- Email: [email protected]
Treatment of patients with elevated plasma levels of low-density lipoproteins with a cholestyramine tablet compared with cholestyramine powder
CURRENT THERAPEUTIC RESEARCH VOL. 52, NO. 2, AUGUST1992
TREATMENT OF PATIENTS WITH ELEVATED PLASMA LEVELS OF LOW-DENSITY LIPOPROTEINS WITH A CHOLESTYRAMINE TABLET COMPARED WITH CHOLESTYRAMINE POWDER PETER O. KWITEROVICH, JR., 1 JAMES H. ZAVORAL,2 STEPHANIE D. KAFONEK,1 FAYE BULLEMER, 2 AND BERT KITTNER1'* 1The Johns Hopkins University, Baltimore, Maryland and 2Minneapolis Heart Institute, Minneapolis, Minnesota
ABSTRACT A p r i m a r y elevation of plasma low-density lipoproteins (LDL) is a c o m m o n cause of c o r o n a r y artery disease. C h o l e s t y r a m i n e powder is often used to t r e a t such patients, b u t compliance c a n be less t h a n optimal. This study was designed to assess the efficacy of a wax-coated tablet form of c h o l e s t y r a m i n e resin (1 gm per tablet). Ninety-six male a n d female subjects with total and LDL cholesterol c o n c e n t r a t i o n s above the 90th percentile, after a n A m e r i c a n H e a r t Association step I diet, were r a n d o m i z e d to receive either the tablet or powder f o r m a t i o n (dose of 16 gm per day). Forty-three subjects in each group completed a m i n i m u m o f 6 weeks of t r e a t m e n t . S i m i l a r reductions in total (20% powder, 21% tablet) a n d LDL cholesterol (29% powder, 31% tablet) c o n c e n t r a t i o n s occurred i n each group. Compliance in the two groups was identical (91% powder, 92% tablet). G a s t r o i n t e s t i n a l side effects were reported by 97% of the subjects from both groups. The cholest y r a m i n e tablet was as effective as c h o l e s t y r a m i n e powder i n the treatm e n t of hypercholesterolemia and c a n provide a n a l t e r n a t e and more c o n v e n i e n t dosage form. INTRODUCTION
Cholestyraminet is a bile acid sequestrant available for the treatment of hypercholesterolemia. The Lipid Research Clinics Coronary Primary Prevention Trial demonstrated that cholestyramine was effective in lowering low-density lipoprotein (LDL) cholesterol concentrations and subsequently reducing the incidence of coronary heart disease.l'2 ~ile acid sequestrants are recommended as first-line therapy for LDL red:,ction if dietary therapy is unsuccessful in sufficiently lowering LDL cholesterol concentrations.3 Some patients may find preparing the powder formulation an annoyance * Present address: Burroughs WellcomeCompany, 3030 CornwallisRoad, Research Triangle Park, NC 27709. t Trademark: Questran®(Bristol-MyersSquibbCo., Princeton,New Jersey). Received for publication on May 22, 1992. Printed in the U.S.A. Reproductionin whole or part is not permitted. Address correspondenceto: Peter O. Kwiterovick_,Jr., M.D., The Johns Hopkins University Lipid Clinic, 550 Building,Suite 308, 550 North Broadway, Baltimore, Maryland 21205. 330
