Low-Dose Combined Therapy with Fluvastatin and Cholestyramine in Hyperlipidemic Patients

Methods

The study protocol was designed by mutual consent of the investigators and Sandoz Research Institute, with all data collected by the investigators subject to review and analysis by Sandoz Research Institute. The interpretation of the data in this article is based on the mutual consent of all submitting authors.

All patients were consecutively randomized based on a diagnosis of hypercholesterolemia confirmed during drug washout with an LDL cholesterol level of at least 4.14 mmol/L (160 mg/dL), despite dietary intervention, and a plasma triglyceride level of no more than 3.39 mmol/L (300 mg/dL). Persons were excluded if they had a history of homozygous familial hypercholesterolemia, secondary hyperlipidemia, liver disease, renal disease, diabetes, myocardial infarction or angioplasty within 6 months of study entry, or uncontrolled hypertension.

The patients' mean age was 54.1 years; 54% were male; 95% were white and 3% were black. The treatment groups did not differ in baseline demographic characteristics. The study was approved by the institutional review boards for human research of all participating institutions. Informed consent was obtained from all patients.

Treatment Plan

This study consisted of a 6-week, single-blind, placebo washout period followed by a 24-week, double-blind treatment period divided into three phases (Figure 1). Patients were withdrawn from hypolipidemic therapy for at least 4 weeks (1 year for probucol) before entry into the washout period. In addition, patients were instructed by a registered dietitian to follow a cholesterol-lowering diet (American Heart Association or National Cholesterol Education Program step 1) for at least 8 weeks before entry into the washout period and throughout the study, and a Food Record Rating score of 15 or less was required for study entry [9]. Patients with aspartate aminotransferase or alanine aminotransferase values greater than 1.5 times the upper limit of laboratory normal during the washout period were excluded from the study.

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Figure 1. Monotherapy groups received either placebo, fluvastatin, 10 mg/d, or fluvastatin, 20 mg/d, throughout the study. In the combined therapy groups, cholestyramine, 8 mg/d, was added in phase 2 and the dose increased to 16 mg/d in phase 3. CME = cholestyramine; FL = fluvastatin. Study design and numbers of patients initially assigned to each treatment group.

At the end of the placebo washout period, patients who satisfied all entry criteria entered the 24-week, double-blind treatment period, which consisted of three 8-week phases. For the first 8 weeks (phase 1), patients were assigned randomly into six groups receiving blinded study medication: two groups receiving placebo; two receiving 10 mg of fluvastatin; and two receiving 20 mg of fluvastatin. In phases 2 and 3 of the study, one placebo group, one 10-mg fluvastatin group, and one 20-mg fluvastatin group received open-label cholestyramine in addition to the blinded study drug, whereas the other three groups remained on fluvastatin or placebo monotherapy for the rest of the trial. In phase 2, the dose of cholestyramine added to the regimen of patients in the three combination groups was 4 g twice daily. In phase 3, the dose of cholestyramine was increased to 8 g twice a day for these patients.

Blinded medication was taken once daily at bedtime, approximately 4 hours after the evening meal. Patients receiving open-label cholestyramine took their medication just before breakfast and dinner. Compliance with all treatment regimens was assessed by pill or packet count.

Study Evaluations

Patients were assessed every 2 weeks during the placebo washout period and every 4 weeks during the 24-week treatment period. Dietary compliance was determined by Food Record Rating scores derived from dietary records collected throughout the study [9].

Twelve-hour fasting blood samples were obtained at each visit for lipid determinations, which were done by a central laboratory (Medical Research Laboratories; Cincinnati, Ohio). Low-density lipoprotein cholesterol was calculated according to the Friedewald formula [10]. Total cholesterol, high-density lipoprotein cholesterol, and plasma triglycerides were measured on a 737 Hitachi analyzer (Boehringer Mannheim Diagnostics; Indianapolis, Indiana) with microenzymatic procedures [11] fully standardized, and part 3 was monitored through the National Heart, Lung, and Blood Institute and Centers for Disease Control and Prevention Lipid Standardization Program [12, 13].

