Fluvastatin in familial hypercholesterolemia: A cohort analysis of the response to combination treatment

A Cohort Analysis ofthe Response to Combination Treatment Eleonora N. Muratti,

PhD,

Tim K. Peters, MD, and Eran Leitersdotf, MD

ArecwtrandomDed,doubk-bfind,doubkdummytrial reveakddtfferwcesintherespowe OfpatklltSWHh ~famMalhyperchoksteroiemiatocombinatkntherapywlththe new,who3ysynthetk3-hydroxy-3-methy@lutaryJwenxyme A (HMG-CoA) reductase inhlbttor fluvastatln, 20 mg/day and then 40 mg/day, plus the fibrk add anakgue bwafibrate, 400 mg/day, vs combination therapy with fluvastatln, 40 mg/day, pksthebileaddsequwtrant(resJn)chokstyramine, 8 g/day. The main purpose of the present whortanalyskwastodetermlm,whetherthese wererelatedtoimdlRwnwsInlfpldresponw balances in the patients’ prior responses to up to 42wwksoffluvastatinmowthera PYI 20 mg/aavl 40 mfWay, and, In some patients, SOmiWa~, in 2earJkrstudks.Forthepresentanalysis,we k&ntMed 18 patients in the fluvastatk plus bexa= flbrategroup(cohortl)andlGpatkntsIntbs fluvastatin plus dmkstywmiw group (cohort 2) forwhomcomplete -datawere avallabk for the full SGweek duratkn of all 3 studies. Subsets of 7 patients In cohort 1 and 8 patkntsIncohort2hadrewivedtheGOmg/day fluvastatin dose during a previous monotherapy study.Incohorti,lowdensltyllpoprotelnchoksterol (LDLC) dwreasd by lS%wtth 20 mg/day fluvastathr, by27%wtth 40 mg/dayfluvastatin, by 31%with 20 mg/day fluvastatin plus bezafibrate, andby35%wJth4Omg/dayfluvastatkplusbezaf&ate, and the U)LC/hlgh density lipoprotein wokstew (HDLC) ratio had fallen by 43% at the end of combhfatkn therapy. In whort 2, LDLC deched by lS% with 20 mg/day flurrastatln, by 23%vtith 40 mg/day AuvastaUn, and by 31% with From the Division of Medicine and the Center for Research, Prevention and Treatment of Atherosclerosis, Hadassah University Hospital, Jerusalem, Israel (E.L.), and Clinical Research and Development, Sandoz Pharma Ltd., Basel, Switzerland (E.N.M., T.K.P.). Address for reprints: E. Leitersdorf, MD, Division of Medicine and the Center for Research, Prevention and Treatment of Atherosclerosis, Hadassah University Hospital, IL-91120 Jerusalem, Israel.

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fluvastaUn plus chokstyramiw, and the LDLC/ HDLCratkwaskwered by3S%atthewmbkatkn therapy endpoint. Thus, the LDLC responw was similar in both cohorts, except for the enhancement of the effect on the U)LC/HDLC ratio seen with the comMnatkn of fluvastatin plus bezafibrate, compared with the combkation of fluvastatin plus cholestyramiw. 7hat iq the addG tkm of either bezafibrate or wokstywmine kwered LDLC levels by an additknal +lO% rektke to the decwaws achieved with 40 mg/day fluvastatin alone. According to the findings of the w hott analysk, some of the dMerenws ineffkw obsewedbetweentbs2comMnatknregimens were reiated to prior response to mowtherapy, whkh, in turn, may have refkcted patknt gender and/or compliance wtth therapy. No clinkally meaningful abnormalttks in aspartate amino= transferaw, alaniw amlnotransferase, or creatine klnase levels were notedwfth etther wmbinatknreghn&,whkhsuggeststhatthe ~msnswereequaliysafe.Afthou@bothcomMnatkms were effectbe, fluvastath plus bezafibrate appeared to be superkr, since R lowered triglyceride ievels by 24%, in contrast to the 3% increase seen with fluvastatk plus chokstywmine. We wnclude that the combfnation offluvastatin with bexaflbrate k a good alternative for the treatmwt of severe familial hypewholesterokmia when a fluvastatim wmblnation is poorly tolerated and/or does not achieve goal lipid levels. However, careful monitorkg Is recommended CnPght of reports of the development ofmyopathyand rhabdomyolyskwith theuseof flbratw alone or in combinatkn wfth other fungaily derived HMG-CoA reductase inhibitors. (Am J Cardkl1~7390~D)