0011-393x/92/$3.50
P. O. KWITEROVICH,JR. ET AL.
and some may find it unpalatable. Thus compliance with the prescribed dose of cholestyramine is frequently a problem. Since cholestyramine is not absorbed into the bloodstream, its observed and potential toxicity is quite low. 1-3 The development of more acceptable preparations of cholestyramine should permit a greater use of this safe and effective drug. This study compares a newly formulated, 1-gm tablet of cholestyramine with the original powder formulation. P A T I E N T S AND M E T H O D S
A randomized clinical trial comparing cholestyramine powder with newly formulated cholestyramine tablets was performed at The Johns Hopkins University Lipid Clinic and the Minneapolis Heart Institute. The patients followed a step I American Heart Association diet for 6 weeks. Once stabilized, they were stratified by age, sex, and body weight, and randomly assigned to receive either cholestyramine powder or wax-coated cholestyramine tablets for 8 weeks. Each tablet contained 1 gm of cholestyramine; each powder packet contained 4 gm of cholestyramine in 9 gm of total powder. The oval tablets consisted of cholestyramine and a tabletting lubricant (magnesium stearate) to which a wax-like coating (primarily stearic acid) was applied. The coating delays tablet disintegration, allowing time for the tablet to reach the stomach. Laboratory data indicate that the tablets disintegrate within an average of 10 minutes or a range of 5 to 30 minutes (data on file, Bristol-Myers Squibb Company, Evansville, Indiana). Patients were instructed to take 16 gm of cholestyramine per day as either two packets of powder or eight tablets, twice a day. Patients were allowed concurrent use of stool softeners and antacids, but were asked to refrain from using fiber-based laxatives. To rate the convenience and ease of preparation of the two products and their taste and palatability, the final 43 participants (24 tablet, 19 powder) were offered the opposite formulation for a 2-week period and asked their overall preference of the two formulations. Ninety-six men and women between 24 and 75 years of age were enrolled in the study. Informed consent was obtained after the nature of the study and the procedures used were explained. Each patient had a total or LDL cholesterol concentration greater than the 90th percentile and a triglyceride level less than 200 mg/dl (type IIa hyperlipoproteinemia). Fifty patients were randomly assigned (after stratification for age, gender, and body weight) to receive tablets and 46 to receive powder. All blood for lipid and lipoprotein analyses was collected in sodium/ potassium ethylenediaminetetraacetate (1 mg/ml). Samples were separated within 4 hours, and the plasma was transferred to polyethylene containers and stored at 4 °C until shipment to the central laboratory 331
CHOLESTYRAMINE TABLET COMPARED WITH CHOLESTYRAMINE POWDER
(Medical Research Laboratories, Cincinnati, Ohio). Samples were shipped by overnight courier in styrofoam boxes with temperature controlled at 4 °C. Upon arrival, samples were immediately unpacked and analyzed the same day. Plasma total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were measured on an Hitachi 737 instrument (Boehringer Mannheim Diagnostics, Indianapolis, Indiana) with standardized enzymatic procedures.4 HDL cholesterol was measured by precipitating the apolipoprotein B-containing lipoproteins with heparin manganese and determining the cholesterol concentration of the supernate. ~ LDL cholesterol was calculated by the formula of Friedewald and coworkers.6 Serum chemistries, including bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, creatine phosphokinase, and creatinine, were also performed at the central laboratory. Analyses were performed on an Hitachi 737 instrument. Quality assurance was monitored by the College of American Pathologists Quality Assurance Program (Traverse City, Michigan). Two-way analyses of covariance (ANACOVA) were used to evaluate differences within and between treatment groups. Initially, patient gender, age, weight, and dosing compliance were evaluated as potential covariates. Nonsignificant covariates (P > 0.05) were excluded from the model, and then a test for equality of slopes was performed. If this hypothesis was not rejected, a parallel slopes model was used to perform within and between treatment-group tests. Adjusted (least squares) means from the ANACOVA are reported for each treatment group along with the estimated mean differences between the treatment groups. Ninety percent confidence limits for the mean difference in percent change were computed using the estimated standard error from the ANACOVA. The incidence of reported adverse events and changes in physical examinations were compared between the two treatment groups using Fisher's exact test. Within each treatment group changes in vital signs were evaluated using paired t tests, while changes in clinical laboratory parameters were assessed using sign and Stuart-Maxwell/McNemar's tests. RESULTS
There were no statistically significant differences in age, weight, male-tofemale ratio, or body-frame size between the two study groups (Table I). Eight of 50 patients (16%) in the tablet group and five of 46 (10.9%) in the powder group withdrew before 8 weeks were completed. Three of the 13 patients (1 patient in the tablet group and 2 in the powder group) had completed at least 28 days of treatment and were included in the efficacy analysis (see below). One patient in the tablet group withdrew to resume taking estrogen and one was unable to swallow the tablet. The other six 332
P. O. KWITEROVICH, JR. ET AL.
Table I. Baseline characteristics of patients randomized to cholestyramine tablet or powder. Parameter
Tablet (n = 50)
Powder (n = 46)
Age (yr) Mean Range Wel~lgehatn(I bs)
50.8 27-72
49.9 24-75
167.9 102-253
168.5 113-239
38 62
33 67
94 6
96 4
Range Sex Female (%) Male (%) Race White (%) Other (~°"%)
patients reported gastrointestinal complaints (1 constipation and 5 gastric distress). Each of the five patients withdrawing from the powder group reported gastrointestinal complaints (1 gastric distress and 4 constipation). None of the patients reporting mild gastrointestinal symptoms withdrew from the study. Forty-three patients from each study group completed at least 28 days of active medication t r e a t m e n t and constituted the subset for efficacy analysis. The mean compliance among patients in this efficacy subset was 92% (14.7 gm cholestyramine/day) in the tablet group and 91% (14.6 gm cholestyramine/day) in the powder group. The mean lipid and lipoprotein cholesterol concentrations for the 86 patients completing at least 28 days of treatment are presented in Table II. Baseline measurements were obtained at the initial visit prior to dietary
Table II. Lipid and lipoprotein cholesterol concentrations before and after treatment with cholestyramine. (Values are expressed as mean _+SE.)