Safety was evaluated at baseline and at intervals throughout the study. These evaluations included measurements of blood pressure and pulse; physical, ophthalmologic, and electrocardiographic examinations; and routine laboratory tests. Investigators were asked to assess, in a blinded fashion, each adverse event and laboratory abnormality for a potential relation to blinded study drug administration, based on their clinical experience and judgment.

Statistical Analysis

All statistical comparisons were made using two-tailed tests at the P < 0.05 level. Data were pooled across all clinical centers for analysis. The Statistical Analysis System (SAS Institute, Inc.; Cary, North Carolina) software was used for all analyses. All confidence intervals are 95% and represent the difference in mean percent change from baseline between two treatment groups of interest.

For each patient, the baseline lipid value was defined as the average of the week −2 and week 0 lipid measurements during the washout phase. In evaluating efficacy by treatment phase, lipid results were calculated as the averages of the values for weeks 4 and 8, weeks 12 and 16, and weeks 20 and 24. For end-point analyses, the end point was defined as the last active treatment phase visit for which lipid data were available.

One-way analysis of variance models were used to compare the mean percentage change in total cholesterol, LDL cholesterol, high-density lipoprotein cholesterol, and triglycerides between the treatment groups. In each model, we did tests of significance of the percentage change from baseline within each group and of differences in mean percentage change between treatment groups.

In determining safety, a newly occurring abnormality was defined as an abnormality reported during the active treatment period but not reported during the placebo washout period, and a worsening abnormality was an abnormality that worsened from the placebo washout period to the active treatment period. The number of patients with newly occurring or worsening abnormalities in each treatment group was determined, and the proportions were compared using the Fisher exact test.

Results

Of 460 patients from nine study centers screened, 224 met study criteria and were randomized into the double-blind treatment period of this study; 203 completed all phases of treatment. Fifteen (10%) of 150 fluvastatin-treated patients and 6 (8%) of 74 placebo- or cholestyramine-treated or both (that is, non-fluvastatin-treated) patients were dropped during the double-blind treatment period. Five fluvastatin-treated patients (1 receiving concomitant cholestyramine) and 1 placebo-treated patient (receiving concomitant cholestyramine) dropped out because of adverse events. These events, each of which occurred in one patient, were angina, myalgia, stomatitis and glossitis, heartburn and indigestion, elevated transaminase levels, and alopecia. Of these, only the instance of stomatitis and glossitis was judged by the investigator to be definitely related to the drug. One patient receiving 10-mg fluvastatin monotherapy died of a myocardial infarction as a consequence of severe atherosclerotic heart disease. The investigator reported that this event was probably not related to the study drug. The 14 patients who dropped out for reasons unrelated to study medication included 4 who were uncooperative, 2 who developed an unrelated illness, and 8 who withdrew for various other reasons such as a geographic move or a lack of desire to continue.

Medication and Dietary Compliance

Mean fluvastatin compliance was excellent, ranging from 92% to 99% at each 4-week interval in all six treatment groups. The mean daily dose in the 10-mg fluvastatin and the 10-mg fluvastatin plus cholestyramine groups ranged from 9.5 mg to 9.9 mg. The mean daily dose in the two 20-mg fluvastatin groups ranged from 18.4 to 19.7 mg.

Compliance rates with the cholestyramine regimen were somewhat lower (ranging from 73% to 87% in the three combination therapy groups) and declined over time, possibly as a result of the increase in cholestyramine dose in phase 3. Mean daily doses during phases 2 and 3 ranged from 6.6 g to 7.2 g and from 11.7 g to 13.1 g, respectively, across the three combination groups. Mean dietary compliance assessed by serial Food Record Rating scores remained stable during the placebo and treatment periods.