B

ecause patients with heterozygous familial hypercholesterolemia face an increased risk of coronary artery disease, they constitute an important target population for primary and MAY 26, 1994

secondary prevention efforts through lipid-lowering therapy. In the majority of patients with severe familial hypercholesterolemia, however, monotherapy with a bile acid sequestrant (resin) or a 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase inhibitor often fails to achieve adequate control of lipid and lipoprotein levels. In such cases, combination treatment is required, consisting of at least 2 lipid-lowering agents with synergistic mechanisms of action.lt2 Although HMG-CoA reductase inhibitors are most frequently combined with bile acid sequestrants,3*4 combination regimens using fibric acid derivatives (fibrates) have also been employed.5-9 Such combinations are not without drawbacks, however. For example, the use of resins is often limited by adverse gastrointestinal effects that lead to patient noncompliance with the prescribed medication.lO Moreover, resins may increase triglyceride levels.‘O In contrast, although fibrates are usually less potent than the HMG-CoA reductase inhibitors in lowering low density lipoprotein cholesterol (LDL-C) levels, they do raise high density lipoprotein cholesterol (HDL-C) levels and decrease triglyceride levels. Despite these advantages, the use of HMG-CoA reductase inhibitorfibrate combinations has been restricted by concerns about an increased risk of myopathy and rhabdomyolysis associated with some regimens.“,‘* We recently performed a study in which the combination of the new, wholly synthetic HMGCoA reductase inhibitor fluvastatin with the fibric acid analogue bezafibrate proved safe and well tolerated in patients with genetically documented, heterozygous familial hypercholesterolemia.13 The unique biopharmaceutical profile of fluvastatin theoretically supports the safety results obtained in our long-term fluvastatin-bezafibrate combination, Fluvastatin has the shortest systemic exposure time (1.2 hours), no active circulating metabolites, almost complete liver extraction (95%), and is hydrophilic, thereby minimizing tissue penetration. When fluvastatin is administered 12 hours apart from bezafibrate, the biopharmaceutical profile of fluvastatin should minimize systemic (i.e., nonhepatic) tissue interactions. These patients represented one treatment arm of a randomized, double-blind, double-dummy trial comparing fluvastatin plus bezafibrate versus fluvastatin plus cholestyramine.13 The combination therapy trial was an extension of 2 earlier studies of fluvastatin monotherapy, which were also carried out at Hadassah University Hospital in Jerusalem, Israel.14,15 In these monotherapy studies, fluvastatin emerged as an effective approach to the treatment of familial

hypercholesterolemia, producing a 16-30% decrease in plasma LDL-C levels and a 9-25% increase in HDL-C levels, depending on the specific genetic group.14 Because we observed differences in lipid response to the 2 combination regimens,13 we conducted a retrospective cohort analysis to determine whether the variations in response to combination therapy paralleled variations in response in the earlier monotherapy trials and to evaluate whether the efficacy of combination therapy in each individual patient was related to that patient’s previous response to monotherapy. METHODS Patients: The study population consisted of patients with heterozygous familial hypercholesterolemia who, after open-label monotherapy with fluvastatin, 40 mg/day for 12 weeks, had been randomized in double-blind fashion to fluvastatin, 20 mglday, and, later, 40 mglday, with bezafibrate, 400 mg/day, plus cholestyramine placebo; or to fluvastatin, 40 mg/day, with cholestyramine, 8 g/day, plus bezafibrate placebo for two 6-week periods.i3 All had previously participated for up to 42 weeks in a single-blind, forced-titration study of fluvastatin monotherapy, 20 or 40 mg/day,14 as well as in a randomized, double-blind, parallel-group comparison of 40 versus 60 mg/day.15 The 34 patients selected for the current cohort analysis were those for whom complete dose-response data were available for the entire 56-week duration of all 3 trials.i3-l5 Cohort 1 consisted of 18 patients who had been randomized to fluvastatin plus bezafibrate in the combination therapy trial, and cohort 2 included 16 patients who had been assigned to fluvastatin plus cholestyramine. l3 Also identified were a subset of 7 patients within cohort 1 (cohort la) and a subset of 8 patients within cohort 2 (cohort 2a) who had received the 60 mg/day dose of fluvastatin in the comparative monotherapy trial.15 Efficacy measurements: Efficacy analysis was based on the percent changes in plasma levels of LDL-C, HDL-C, and triglycerides and in the LDLC:HDL-C ratio at given endpoints relative to baseline. These changes were considered to serve as a surrogate for the expected benefits of treatment. Baseline was defined as the last pretreatment value measured after a 4-week placebo lead-in period and prior to entry into the active treatment phase of the forced-titration study.14 Endpoints were defined as the last values measured while a patient was receiving fluvastatin monotherapy or A SYMPOSIUM:

HMG-CoA

REDUCTASE

INHIBITORS

31D

combination therapy during a designated study period. Evaluations: The procedures and evaluations performed in the 3 individual trials have been described in detail elsewhere.13-l5 Patients were enrolled in the forced-titration study only when they had been counseled by a certified dietitian at least 8 weeks prior to the beginning of the study. Compliance with a diet that prescribed a fat intake of <30% of total calories, a polyunsaturated-tosaturated fatty acids ratio of >0.9, and a cholesterol intake of ~250 mg/day was encouraged, monitored, and regularly evaluated. Physical examinations were performed at regular intervals, and any coexistent diseases or use of nonstudy medications was recorded. Hematology and blood chemistry evaluations were also carried out at regular intervals, with particular attention paid to the key HMG-CoA reductase inhibitor safety parameters: aspartate aminotransferase, alanine aminotransferase, and creatine kinase. Patients who experienced a severe adverse event or showed a deterioration in hepatic or renal function during monotherapy were excluded from participation in the combination therapy trial. Fasting blood samples were obtained on the morning of each visit in order to measure plasma levels of total cholesterol, HDL-C, and triglycerides. LDL-C concentrations were calculated.16 Throughout the 3 studies, all lipid measurements were performed with the same methods in the same laboratory.13-l5 Compliance was checked by a medication count at each visit, and mean compliance was evaluated by determining the percentage of prescribed medication that was actually taken. Noncompliance in an individual patient was defined as an intake of < 80% of prescribed medication. The onset, duration, severity, and outcome of any adverse events, whether reported by the patient or observed by the investigator, were recorded. Overall drug tolerability was assessedby both investigator and patient at the end of the study or at early termination, and, if applicable, reasons for early termination were noted. Doses and tlme points of analysis: After titration of the fluvastatin dose up to 20 mg/day in the forced-titration study,14 patients in both major cohorts of the current analysis received the following doses during the monotherapy period: 20 mg every evening for 4 weeks, 40 mg every evening for at least 26 weeks in total, and, in a subset of each cohort, 40 mg every evening plus 20 mg every morning (60 mg/day) for 6 weeks.14J5The response 32D

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to fluvastatin, 20 mg every evening, was assessed after 4 weeks at that dose (study week 16), and the response to the 40 mg dose was also assessedafter 4 weeks at that dose level (study week 20) and after 38 and 50 weeks of active treatment (study weeks 42 and 54, respectively). The time point of analysis for the 60 mg dose was study week 30. During the combination therapy trial,13 patients in cohort 1 received fluvastatin, 20 mg every evening, plus bezafibrate, 400 mg every morning, for 6 weeks, then fluvastatin monotherapy, 40 mg every evening, for 6 weeks, and, finally, fluvastatin, 40 mg every evening, plus bezafibrate, 400 mg every morning, for another 6 weeks. Patients in cohort 2 received fluvastatin, 40 mg every evening, plus cholestyramine, 8 g/day, for 6 weeks, followed by 6 weeks of monotherapy with fluvastatin, 40 mg every evening, and ending with fluvastatin, 40 mg every evening, plus cholestyramine, 8 g/day. In both cohorts, efficacy was measured after each 6-week combination therapy interval (that is, after 48 weeks and 60 weeks of fluvastatin treatment in total). Statistkal analyses: Within-group changes from baseline were assessed using analysis of variance for repeated measures. To determine significant differences between cohorts in baseline demographics and efficacy parameters, means and proportions were analyzed using the t test and Z test for independent samples, respectively. Wilcoxon’s signed rank tests were carried out to detect the significance of the median percent change from 0. RESULTS Demographic characteristics and baseline plasma lipid and lipoprotein levels for both major cohorts and the cohort subsets are given in Table I. The only noteworthy differences between the cohorts were the greater number of male patients (p <0.05) and the higher LDL-C and triglyceride levels (p = NS) seen in cohort 2. Percent changes in mean plasma levels of LDL-C, HDL-C, and triglycerides and in the LDL-C:HDL-C ratio for both cohorts during monotherapy and combination therapy are summarized in Table II. Low density llpoproteln cholesterol: The LDL-C response to monotherapy with fluvastatin, 20 mg every evening, was similar in both cohorts. Mean plasma LDL-C levels fell by 56 mg/dL in cohort 1 and by 53 mg/dL in cohort 2, with both cohorts reaching the same level during combination therapy despite differences in their baseline levels. At weeks 20, 42, and 54, the LDL-C reMAY 26, 1994

TABLE I Demographics and Baseline Lipid and Lipoprotein Levels

Cohort 1 Sample size (n)

Cohort 2

Cohort la

18

7

16

39.1 2 10.1

40.4 + 9.0

Cohort 2a

Cohort 1 vs Cohort 2, p Value*

Cohort la vs Cohort 2a, p Value*

NS NS 0.0391 NS NS NS NS NS

NS NS NS NS NS NS NS

NS NS NS NS NS NS

NS NS NS NS NS NS

8

Parameter (unit) Age (mean f SD)

44.3 * 11.9

a 65 years (%)

41.1 -+ 8.4

5.6

0.0

0.0

0.0

Male (%I

33.3

42.9

68.8

62.5

Female <49 years: n (%)

33.3

42.9

18.8

25.0

Weight (kg 2 SD)

68 + 10.4 25.1 + 2.3

8MI (kg/m2)

69 2 10.1 24.3 r 2.3

77.7 + 17.3

74.8 + 21.5

25.9 2 7.6

25.5 2 2.5

6MI > 28 (%I

16.7

14.3

25.0

25.0

History of CAD (%f

77.8

85.7

62.5

62.5

Lipids and lipoproteins (mg/dL) LDL-C

297.6

HDL-C Triglycerides Triglycerides LDL-UHDL-C

f 68.1

280.7

83.3

LDL-C > 240 mg/dL (%)

283.4

t 44.3

292.3

87.5

f 31.2 100

37.2 t 8.2

36.9 + 7.6

36.3 + 8.7

140.5 f 66.7

132.7 2 45.2

131.8 2 54.6

> 200 mg/dL (%) ratio

+ 53.1 85.7

37.3 2 10.4 124.9 + 45.4

11.1

14.3

12.5

12.5

8.3 + 2.4

7.9 ” 2.3

8.2 + 2.1

8.3 2 2.1

l p Values

for means are based on 2-tailed f-test: tp ~0.05; p Values for proportions are based on P-tailed Z-test. BMI = body mass index; CAD = coronary artery disease; LDL-C = low density lipoprotein cholesterol; HDL-C = high density lipoprotein

cholesterol.