Total cholesterol (mg/dl) Predrug* Postdrugt Low-density lipoprotein cholesterol (mg/dl) Predrug Postdrug High-density lipoprotein cholesterol (mg/dl) Predrug Postdrug Triglycerides (mg/dl) Predrug Postdrug
Tablet (n = 43)
Powder (n = 43)
288.3 -+ 6.3 226.2 -+ 5.9
294.2 + 4.5 233.6 +- 4.5
212.1 -+ 6.4 146.2 + 5.8
219.9 -+ 4.8 154.3 -+ 4.4
49.4 _+ 1.8 51.6 -+ 1.9
50.2 _+ 2.1 52.1 _+ 2.2
133.8 _+ 8.3 142.0 _+ 8.7
120.8 _+ 7.5 136.0 -+ 10.8
* Predrug = value after 6 weeks of diet stabilization and prior to randomization to either tablet or powder. t Postdrug = final value after at least 28 days on cholestyramine treatment.
333
CHOLESTYRAMINE TABLET COMPARED WITH CHOLESTYRAMINE POWDER
instruction. Most of the study patients were already following a step I American H e a r t Association diet prior to entry into the study. Six weeks after the diet instruction, patients were randomized to receive either the tablet or powder formulation for 8 weeks and predrug measurements were made. There were no significant differences in lipoprotein cholesterol concentrations over the 6-week dietary stabilization period. The mean triglyceride level increased 11.5% in the tablet group and decreased 1.8% in the powder group during the diet stabilization period. Postdrug measurements were obtained at the final visit, at least 28 days after randomization to either cholestyramine tablets or powder. All patients had type IIa hyperlipoproteinemia. The mean total and LDL cholesterol concentrations at randomization (predrug) were 288.3 mg/ dl and 212.0 mg/dl, respectively, in the tablet group, and 294.2 mg/dl and 219.9 mg/dl, respectively, in the powder group. The overall percent reductions in total cholesterol between the randomization (predrug) visit and the end of the treatment interval were 21.3 in the tablet group and 20.3 in the powder group (Table III). Similarly, the overall percent reductions in LDL cholesterol between the two visits were 30.8 in the tablet group and 29.4 in the powder group. These reductions represent a statistically significant decrease in both treatment groups (P < 0.01). The efficacy of the tablet in lowering total and LDL cholesterol was compared with the powder by examining the magnitude of the difference between the two dosage forms with respect to the mean change from the predrug to postdrug values (Table III). No statistically significant differences were noted for any of the lipid or lipoprotein parameters. The 90%
Table III. Comparison of the effect of cholestyramine tablets and powder preparations on lipid and lipoprotein concentrations. (Values are expressed as m e a n -+ SE.) Tablet-Powder Parameter Total cholesterol (mg/dl) Difference* % changet Low-density lipoprotein cholesterol (mg/dl) Difference % change High-density lipoprotein cholesterol (mg/dl) Difference % change Triglycerides (mg/dl) Difference % change
Tablet (n = 43)
Powder (n = 43)
Difference
P value
-62.5 _+ 4.9 -21.3_+ 1.5
-60.3 +- 4.9 -20.3 _+ 1.5
2.25 _+ 6.9 -0.99 -+ 2.09
0.74 0.64
-66.4 +- 4.5 -30.8-+ 1.8
-65.1 -+ 4.5 -29.4-+ 1.8
-1.30 -+ 6.4 -1.35 -+ 2.56
0.84 0.60
2.2 _+ 1.1 5.4 _+ 2.2
1.8 -+ 1.1 4.3 -+ 2.2
0.38 _+ 1.5 1.13 _+ 3.17
0.80 0.72
8.3 -+ 7.8 11.1 -+ 6.0
15.0 +- 7.8 15.4 -+ 6.0
6.7 -+ 11.0 -4.32 _+ 8.54
0.55 0.61
* Mean difference (_+SE) between predrug and postdrug values; adjusted for initial body weight. t Percentage change of difference between randomization and endpoint; mean (-+SE). 334
