-C reduction while receiving the highest doses of currently approved statins, which for rosuvastatin is up to 40 mg/d. However, gastrointestinal symptoms may limit the usefulness of this combination of treatments in patients who tolerate cholestyramine poorly. As with other statins, the combination of rosuvastatin with cholestyramine was otherwise well tolerated. AC KN O W L E DG M E N T S

This research was supported by AstraZeneca LP (Wilrnington, Delaware). Dr. Ballantyne has previously received grants/research support from AstraZeneca, diaDexus, Inc. (South San Francisco, California), Gene Logic, Inc. (Gaithersburg, Maryland), GlaxoSmithKline (Research Triangle Park, North Carolina), Integrated Therapeutics Group (Kenilworth, New Jersey), Kos Pharmaceuticals, Inc. (Miami, Florida), Merck gz Company, Inc. (Whitehouse Station, New Jersey), Novartis Pharmaceuticals Corporation (East Hanover, New Jersey), pfizer Inc. (New York, New York), Reliant Pharmaceuticals, LLC (Liberty Corner, New Jersey),

C.M. Ballantyne et al.

Sankyo Pharma, Inc. (Parsippany, New Jersey), and Schering-Plough Corporation (Kenilworth, New Jersey). He has served as a consultant to AstraZeneca, Bayer Pharmaceuticals Corporation (West Haven, Connecticut), Merck, Novartis, Pfizer, Reliant, and Schering-Plough. Dr. Ballantyne has also served on the speakers' bureaus for AstraZeneca, Bristol-Myers Squibb Company (Princeton, New Jersey), Kos, Merck, Novartis, Pfizer, Reliant, Sanofi-Synthelabo Inc. (New York, New York), and Schering-Plough. The authors wish to thank the investigators, their coinvestigators and study coordinators, and the patients who participated in this trial. They also wish to thank Donna Curtis and Karen McFadden of AstraZeneca LP for their editorial assistance. In addition to the authors, the following investigators participated in this trial: Michael Davidson, MD, Chicago, Illinois; Robert Detrano, MD, Torrance, California; Karen Friday, MD, New Orleans, Louisiana; Anne Goldberg, MD, St. Louis, Missouri; Charles Herring, MD, Wilmington, North Carolina; Paul Hopkins, MD, Salt Lake City, Utah; Moti Kashyap, MD, Long Beach, California', Leonard Keilson, MD, Portland, Maine', Michael Koren, MD, St. Augustine, Florida; Mary McGowan, MD, Manchester, New Hampshire; James McKenney, MD, Richmond, Virginia', Helmut Schrott, MD, Iowa City, Iowa; Evan Stein, MD, Cincinnati, Ohio', Stuart Weiss, MD, San Diego, California; and Barbara Zedler, MD, Richmond, Virginia. REFERENCES

1. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). 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 3~t21. 2. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: Results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study JAMA. 1998;279:1615-1622. 3. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pmvastatin in men with hypercholesterolemia. West of Scotland Coronary

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Blood Institute Lipid Standardization Program. An approach to accurate and precise lipid measurements. Clin Lab Med. 1989;9:105 135. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499-502. Ravel R. Clinical Laboratory Medicine: ClinicalApplication of Laboratory Data. 6th ed. St. Louis, Mo: Mosby; 1995. Pravastatin Multicenter Study Group II. Comparative efficacy and safety of pravastatin and cholestyramine alone and combined in patients with hypercholesterolemia. Arch Intern Med. 1993;153:1321-1329. Athyros VG, Papageorgiou AA, Demitriadis DS, Kontopoulos AG. Atorvastatin plus pravastatin for the treatment of heterozygous familialhyperchdesterolaemi~ a pilot study. Curr Med Res Opin. 2001; 17:26G272. Betteridge DJ, Bhatnager D, Bing RE, et al. Treatment of familial hypercholesterolemia. United Kingdom lipid clinics study of pravastatin and cholestyramine. BMJ. 1992;304:1335 1338.

20. Eriksson M, Hadell K, Holme I, et al. Compliance with and efficacy of treatment with pravastatin and cholestyramine: A randomiTed study on lipid lowering in primary care. d Intern Med. 1998;243:373 380. 21. Mol MJ, Stwt PM, Demacker PN, Stalenhoef AE The effects of simvastatin on serum lipoproteins in severe hypercholesterolaemia. Neth J Med. 1990;36:182-190. 22. Stein EA, Strutt K, Southworth H, et al, for the HeFH Study Group. Comparison of rosuvastatin versus atorvastatin in patients with heterozygous familial hypercholesterolemia. Am J Cardiol. 2003;92:12871293. 23. Brewer HB Jr. Benefit-risk assessment of rosuvastatin 10 to 40 milligrams. Amd Cardiol. 2003;92:23K 29K. 24. Pan HY, DeVault AR, Swites BJ, et al. Pharmacokinetics and pharmacodynamics of pravastatin alone and with cholestyramine in hypercholesterolemia. Clin P}~armacol Ther. 1990;48:201 207. 25. Wierzbicki AS, Lumb PJ, Semra YK, Crook MA. High dose atorvastatin therapy in severe heterozygous famil ial hypercholesterolaemia. QJM. 1998;91:291 29~t.

Address c o r r e s p o n d e n c e to: Christie M. Ballantyne, MD, Baylor College of Medicine, Department of Medicine, 6565 Fannin, MS A601, Room A656, Houston, TX 77030. E-maih [email protected]

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