TABLE II Changes in Lipid and Lipoprotein Levels over 56 Weeks in Cohorts 1 and 2* ForcedTitration Study Baseline Parameter (unit)

N

Endpoint for 20 mg FL Mean % Changet

SD

Endpoint for 40 mg FL Mean % Changet

SD

Week 42 40 mg FL Monotherapy Mean % Changet

Week 48 20 mg FL in Combination Mean % Change7

SD

SD

Week 54 40 mg FL Monotherapy Mean % Changet

Mean

SD

SD

Totalcholesterol (mg/dL) LDL-C (Friedewald) (mg/dL) HDL-C(mg/dL)

18 362.9

72.66

-14.7

5.96

-20.6

6.33

-18.5

8.64

-23.6

9.11

-17.4

10.66

18 297.6

68.11

-18.8

7.21

-27.1

8.51

-23.3

10.71

-30.5

8.39

-24.2

13.25

18

37.2

8.22

LDL-C (FriedewaldU HDL-C ratio Triglycerides

18

8.3

2.42

-25.9

8.66

-39.7

9.33

-27.5

14.38

-45.5

8.51

18 140.5

66.66

-3.9

22.92

-10.3

19.35

-2.8

34.43

-17.2

37.50

16 346.0

45.11

-14.6

6.24

-18.6

8.70

-17.5

9.77

-22.6

11.45

16 283.4

44.34

-18.6

6.21

-23.1

8.79

-21.0

10.10

-30.0

14.49

Week 60 20 mg FL in Combination Mean % Changet

SD

pValueS

-28.7

12.03

0.0001

-35.4

13.25

0.0001

Cohort 1 MZAI

10.3

9.75

22.2

12.96

8.2

16.02

28.6

13.37

11.3

17.70

0.0001

14.16

-45.8

13.28

0.0001

35.47

-23.5

30.50

0.0001

-18.2

7.25

-23.6

10.56

0.0022

-21.2

8.07

-31.1

12.07

0.0001

13.63

0.0013

13.25

0.0001

30.25

0.0029

-31.0

14.4

13.00

21.1

h&IL)

Cohort 2 KME) Total cholesterol hg/dL) LDL-C (Friedewaldf (mg/dL) HDL-C(mg/dL) LDL-C (FriedewaldY HDL-C ratio Triglycerides (mg/dL)

16

36.3

8.67

16

8.2

2.12

-22.2

6.53

16 131.8

54.55

-2.2

16.54

5.3

10.82

13.7 -32.0

17.2

11.67

5.6

6.91

8.87

-25.1

8.95

19.37

-11.4

24.41

13.7 -38.1

2.6

7.25

4.0

11.25

14.05

23.8

7.93

27.71

-12.3

18.20

11.9 -37.6

8.2

‘Baseline: week 4 of forced-titration study. tChange from forced-titration study baseline. tp values from repeated measures analysis for testing equality of mean percent changes across time points. BEZA = berafibrate; CME = cholestyramine; FL = fluvastatin. SeeTable I forotherabbreviations.

A SYMPOSIUM: HMG-CoA REDUCTASE INHIBITORS

=

sponse to monotherapy with fluvastatin, 40 mg every evening, was 2-S% lower in cohort 2 than in cohort 1 (p <0.05 at week 20). Combined treatment led to further declines in plasma LDL-C levels, such that patients in both cohorts showed a total decrease of approximately 30% at week 48. Thus, the combination of 20 mg fluvastatin and bezafibrate was more effective than the 20 mg dose alone and was equivalent to the combination of 40 mg fluvastatin and cholestyramine in lowering LDL-C levels. Combining the full 40 mg dose of fluvastatin with bezafibrate produced an additional 5% decrease in LDL-C levels relative to 20 mg/day fluvastatin plus bezafibrate or 40 mg/day fluvastatin plus cholestyramine (-35% relative to baseline). However, when compared with the endpoint of the 6-week 40 mg fluvastatin monotherapy interval in the combination therapy trial, LDL-C levels decreased by an additional 10% with 40 mg/day fluvastatin plus bezafibrate or 40 mg/day fluvastatin plus cholestyramine. Patients in cohort la showed a clear LDL-C response at all doses of fluvastatin monotherapy (Table III). LDL-C levels declined by 19.2% with 20 mg, by 28.5% with 40 mg, and by 36.1% with 60 mg, reaching a total reduction of 39.1% at week 60 with 40 mg/day fluvastatin plus bezafibrate. The 30.1% decrease seen at week 48 with 20 mglday fluvastatin plus bezafibrate was virtually equivalent to the 28.8% decrease recorded 6 weeks earlier with 40 mg fluvastatin monotherapy. In contrast, patients in cohort 2a showed a less pronounced response to fluvastatin monotherapy. LDL-C levels decreased by 17.7% with 20 mg, by 22.9% with 40 mg, and by 29.0% with 60 mg and did not decline further until week 60 with 40 mg/day fluvastatin plus cholestyramine. The 27.4% decrease in LDL-C levels at week 60 was equivalent to the decrease achieved with 60 mg fluvastatin monotherapy in this subgroup. High density lipoprotein cholesterol: Plasma HDL-C levels increased with all fluvastatin regimens in both cohorts. In cohort 1, the 22.2% increase in HDL-C seen with 40 mg fluvastatin at week 20 was not sustained either after prolonged treatment at week 42 or after the 6-week monotherapy interval. The 13.7% increase in HDL-C in cohort 2 at week 20 was likewise not sustained through the monotherapy interval. The largest increase in HDL-C levels (28.6%) was observed in cohort 1 during treatment with 20 mg/day fluvastatin plus bezafibrate. However, the difference in HDL-C levels between the 2 cohorts at the 60week endpoint (21.2% vs 11.9%) was related to the 340