Effects on Lipids and Lipoproteins

Baseline plasma lipid levels were generally similar for all six treatment groups. The mean baseline total cholesterol level (± SD) for the entire study group was 7.55 ± 1 mmol/L (292 ± 38.9 mg/dL), the mean LDL cholesterol level was 5.40 ± 0.96 mmol/L (209 ± 37.2 mg/dL), and the mean triglyceride level was 1.74 ± 0.62 mmol/L (154.2 ± 54.9 mg/dL). The mean high-density cholesterol level was 1.74 ± 0.15 mmol/L (51.6 ± 13.1 mg/dL), and the mean ratio of LDL to high-density-lipoprotein cholesterol was 4.3 ± 1.5. The mean LDL cholesterol levels during the washout period were similar in all groups.

Both groups receiving fluvastatin monotherapy (10 mg or 20 mg) showed considerable reductions in LDL cholesterol after 4 weeks of treatment, which were maintained throughout the remainder of the study. From baseline to the average of weeks 4 and 8, the 20-mg fluvastatin group showed a slightly greater mean percent reduction than the 10-mg fluvastatin group, but this difference did not achieve statistical significance (20-mg fluvastatin − 10-mg fluvastatin, −1.0%; CI, −4.4% to 4.2%). Except for a transient reduction in LDL cholesterol levels at week 4, a cholesterol-lowering effect was not observed in the placebo monotherapy group.

During phase 1, the three combination therapy groups who later received cholestyramine showed reductions in mean LDL cholesterol similar to those seen for the monotherapy group receiving the same treatment throughout the duration of the study (Table 1). The addition of cholestyramine, 8 g/d, in phase 2 (weeks 9 to 16) in these three groups resulted in mean decreases in LDL cholesterol higher than those seen in monotherapy groups at the same time. In each of the fluvastatin plus cholestyramine groups, the increase in cholestyramine dose from 8 g/d to 16 g/d in phase 3 (weeks 17 to 24) provided only a modest additional response (Figure 2). In comparing LDL cholesterol values by fluvastatin and cholestyramine dose (Table 1), the addition of 8 g (and later 16 g) of cholestyramine to placebo resulted in LDL cholesterol responses similar to those achieved with 10-mg and 20-mg fluvastatin monotherapy, respectively. A greater percentage reduction in LDL cholesterol occurred with the combination of 10 mg of fluvastatin with 8 g of cholestyramine (25.2%) than with 20-mg fluvastatin monotherapy (20-mg fluvastatin − [10-mg fluvastatin plus cholestyramine], 6.2%; CI, 1.0% to 11.3%).

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Figure 2. In phase 1 (weeks 1 to 8), each group showed reductions in mean low-density lipoprotein (LDL) cholesterol similar to those seen in the monotherapy group receiving the same treatment. Increased LDL cholesterol reductions were seen with the addition of cholestyramine, 8 g/d, in phase 2 (weeks 9 to 16), and modest additional reductions occurred when the dose was increased to 16 g/d in phase 3 (weeks 17 to 24). Mean low-density lipoprotein cholesterol values in the combination therapy groups during the course of the study.

Statistically significant declines in LDL cholesterol from baseline measurements were observed in all groups except the placebo group and in all phases in which an active medication was administered (Table 1). At the study end point, significant reductions in LDL cholesterol and total cholesterol were observed in all groups receiving an active medication or combination (Table 2). Moderate elevations in high-density lipoprotein cholesterol occurred in some treatment groups, particularly in the fluvastatin monotherapy groups, but not in the combined statin-resin treatment groups. The placebo plus cholestyramine control group had an increase in triglycerides of 19.6%, a finding that was statistically significant relative to the placebo and 10-mg fluvastatin plus cholestyramine groups ([placebo plus cholestyramine] − [10-mg fluvastatin plus cholestyramine], 22.3%; CI, 8.6% to 36.1%) and of borderline significance relative to the 20-mg fluvastatin plus cholestyramine group ([placebo plus cholestyramine] − [20-mg fluvastatin plus cholestyramine], 12.5%; CI, 1.2% to 26.3%).