P. O. KWITEROVICH, JR. ET AL.
confidence limits indicate that the tablet was at least 97% as efficacious as the powder in lowering total and LDL cholesterol. Similarly, there were no significant differences in the percent change of either HDL cholesterol or triglyceride between the dosage forms. The percent increase in HDL cholesterol was 5.4 and 4.3, respectively, for the tablet and powder groups; the percent increase in total triglyceride was 11.1 and 15.4, respectively. The effects of cholestyramine on plasma lipid and lipoprotein cholesterol concentrations were clinically significant within the first 14 days of therapy and were generally stable within 4 to 5 weeks following the institution of the treatment phase. Of the final 43 patients who were offered the opportunity to participate in a poststudy preference assessment, 41 responded (23 receiving powder, 18 receiving the tablets). Of those 41 patients, 73% preferred the tablets, 17% preferred the powder, and 10% had no preference. The tablets were preferred over the powder formulation primarily because of their convenience. Most participants disliked the preparation required with the powder formulation both at home and particularly outside the home. The overall frequency of side effects was comparable in the two groups (Table IV). Some patients reported more than one symptom. There were no statistically significant differences between treatment groups with respect to overall incidence or severity of adverse events. Ninety-seven percent of the tablet group and 96.7% of the powder group reported adverse events that involved the gastrointestinal system. Approximately 89% of symptoms in the tablet group and 93% in the powder group were of only mild to moderate severity. DISCUSSION
Newly formulated cholestyramine tablets proved comparable to cholestyramine powder in their ability to reduce plasma total and LDL cholesTable IV. Adverse events reported during treatment phases.*t Tablets (n = 50)
Mild Constipation/hard stools Hemorrhoids/rectal bleeding Bowel frequency increased/diarrhea Bloating/flatulence Heartburn/gastric distress Nausea/vomiting Others Total
8 6 1 15 11 3 1 45
Moderate 8 3 0 4 3 1 1 20
* Events felt to be related to drug.
Powder (n = 46)
Severe
Mild
2 0 2 1 3 0 1 9
13 1 0 12 2 2 0 30
t Some patients reported multiple events. :~ Other = back pain, difficulty swallowing, fatigue, and headache, 335
Moderate 8 1 0 5 7 3 0 24
Severe 2 1 0 0 1 0 1 5
CHOLESTYRAMINETABLETCOMPAREDWITHCHOLESTYRAMINEPOWDER
terol concentrations. The patients were prescribed 16 gm of cholestyramine per day, and were randomized to receive either eight wax-coated tablets twice a day or two packets of cholestyramine powder twice a day. Both formulations effectively lowered LDL cholesterol concentrations by 30% by the end of the 4-week treatment period. Previous work by Levy and coworkers 7 demonstrated that 80% of the effect of cholestyramine in lowering LDL cholesterol was observed in 1 week and the maximum effect was observed by 4 weeks. Thus the treatment period in this study was sufficient to allow maximal lowering of LDL cholesterol by cholestyramine. The prescribed dose in this study was 16 gm of cholestyramine per day. Although the maximum recommended dose of cholestyramine (24 gm/day) was warranted based on the initial LDL cholesterol concentrations, a lower than maximal dose was chosen to minimize gastrointestinal adverse reactions and ensure compliance with the prescribed dose. The incidence and severity of gastrointestinal side effects were similar in both study groups. Most patients reported one or more symptoms related to gastrointestinal function (ie, constipation, bloating, or heartburn). In the tablet group approximately 89% of these symptoms were rated to be of only mild to moderate severity by the patient and in the powder group 93% were rated similarly. Of the subset of patients who were queried as to their preference of dosage forms, almost three fourths preferred the tablets over the powder. Convenience and ease of administration were the most frequently cited reasons for preferring the tablet formulation. In summary, this study shows that a tablet form of cholestyramine was as efficacious as cholestyramine powder in lowering both plasma total and LDL cholesterol concentration. The side-effect profiles of the two dosage forms did not differ and the majority of patients preferred the tablet because of its convenience. The cholestyramine tablet offers a desirable alternative to cholestyramine powder for the treatment of hypercholesterolemia.
Acknowledgments The authors wish to acknowledge Norman R. Marquis, Ph.D., for his help in the conduct of the study, and Gary D. Hutton, M.S., for performing the statistical analyses. The study was supported by a grant from BristolMyers Squibb Company. References: 1. Lipid Research Clinics Program. The Lipid Research Clinics Coronary P r i m a r y Prevention Trial results: I. Reduction in incidence of coronary h e a r t disease. JAMA 1984; 241: 351-364. 336
P. o. KWITERO¥ICH,JR. ET AL.
2. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results: II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. J A M A 1984; 241:365-374. 3. Recommendations for treatment of hyperlipidemia in adults. Circulation 1984; 69: 1067a- 1090a. 4. Myers GL, Cooper GR, Winn CL, Smith SJ. The Centers for Disease Control--National Heart, Lung, and Blood Institute Lipid Standardization Program: An approach to accurate and precise lipid measurements. Clin Lab Med 1989; 9:105-135. 5. Warnick GR, Albers JJ. A comprehensive evaluation of the heparin-manganese precipitation procedure for estimating high-density lipoprotein cholesterol. J Lipid Res 1978; 19:65-73. 6. Friedewald WT, Levy RI, Frederickson DS. Estimation of concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18:499-502. 7. Levy RI, Fredrickson DS, Stone NJ, et al. Cholestyramine in type II hyperlipoproteinemia: A double-blind trial. A n n Intern M e d 1973; 79:51-58.