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fact that the rise in HDL-C during monotherapy was greater in cohort 1 than in cohort 2. In cohort la, the largest increase in HDL-C (24.8%) was observed at the week 60 endpoint, but this increase did not differ significantly from the 25.3% rise noted with 40 mg fluvastatin monotherapy at week 20. Interestingly, this increase was not sustained with 60 mg fluvastatin monotherapy at week 30. In cohort 2a, the increases in HDL-C relative to baseline were not clearly related to dose. For example, the 13.4% increase seen with fluvastatin plus cholestyramine at week 60 was equivalent to the 16.2% increase noted with 40 mg monotherapy at week 20. With 60 mg fluvastatin monotherapy at week 30, the increases in HDL-C were even smaller (13.2%). lDl&HDLC ratio: At week 60, the LDL-C: HDL-C ratio declined from 8.3 to 4.5 in cohort 1 and from 8.2 to 5.2 in cohort 2. It is evident that the decrease was already attenuated in cohort 2 in response to monotherapy with 40 mg fluvastatin and was probably unrelated to the addition of cholestyramine. During combination treatment, the LDL-C: HDL-C ratio declined by 50.5% in cohort la and by 34.6% in cohort 2a, corresponding to the differences in LDL-C and HDL-C responses that had been previously observed during monotherapy. In cohort 2a, a maximal decrease of 37.1% in the LDL-C:HDL-C ratio was achieved with 60 mg fluvastatin monotherapy, and a further lowering was not seen during combination therapy. Triglycerides: In cohort 1, triglyceride levels were lowered by 17.2% (p <0.05) during 20 mg/ day fluvastatin plus bezafibrate, which represented an additional decrease to the reductions already seen during monotherapy. Triglyceride levels declined even further (23.5% relative to baseline) in those receiving 40 mg/day fluvastatin plus bezafibrate at week 60. In contrast, although triglycerides fell by ll-17% in cohort 2 during monotherapy, they rose to baseline levels following the addition of cholestyramine. In the subgroups that received 60 mg fluvastatin, the greatest triglyceride response-a 34% reduction-was seen with 40 mg/day fluvastatin plus bezafibrate in cohort la at week 60. At week 48, triglycerides were reduced by 21.7% in cohort la. During monotherapy, no clear relation between dose and triglyceride response was noted in either subgroup. With 60 mg fluvastatin, the 6.5% fall relative to baseline in cohort la was similar to the 6.4% decline observed in cohort 2a. After the addition of cholestyramine in cohort 2a, triglycerMAY 26, 1994

8

124.9

53.44

45.45

2.05

10.44

31.19

30.68

45.19

2.37

7.56

53.13

3.3

-20.4

4.1

-17.7

-13.8

-6.9

-24.6

8.5

- 19.2

-15.0

Mean% Changet

14.75

7.38

13.38

7.78

7.83

23.69

10.50

12.37

5.04

5.79

SD

Endpoint for 20 mg FL

-13.3

-33.0

16.2

-22.9

-17.8

- 15.3

-41.7

25.3

-28.5

-21.2

Mean % Changet

-6.4

-37.1

13.2

-29.0

-22.7

-6.5

-44.8

17.7

-36.1

-27.6

Mean % Changet

10.98

8.62

10.57

10.66

9.21

21.15

13.23

17.53

12.16

10.56

SD

Endpoint for 60 mg FL

-21.7

3.2

-22.2

5.2

-18.3

-14.3

2.6

-34.0

11.5

-28.8

27.62

10.60

8.88

11.47

10.96

25.95

16.31

20.41

10.74

9.61

SD

Week 42 40 mg FL Monotherapy Mean % Change?

of mean percent changes across timepoints.