Figure 3 shows the percentages of patients in each treatment group who had achieved, by the study end point, a reduction in LDL cholesterol to less than 4.14 mmol/L (160 mg/dL), the lower limit of moderate cholesterol elevations identified by the National Cholesterol Education Program. At 24 weeks, more patients achieved LDL cholesterol levels lower than 4.14 mmol/L (160 mg/dL) on 10 mg of fluvastatin plus 16 g of cholestyramine (67%) than did those who received 20-mg fluvastatin monotherapy (43%) (P = 0.05). At the end of treatment phase 2, National Cholesterol Education Program guidelines were met by a higher proportion of patients receiving low-dose combined therapy with fluvastatin, 10 mg/d, and cholestyramine, 8 g/d, (67%) than those receiving fluvastatin, 20 mg/d (47%); however, the difference in the proportion between these two groups did not achieve statistical significance (P = 0.1).

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Figure 3. 14 mmol/L (<160 mg/dL) at study end point. End-point analysis includes last available lipid measurements for patients who did not complete the study. The highest proportions of patients achieving National Cholesterol Education Program guidelines (low-density lipoprotein cholesterol < 4.41 mmol/L [<160 mg/dL]) were in the combination therapy groups. Percentage of patients in each treatment group achieving low-density lipoprotein cholesterol levels less than 4.

Safety and Adverse Events

Overall, the study drugs were well tolerated in this study. No clinically relevant differences were seen among groups with regard to vital signs, physical examinations, electrocardiographic examinations, or ophthalmologic examinations or in hematology, urinalysis, or chemistry analyses. Table 3 shows the most common newly occurring or worsening adverse events. The most frequent adverse events in all patient groups were gastrointestinal in nature and were particularly common in those receiving resin.

With monotherapy, adverse events occurred slightly more frequently in the placebo group (57%) than in either of the fluvastatin monotherapy groups: 10 mg (46%) or 20 mg (53%). With the addition of cholestyramine, adverse events were reported by 87% of the placebo plus cholestyramine group, by 86% of the 10-mg fluvastatin plus cholestyramine group, and by 81% of the 20-mg fluvastatin plus cholestyramine group. This increased incidence was attributed almost entirely to a twofold to threefold increase in the number of patients with gastrointestinal complaints related to the use of resin.

Other than the higher incidence of flatulence in the 10-mg fluvastatin plus cholestyramine group compared with the group receiving placebo plus cholestyramine (P = 0.04), no differences between groups in the incidence of individual adverse effects were statistically significant. However, constipation was particularly common in the cholestyramine-treated groups.

Thirteen patients had newly occurring or worsening adverse events that were reported to be severe at some time during the study; all of these patients were receiving cholestyramine. Eight patients had gastrointestinal events, including constipation, nausea, gas, and dyspepsia. A patient who developed glossitis and stomatitis withdrew from the study. Several of the gastrointestinal complaints were attributed by the investigators to cholestyramine treatment. The relations of the remaining serious events (arthritis, arthralgia, and upper respiratory tract infection) to the study drug were uncertain.

Discussion

The addition of 8 g of cholestyramine to low-dose fluvastatin was generally equivalent in LDL cholesterol lowering to the addition of 16 g of cholestyramine (even though compliance was poorer at this higher dose); adding 8 or 16 g of cholestyramine to 10 mg of fluvastatin was more effective than simply doubling the statin dosage; and, two thirds of patients treated with 10 mg or 20 mg of fluvastatin plus 8 g of cholestyramine achieved LDL cholesterol levels less than 4.14 mmol/L (<160 mg/dL), the initial goal in the National Cholesterol Education Program adult guidelines. These advantages provided by combination therapy must be viewed in light of a modest increase in adverse effects, primarily gastrointestinal in nature, attributable to the resin.