337
TREATMENT OF PATIENTS WITH ELEVATED PLASMA LEVELS OF LOW-DENSITY LIPOPROTEINS WITH A CHOLESTYRAMINE TABLET COMPARED WITH CHOLESTYRAMINE POWDER PETER O. KWITEROVICH, JR., 1 JAMES H. ZAVORAL,2 STEPHANIE D. KAFONEK,1 FAYE BULLEMER, 2 AND BERT KITTNER1'* 1The Johns Hopkins University, Baltimore, Maryland and 2Minneapolis Heart Institute, Minneapolis, Minnesota
ABSTRACT A p r i m a r y elevation of plasma low-density lipoproteins (LDL) is a c o m m o n cause of c o r o n a r y artery disease. C h o l e s t y r a m i n e powder is often used to t r e a t such patients, b u t compliance c a n be less t h a n optimal. This study was designed to assess the efficacy of a wax-coated tablet form of c h o l e s t y r a m i n e resin (1 gm per tablet). Ninety-six male a n d female subjects with total and LDL cholesterol c o n c e n t r a t i o n s above the 90th percentile, after a n A m e r i c a n H e a r t Association step I diet, were r a n d o m i z e d to receive either the tablet or powder f o r m a t i o n (dose of 16 gm per day). Forty-three subjects in each group completed a m i n i m u m o f 6 weeks of t r e a t m e n t . S i m i l a r reductions in total (20% powder, 21% tablet) a n d LDL cholesterol (29% powder, 31% tablet) c o n c e n t r a t i o n s occurred i n each group. Compliance in the two groups was identical (91% powder, 92% tablet). G a s t r o i n t e s t i n a l side effects were reported by 97% of the subjects from both groups. The cholest y r a m i n e tablet was as effective as c h o l e s t y r a m i n e powder i n the treatm e n t of hypercholesterolemia and c a n provide a n a l t e r n a t e and more c o n v e n i e n t dosage form. INTRODUCTION
Cholestyraminet is a bile acid sequestrant available for the treatment of hypercholesterolemia. The Lipid Research Clinics Coronary Primary Prevention Trial demonstrated that cholestyramine was effective in lowering low-density lipoprotein (LDL) cholesterol concentrations and subsequently reducing the incidence of coronary heart disease.l'2 ~ile acid sequestrants are recommended as first-line therapy for LDL red:,ction if dietary therapy is unsuccessful in sufficiently lowering LDL cholesterol concentrations.3 Some patients may find preparing the powder formulation an annoyance * Present address: Burroughs WellcomeCompany, 3030 CornwallisRoad, Research Triangle Park, NC 27709. t Trademark: Questran®(Bristol-MyersSquibbCo., Princeton,New Jersey). Received for publication on May 22, 1992. Printed in the U.S.A. Reproductionin whole or part is not permitted. Address correspondenceto: Peter O. Kwiterovick_,Jr., M.D., The Johns Hopkins University Lipid Clinic, 550 Building,Suite 308, 550 North Broadway, Baltimore, Maryland 21205. 330
0011-393x/92/$3.50
P. O. KWITEROVICH,JR. ET AL.
and some may find it unpalatable. Thus compliance with the prescribed dose of cholestyramine is frequently a problem. Since cholestyramine is not absorbed into the bloodstream, its observed and potential toxicity is quite low. 1-3 The development of more acceptable preparations of cholestyramine should permit a greater use of this safe and effective drug. This study compares a newly formulated, 1-gm tablet of cholestyramine with the original powder formulation. P A T I E N T S AND M E T H O D S
A randomized clinical trial comparing cholestyramine powder with newly formulated cholestyramine tablets was performed at The Johns Hopkins University Lipid Clinic and the Minneapolis Heart Institute. The patients followed a step I American Heart Association diet for 6 weeks. Once stabilized, they were stratified by age, sex, and body weight, and randomly assigned to receive either cholestyramine powder or wax-coated cholestyramine tablets for 8 weeks. Each tablet contained 1 gm of cholestyramine; each powder packet contained 4 gm of cholestyramine in 9 gm of total powder. The oval tablets consisted of cholestyramine and a tabletting lubricant (magnesium stearate) to which a wax-like coating (primarily stearic acid) was applied. The coating delays tablet disintegration, allowing time for the tablet to reach the stomach. Laboratory data indicate that the tablets disintegrate within an average of 10 minutes or a range of 5 to 30 minutes (data on file, Bristol-Myers Squibb Company, Evansville, Indiana). Patients were instructed to take 16 gm of cholestyramine per day as either two packets of powder or eight tablets, twice a day. Patients were allowed concurrent use of stool softeners and antacids, but were asked to refrain from using fiber-based laxatives. To rate the convenience and ease of preparation of the two products and their taste and palatability, the final 43 participants (24 tablet, 19 powder) were offered the opposite formulation for a 2-week period and asked their overall preference of the two formulations. Ninety-six men and women between 24 and 