21.75

8.82

15.90

8.29

8.75

14.47

13.53

16.74

10.79

8.12

SD

Endpoint for 40 mg FL

*Baseline: week 4 of forced-titration study. tChange from forced-titration study baselme. $p Values from repeated measures analysis for testing equality BEZA = bezahbrate; CME = cholestyramlne; FL = fluvastatin. See Table I forotherabbteviations.

Triglycerides (mgldL1

8

8.3

37.3

8

HDL-C (mg/dL)

LDL-C (FriedewaldUHDL-C

ratio

292.3

8

8

354.6

132.7

LDL-C (Friedewald) (mg/dL)

7

Total cholesterol (mg/dL)

Cohort 2a (CME)

Triglycerides (mg/dL)

7.9

36.9

7

7

ratio

HDL-C (mg/dL)

LDL-C (FriedewaldUHDL-C

344.1

280.7

7

7

LDL-C (Friedewald) Img/dL)

N

Total cholesterol (mg/dL)

Cohort la (BEZA)

Parameter (unit)

Forced-Titration Study Baseline ~ Mean SD

TABLE III Changes in Lipid and Lipoprotein Levels over 56 Weeks in Cohorts la and 2a*

12.1

-31.8

12.1

-24.2

-17.5

-21.7

-46.8

31.1

-30.1

-23.1

Mean % Changet

27.52

15.17

8.27

14.44

11.13

33.33

7.56

7.13

11.78

13.32

SD

Week 48 20 mg FL in Combination

-9.2

-21.2

6.4

-16.9

-14.1

23.3

-38.5

15.2

-30.3

-20.8

Mean % Change?

15.35

8.70

12.55

6.81

5.82

27.05

14.83

16.34

15.22

12.34

SD

Week 54 40 mg FL Monotherapy

11.4

-34.6

13.4

-27.4

-20.3

-34.0

-50.5

24.8

-38.5

-31.0

Mean % Changet

28.42

13.13

18.81

10.11

9.74

12.67

9.00

17.15

12.31

12.24

SD

Week 60 40 mg FL in Combination

0.1044

0.0011

0.1093

0.0047

0.0681

0.0003

0.0001

0.0457

0.0002

0.0003

p Value*

TABLE IV Compliance with Fluvastatin by Cohort Treatment

Week

Cohort 1 (mean + SD)

Cohort 2 (mean + SD)

97.7 2 98.7 k 98.5 k 99.3 f

FL 40 mg

95.8 + 6.0

95.1 f 4.8 96.0 lr 5.8 84.9 f 28.3 87.4 f 24.2 95.5 + 6.3

FL 40 mg + 400 mg BEZA

95.2 t 9.7 -

92.1 f 24.9

16

FL 20 mg

20 42 48 48 54 60 60

FL 40 mg FL 40 mg FL 20 mg + 400 mg BEZA

4.6 3.6 4.0 7.4

FL20mg+8gCME

FL40mg+8gCME

-

Forabbreviations, seeTables II and Ill.

ides increased by 12.1% at week 48 and by 11.4% at week 60. Compliance: Full details on patient adherence to the study medications have been reported elsewhere.13-l5Compliance with fluvastatin was good, generally exceeding 90%. Only a few noncompliant patients were identified, with compliance slightly but consistently lower in cohort 2 than in cohort 1. During the combination therapy periods, compliance with cholestyramine was significantly lower than that with bezafibrate. As many as 4O-50% of patients in cohort 2 did not take the full 8 g dose of cholestyramine, whereas only ll-16% of patients in cohort 1 did not take bezafibrate as prescribed. In the subgroups, patients who were noncompliant with fluvastatin were identified only in cohort 2a (1 patient at week 42 and another patient at week 50). As was observed for the main cohorts (Table IV), mean compliance with fluvastatin was consistently lower in cohort 2a than in cohort la. Tolerablllty and sapiety: During the entire 60week observation period, the most frequent clinical adverse experiences were gastrointestinal disorders. With combination therapy, no single adverse event occurred in >2 patients, and there were no discontinuations consequent to adverse events. At the end of the full combination therapy period, there were no statistically significant differencesbetween the cohorts in the primary biochemical safety parameters: aspartate and alanine aminotransferases and creatine kinase. No patient experienced increases of > 2 times the upper limit of normal in alanine aminotransferase or aspartate aminotransferase or elevations of > 10 times the upper limit of normal in creatine kinase. Detailed tolerability and safety data from the individual trials have been reported elsewhere.13-l5 DlSCUSSlON

The first entirely synthetic HMG-CoA reductase inhibitor, fluvastatin, has proved to be effec36D