Many articles have already been published regarding high-dose statin-resin combination therapy, especially in patients with very high cholesterol levels [14-22]. The combination appears to provide a clear advantage over monotherapy in achieving marked cholesterol lowering. Both lovastatin (20 mg twice daily) and pravastatin (20 mg twice daily) have been shown to reduce LDL cholesterol by approximately 30% to 35% in patients with primary hypercholesterolemia [1]. Increasing the lovastatin dose to 40 mg twice daily resulted in an overall reduction of approximately 40% [14, 15]. Combined drug therapy with colestipol (20 g/d) and lovastatin or pravastatin (20 mg twice daily) lowers LDL cholesterol by 50% to 55% and is thus superior to monotherapy [1, 14-22]. Simvastatin alone (40 mg/d) was administered to 14 patients with familial hypercholesterolemia (mean LDL cholesterol of 10.06 mmol/L ± 1.16 mmol/L [389 mg/dL ± 45 mg/dL]) [16]. The LDL cholesterol was reduced approximately 37% with simvastatin at 40 mg/d and 53% overall with the combination therapy. No further cholesterol lowering was achieved with simvastatin at 80 mg/d.

Considerably less is known about lower-dose combinations. Similar LDL cholesterol lowering was observed with a 10-mg dosage of pravastatin as with 40 mg when it was administered with an additional 24 g of cholestyramine, resulting in approximately a 50% reduction [20]. In contrast, 8 g and 16 g of cholestyramine, when added to 40 mg or 80 mg of lovastatin, led to LDL cholesterol reductions of 45% to 61% [1, 23]. Both low-dose cholestyramine regimens added considerably to the overall effect of the statin agent [1]. The dramatic efficacy of a low-dose resin-statin regimen we have shown should not be surprising for several reasons. First, a recent report by Superko and colleagues [5] concluded that more than 50% of the cholesterol reduction achieved with full-dose colestipol (15 g/d) was achieved with the first 5 g. The 5-, 10-, and 15-g colestipol dosages produced reductions of 14.7%, 22.5%, and 26.9% in LDL cholesterol, respectively. A decrease in compliance with increasing doses of resin observed in the 16-g compared with the 8-mg cholestyramine dose in our study may contribute to this progressively diminished cholesterol-lowering effect. The dose-response characteristics for the statin agents have shown a similar asymptotic curve, with the greatest reductions achieved within the first 10% to 20% of the dosing range. These reasons alone suggest that a low-dose statin-resin combination would be more effective than anticipated.

We have shown that the addition of resin to low-dose (10 mg/d) statin therapy with fluvastatin was more effective in lowering cholesterol than doubling the statin dosage. At low doses, we did not find the cholesterol-lowering effect of the drugs to be synergistic, as has been previously suggested [24], but at best additive. The mean baseline LDL cholesterol concentration for each group of patients studied, selected for drug treatment by the National Cholesterol Education Program adult guidelines, was approximately 5.43 mmol/L (210 mg/dL). That level is lower than in many previous studies where combination therapy was provided. When 10 mg of fluvastatin plus 8 g of resin was administered (phase 2), 63% of patients achieved LDL cholesterol values of less than 4.14 mmol/L (160 mg/dL). When 20 mg of fluvastatin alone or 16 g of cholestyramine was used alone (phase 3), only 43% and 50% of patients, respectively, had LDL cholesterol similarly altered. Thus, approximately 30% more patients treated with the combination than treated with higher-dose monotherapy attained initial guideline goals.

In the context of serial dosing (that is, groups not totally independent for each treatment regimen and open-label resin use), LDL cholesterol reductions in the range of 25% to 30% can be achieved with low-dose resin-statin combination therapy (8 g/d of resin and 10 to 20 mg/d of statin), the result of an additive cholesterol-lowering effect. The addition of low-dose resin appears to produce greater overall cholesterol reduction than does a simple doubling of the statin dosage and results in a less-than-anticipated resin-induced rise in triglycerides. Fluvastatin is a new, totally synthetic statin agent that is associated with a low occurrence of side effects. However, the addition of resin to the statin agent increases the frequency of gastrointestinal symptoms. Finally, the low-dose combination treatment was found to be highly successful in achieving the goals put forth in the National Cholesterol Education Program guidelines.