75 years of age were enrolled in the study. Informed consent was obtained after the nature of the study and the procedures used were explained. Each patient had a total or LDL cholesterol concentration greater than the 90th percentile and a triglyceride level less than 200 mg/dl (type IIa hyperlipoproteinemia). Fifty patients were randomly assigned (after stratification for age, gender, and body weight) to receive tablets and 46 to receive powder. All blood for lipid and lipoprotein analyses was collected in sodium/ potassium ethylenediaminetetraacetate (1 mg/ml). Samples were separated within 4 hours, and the plasma was transferred to polyethylene containers and stored at 4 °C until shipment to the central laboratory 331
CHOLESTYRAMINE TABLET COMPARED WITH CHOLESTYRAMINE POWDER
(Medical Research Laboratories, Cincinnati, Ohio). Samples were shipped by overnight courier in styrofoam boxes with temperature controlled at 4 °C. Upon arrival, samples were immediately unpacked and analyzed the same day. Plasma total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were measured on an Hitachi 737 instrument (Boehringer Mannheim Diagnostics, Indianapolis, Indiana) with standardized enzymatic procedures.4 HDL cholesterol was measured by precipitating the apolipoprotein B-containing lipoproteins with heparin manganese and determining the cholesterol concentration of the supernate. ~ LDL cholesterol was calculated by the formula of Friedewald and coworkers.6 Serum chemistries, including bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, creatine phosphokinase, and creatinine, were also performed at the central laboratory. Analyses were performed on an Hitachi 737 instrument. Quality assurance was monitored by the College of American Pathologists Quality Assurance Program (Traverse City, Michigan). Two-way analyses of covariance (ANACOVA) were used to evaluate differences within and between treatment groups. Initially, patient gender, age, weight, and dosing compliance were evaluated as potential covariates. Nonsignificant covariates (P > 0.05) were excluded from the model, and then a test for equality of slopes was performed. If this hypothesis was not rejected, a parallel slopes model was used to perform within and between treatment-group tests. Adjusted (least squares) means from the ANACOVA are reported for each treatment group along with the estimated mean differences between the treatment groups. Ninety percent confidence limits for the mean difference in percent change were computed using the estimated standard error from the ANACOVA. The incidence of reported adverse events and changes in physical examinations were compared between the two treatment groups using Fisher's exact test. Within each treatment group changes in vital signs were evaluated using paired t tests, while changes in clinical laboratory parameters were assessed using sign and Stuart-Maxwell/McNemar's tests. RESULTS
There were no statistically significant differences in age, weight, male-tofemale ratio, or body-frame size between the two study groups (Table I). Eight of 50 patients (16%) in the tablet group and five of 46 (10.9%) in the powder group withdrew before 8 weeks were completed. Three of the 13 patients (1 patient in the tablet group and 2 in the powder group) had completed at least 28 days of treatment and were included in the efficacy analysis (see below). One patient in the tablet group withdrew to resume taking estrogen and one was unable to swallow the tablet. The other six 332
P. O. KWITEROVICH, JR. ET AL.
Table I. Baseline characteristics of patients randomized to cholestyramine tablet or powder. Parameter
Tablet (n = 50)
Powder (n = 46)
Age (yr) Mean Range Wel~lgehatn(I bs)
50.8 27-72
49.9 24-75
167.9 102-253
168.5 113-239
38 62
33 67
94 6
96 4
Range Sex Female (%) Male (%) Race White (%) Other (~°"%)
patients reported gastrointestinal complaints (1 constipation and 5 gastric distress). Each of the five patients withdrawing from the powder group reported gastrointestinal complaints (1 gastric distress and 4 constipation). None of the patients reporting mild gastrointestinal symptoms withdrew from the study. Forty-three patients from each study group completed at least 28 days of active medication t r e a t m e n t and constituted the subset for efficacy analysis. The mean compliance among patients in this efficacy subset was 92% (14.7 gm cholestyramine/day) in the tablet group and 91% (14.6 gm cholestyramine/day) in the powder group. The mean lipid and lipoprotein cholesterol concentrations for the 86 patients completing at least 28 days of treatment are presented in Table II. Baseline measurements were obtained at the initial visit prior to dietary
Table II. Lipid and lipoprotein cholesterol concentrations before and after treatment with cholestyramine. (Values are expressed as mean _+SE.)