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tive, safe, and well tolerated over the long term when used alone at dosagesup to 60 mg/dayi4J5 or in combination with either bezafibrate, 400 mg every morning, or cholestyramine, 8 g/day,13 in patients with heterozygous familial hypercholesterolemia. The results of this cohort analysis have shown that at the end of week 60, the mean plasma LDL-C level had decreased significantly, by 35% with fluvastatin plus bezafibrate and by 31% with fluvastatin plus cholestyramine, and the mean plasma HDL-C level had increased significantly, by approximately 21-29% and 12-14%, respectively. These differences in efficacy between the 2 cohorts were related to the blunted response to earlier monotherapy with 40 mg fluvastatin seen in cohort 2. Such a difference may partially reflect the inclusion in cohort 2 of fewer female patients, who have been previously reported to have an enhanced response to fluvastatin monotherapy.17Also not to be overlooked is the consistently lower compliance with fluvastatin in cohort 2, which probably also contributed to the observed differences in response to monotherapy. The differences in response observed in the 2 subgroups, cohorts la and 2a, stemmed from differences in gender distribution and compliance similar to those noted in the main cohorts. It is also conceivable that the differential response to fluvastatin monotherapy may reflect genotypic variations that are expressed phenotypitally as greater or lesser sensitivity to all agents that act by inhibiting the enzyme HMG-CoA reductase. When comparing the combination regimens, it must also be taken into account that a sizable proportion of patients in cohort 2 were noncompliant with cholestyramine and that this cohort had previously shown blunted LDL-C and HDL-C responses to fluvastatin monotherapy. It is apparent that the combination treatments can be considered equally effective in producing further reductions in LDL-C and additional increases in HDL-C relative to monotherapy and that better compliance with cholestyramine might possibly have yielded enhanced responses in cohort 2. However, one major difference between the 2 combination regimens is noteworthy: Fluvastatin plus bezafibrate yielded a maximal decrease of 23.5% in triglyceride levels, whereas triglycerides increased insignificantly, by 8.2%, with fluvastatin plus cholestyramine. Thus, it appears that fluvastatin synergistically augmented the expected triglyceridelowering action of bezafibrate and largely attenuated the so-called paradoxical triglyceride increase that is usually observedwith resins alone.‘O

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As has been reported previously,13 the combination of fluvastatin with bezafibrate in our trial was associated with a low rate of laboratory abnormalities and few minor adverse events, mainly in the gastrointestinal system. The unique biopharmaceutical profile of fluvastatin theoretically supports the safety results obtained in our experience with fluvastatin-bezafibrate combination therapy. Fluvastatin has the shortest systemic exposure time (1.2 hours), no active circulating metabolites, almost complete liver extraction (95%) and is hydrophilic, thereby minimizing tissue penetration. When fluvastatin is dosed 12 hours apart from bezafibrate, the biopharmaceutical profile of fluvastatin should minimize systemic (i.e., nonhepatic) tissue interactions. Although a 1Zweek trial is too short to provide definitive answers to safety questions, these results corroborate a recent report of the safety of long-term treatment with a bezafibrateHMG-CoA reductase inhibitor combination.9 In conclusion, our cohort analysis suggests that the combination of fluvastatin and either cholestyramine or bezafibrate is a valuable approach to controlling plasma lipid and lipoprotein levels in patients with severe hypercholesterolemia in whom goal lipid levels are not achieved with monotherapy alone. We recommend that patients with familial hypercholesterolemia first be treated with fluvastatin, 40 mg/day. If the desired lipid profile modifications are not accomplished with monotherapy, a resin should be added next. This regimen can be continued if it successfully controls lipid levels and if the patient reliably takes the resin as prescribed. However, in light of the 50% frequency of noncompliance with resin treatment seen in our study, an alternative combination regimen that is more tolerable to patients is clearly necessary. In our trial, the combination of fluvastatin and bezafibrate emerged as superior in efficacy and tolerability to that of fluvastatin and cholestyramine. However, it should still be regarded as a second-line approach in light of the precautions to be taken against the possible development of myopathy or rhabdomyolysis with fibrates alone or in combination with other HMGCoA reductase inhibitors. Numerous other studies using other HMG-CoA reductase inhibitors in combination with a fibrate suggest that this combination is efficacious and safe if patients are selected appropriately (excluding those with renal insufficiency, for example) and monitored carefully, particularly if they are receiving concomitant therapy with medications linked to the development of myositis or rhabdomyolysis.1,5-9JgX

At present > a dozen of these studies indicate that the incidence of creatine kinase elevations > 10 times the upper limit of normal is I 1% and the prevalence of hepatic enzyme elevations > 3 times the upper limit of normal is substantially < 1%.1,5-9J8-21~“-26 These biochemical changes were confined to 3 studies in which the combination of lovastatin and gemtibrozil was used. Further studies are needed to establish the long-term efficacy and safety of combined treatment with fluvastatin and a fibrate. In our center, a long-term study of combination treatment with fluvastatin and fibrates in patients from both cohorts in this analysis has now been under way for more than 2 years, and careful monitoring of these patients has revealed no notable safety concerns. Acknowledgment: We are indebted to Beverly Raleigh and Munish Mehra from Clin Trials Research, Inc. for the statistical analyses.