Total cholesterol (mg/dl) Predrug* Postdrugt Low-density lipoprotein cholesterol (mg/dl) Predrug Postdrug High-density lipoprotein cholesterol (mg/dl) Predrug Postdrug Triglycerides (mg/dl) Predrug Postdrug
Tablet (n = 43)
Powder (n = 43)
288.3 -+ 6.3 226.2 -+ 5.9
294.2 + 4.5 233.6 +- 4.5
212.1 -+ 6.4 146.2 + 5.8
219.9 -+ 4.8 154.3 -+ 4.4
49.4 _+ 1.8 51.6 -+ 1.9
50.2 _+ 2.1 52.1 _+ 2.2
133.8 _+ 8.3 142.0 _+ 8.7
120.8 _+ 7.5 136.0 -+ 10.8
* Predrug = value after 6 weeks of diet stabilization and prior to randomization to either tablet or powder. t Postdrug = final value after at least 28 days on cholestyramine treatment.
333
CHOLESTYRAMINE TABLET COMPARED WITH CHOLESTYRAMINE POWDER
instruction. Most of the study patients were already following a step I American H e a r t Association diet prior to entry into the study. Six weeks after the diet instruction, patients were randomized to receive either the tablet or powder formulation for 8 weeks and predrug measurements were made. There were no significant differences in lipoprotein cholesterol concentrations over the 6-week dietary stabilization period. The mean triglyceride level increased 11.5% in the tablet group and decreased 1.8% in the powder group during the diet stabilization period. Postdrug measurements were obtained at the final visit, at least 28 days after randomization to either cholestyramine tablets or powder. All patients had type IIa hyperlipoproteinemia. The mean total and LDL cholesterol concentrations at randomization (predrug) were 288.3 mg/ dl and 212.0 mg/dl, respectively, in the tablet group, and 294.2 mg/dl and 219.9 mg/dl, respectively, in the powder group. The overall percent reductions in total cholesterol between the randomization (predrug) visit and the end of the treatment interval were 21.3 in the tablet group and 20.3 in the powder group (Table III). Similarly, the overall percent reductions in LDL cholesterol between the two visits were 30.8 in the tablet group and 29.4 in the powder group. These reductions represent a statistically significant decrease in both treatment groups (P < 0.01). The efficacy of the tablet in lowering total and LDL cholesterol was compared with the powder by examining the magnitude of the difference between the two dosage forms with respect to the mean change from the predrug to postdrug values (Table III). No statistically significant differences were noted for any of the lipid or lipoprotein parameters. The 90%
Table III. Comparison of the effect of cholestyramine tablets and powder preparations on lipid and lipoprotein concentrations. (Values are expressed as m e a n -+ SE.) Tablet-Powder Parameter Total cholesterol (mg/dl) Difference* % changet Low-density lipoprotein cholesterol (mg/dl) Difference % change High-density lipoprotein cholesterol (mg/dl) Difference % change Triglycerides (mg/dl) Difference % change
Tablet (n = 43)
Powder (n = 43)
Difference
P value
-62.5 _+ 4.9 -21.3_+ 1.5
-60.3 +- 4.9 -20.3 _+ 1.5
2.25 _+ 6.9 -0.99 -+ 2.09
0.74 0.64
-66.4 +- 4.5 -30.8-+ 1.8
-65.1 -+ 4.5 -29.4-+ 1.8
-1.30 -+ 6.4 -1.35 -+ 2.56
0.84 0.60
2.2 _+ 1.1 5.4 _+ 2.2
1.8 -+ 1.1 4.3 -+ 2.2
0.38 _+ 1.5 1.13 _+ 3.17
0.80 0.72
8.3 -+ 7.8 11.1 -+ 6.0
15.0 +- 7.8 15.4 -+ 6.0
6.7 -+ 11.0 -4.32 _+ 8.54
0.55 0.61
* Mean difference (_+SE) between predrug and postdrug values; adjusted for initial body weight. t Percentage change of difference between randomization and endpoint; mean (-+SE). 334
P. O. KWITEROVICH, JR. ET AL.
confidence limits indicate that the tablet was at least 97% as efficacious as the powder in lowering total and LDL cholesterol. Similarly, there were no significant differences in the percent change of either HDL cholesterol or triglyceride between the dosage forms. The percent increase in HDL cholesterol was 5.4 and 4.3, respectively, for the tablet and powder groups; the percent increase in total triglyceride was 11.1 and 15.4, respectively. The effects of cholestyramine on plasma lipid and lipoprotein cholesterol concentrations were clinically significant within the first 14 days of therapy and were generally stable within 4 to 5 weeks following the institution of the treatment phase. Of the final 43 patients who were offered the opportunity to participate in a poststudy preference assessment, 41 responded (23 receiving powder, 18 receiving the tablets). Of those 41 patients, 73% preferred the tablets, 17% preferred the powder, and 10% had no preference. The tablets were preferred over the powder formulation primarily because of their convenience. Most participants disliked the preparation required with the powder formulation both at home and particularly outside the home. The overall frequency of side effects was comparable in the two groups (Table IV). Some patients reported more than one symptom. There were no statistically significant differences between treatment groups with respect to overall incidence or severity of adverse events. Ninety-seven percent of the tablet group and 96.7% of the powder group reported adverse events that involved the gastrointestinal system. Approximately 89% of symptoms in the tablet group and 93% in the powder group were of only mild to moderate severity. DISCUSSION
Newly formulated cholestyramine tablets proved comparable to cholestyramine powder in their ability to reduce plasma total and LDL cholesTable IV. Adverse events reported during treatment phases.*t Tablets (n = 50)
Mild Constipation/hard stools Hemorrhoids/rectal bleeding Bowel frequency increased/diarrhea Bloating/flatulence Heartburn/gastric distress Nausea/vomiting Others Total
8 6 1 15 11 3 1 45
Moderate 8 3 0 4 3 1 1 20
* Events felt to be related to drug.
Powder (n = 46)
Severe
Mild
2 0 2 1 3 0 1 9
13 1 0 12 2 2 0 30
t Some patients reported multiple events. :~ Other = back pain, difficulty swallowing, fatigue, and headache, 335
Moderate 8 1 0 5 7 3 0 24
Severe 2 1 0 0 1 0 1 5
CHOLESTYRAMINETABLETCOMPAREDWITHCHOLESTYRAMINEPOWDER
terol concentrations. The patients were prescribed 16 gm of cholestyramine per day, and were randomized to receive either eight wax-coated tablets twice a day or two packets of cholestyramine powder twice a day. Both formulations effectively lowered LDL cholesterol concentrations by 30% by the end of the 4-week treatment period. Previous work by Levy and coworkers 7 demonstrated that 80% of the effect of cholestyramine in lowering LDL cholesterol was observed in 1 week and the maximum effect was observed by 4 weeks. Thus the treatment period in this study was sufficient to allow maximal lowering of LDL cholesterol by cholestyramine. The prescribed dose in this study was 16 gm of cholestyramine per day. Although the maximum recommended dose of cholestyramine (24 gm/day) was warranted based on the initial LDL cholesterol concentrations, a lower than maximal dose was chosen to minimize gastrointestinal adverse reactions and ensure compliance with the prescribed dose. The incidence and severity of gastrointestinal side effects were similar in both study groups. Most patients reported one or more symptoms related to gastrointestinal function (ie, constipation, bloating, or heartburn). In the tablet group approximately 89% of these symptoms were rated to be of only mild to moderate severity by the patient and in the powder group 93% were rated similarly. Of the subset of patients who were queried as to their preference of dosage forms, almost three fourths preferred the tablets over the powder. Convenience and ease of administration were the most frequently cited reasons for preferring the tablet formulation. In summary, this study shows that a tablet form of cholestyramine was as efficacious as cholestyramine powder in lowering both plasma total and LDL cholesterol concentration. The side-effect profiles of the two dosage forms did not differ and the majority of patients preferred the tablet because of its convenience. The cholestyramine tablet offers a desirable alternative to cholestyramine powder for the treatment of hypercholesterolemia.
Acknowledgments The authors wish to acknowledge Norman R. Marquis, Ph.D., for his help in the conduct of the study, and Gary D. Hutton, M.S., for performing the statistical analyses. The study was supported by a grant from BristolMyers Squibb Company. References: 1. Lipid Research Clinics Program. The Lipid Research Clinics Coronary P r i m a r y Prevention Trial results: I. Reduction in incidence of coronary h e a r t disease. JAMA 1984; 241: 351-364. 336
P. o. KWITERO¥ICH,JR. ET AL.
2. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results: II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. J A M A 1984; 241:365-374. 3. Recommendations for treatment of hyperlipidemia in adults. Circulation 1984; 69: 1067a- 1090a. 4. Myers GL, Cooper GR, Winn CL, Smith SJ. The Centers for Disease Control--National Heart, Lung, and Blood Institute Lipid Standardization Program: An approach to accurate and precise lipid measurements. Clin Lab Med 1989; 9:105-135. 5. Warnick GR, Albers JJ. A comprehensive evaluation of the heparin-manganese precipitation procedure for estimating high-density lipoprotein cholesterol. J Lipid Res 1978; 19:65-73. 6. Friedewald WT, Levy RI, Frederickson DS. Estimation of concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18:499-502. 7. Levy RI, Fredrickson DS, Stone NJ, et al. Cholestyramine in type II hyperlipoproteinemia: A double-blind trial. A n n Intern M e d 1973; 79:51-58.
337