REFERENCES l. East C, Bilheimer DW, Grundy SM. Combination therapy for familial combined hyperlipidemia. Am I&m Med 1988;109:2.%32. 2. Contermans J, Erkelens DW. Combination drug therapy in the treatment of severe hyperlipidaemia. Athemchssir 1992;97:S21-S26. 3.Bilheimer DW, Gmndy SM, Brown MS, Goldstein JL. MevinoIin and colestipol stimulate receptor mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes. hc NatlAcad Sci (IS.4 1983;80:41244128. 4. Witztum JL, Simmons D, Steinberg D, Beltz WF, Weinreb R, Young SG, Lester P, Kelly N, Juliano .I. Intensive combination drug therapy for familial hypercholesterolemia with lovastatin, probucol and colestipol hydrochloride. Cimhion 1989;79:&28. 5. Illingwortb R, Bacon S. Influence of lovastatin plus gemfibrozil on plasma lipids and lipoproteins in patients with heterozygous familial hypercholesterolemia. Circulation 1989;79:59C-596. 6. Glueck U, Speirs .I, Tracy T. Safety and efficacy of combined gemfibrozilovastatin therapy for primary dyslipoproteinemia. .I Lab C/h Md 1990,115:603-

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7. Wiklund 0, Angelin B, Bergman M, Berglund L, Bondjers G, Cadsson A, Linden T, Miettinen T, Odman B, Olofsson S-O, Saarinen I, SipiIa R, Sjostrom P, Kron B, Vanhanen H, Wright I. Pravastatin and gemfibrozil alone and in combination for the treatment of hypercholesterolemia. Am J Med 1993;94:1> 20. &Da Co1 PG, Fonda M, Fisicaro M, Ton&o M, VaIenti M, Cattin L. Tolerability and efficacy of combination therapy with simwstatin plus gemfibrozil in type IIb refractory familial combined hyperlipidemia. Curr Ther Res 1993;53:47343. 9. Deslypere JP. Addition of fibrates to simvastatin therapy in bypertipidaemic patients. Athmscfemis 1992;97:S67-S71. 10. BeiI U, Grouse JR, Einarsson K, Gmndy SM. Effects of interruption of the enterohepatic circulation of bile acids on the transport of vety low density lipoprotein triglycerides. Metab&m 1982;31:438+4. ii. MastagIia FL. Adverse effects of drugs on muscle. Drugs 1982;24z304-321. 12. Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA 1990,264:71. 13. Leitersdorf E, Muratti EN, Eliav 0, Meiner V, Eisenberg S, Dann EJ, Sehayek E, Peters TK, Stein Y. Efficacy and safety of a combination fluvastatiw bezalibrate treatment for familial hypercholesterolemia: comparative analysis to a fluvastatin-cbolestyramine combination. Am .I Med 1994;96:(in press). l4. Leitersdorf E, Eisenbcrg S, EIiav 0, Friedlander Y, Be&man N, Dann EJ, Landsberger D, Sehayek E, Meiner V, Wurm M, Bard JM, Fruchart JC, Stein Y. Differential response of plasma cholesterol to fluvastatin, a new HMG CoA reductase inhibitor, in three groups of genetically defined heterozygote patients with familial bypercholesterolemia. Cimdatim 1993;87(Suppl III):71-78. 15. Leitersdorf E, Eisenberg S, Eliav 0, Berkman N, Dann El, Landsberger

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D, SehayekE, Meiner V, Peters TK, Muratti EN, Bard JM, Fruchart JC, Stein Y. EfIicacy and safety of high dose of fluvastatin in patients with FH. Ew J C!k Phannacol1993;453513-518.

l2. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low density lipoprotein cholesterol in plasmawithout use of the preparative ultracentrifuge. Clin C/rem 197~18:49%502. 17. Peters TR, Muratti EN, Mehra M. Efficacy and safety of tluvastatin in women with primary hypercholesterolaemia.Drugs 1!%4;47(Suppl11)&t-72. 22. Grag A, Grundy SM. Gemtibrozil alone and in combination with lovastatin for treatment of hypertriglyceridemia in NIDDM. Diabetes 1989;38:364-372. l2. Ilhngworth DR, O’MaUey JP. The hypolipidemic effects of lovastatin and clofibrate alone and in combination in patients with type III hyperlipoproteinemia.hfe&wlirm 1990,39:403-409. 22.Lintott CI, Scott RS, Sharpe DN, Nye ER, Charleson H, French JR, White HD, Reuben S, Malmg TJ, Lewis GR, Sutherland WF, Robertson MC, Prampton C. Treatment of primary hypercholesterolemia with simvastathr New Zealand muhicenter evaluation.Med JAwt 1991;155:43+l36.

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2LLintott CI, Scott RS, Nye ER, Robertson ML, Sutherland WI-IF. The hypolipidaemic effects of pravastatin (CS-514) alone and in combination with beratibrate or acipimox in patients with primary hypercholesterolaemia.Diabetes Nt&Metab 1991;4:117-122. 22. Horsmans Y, Desager JP, Harvengt C. Effects of combined bezaftbrate simvastatinappraisedin healthy subjects.J Clin Pharmacol lW,32:422426. 22. Glueck CT, Oakes N, Speirs J, Tracy T, Lang J. Gemfibroxi-kwastatin therapy for primary hyperlipoproteinemias.Am J Cardiol199&7031-9. 24. Wirebaugh SR, Shapiro ML, Mclntyre TH, Whitney ET. A retrospective review of the use of lipid-lowering agentsin combination, specificrdly,gemhbroziI and lovastatin.Phamtacothempy 1992,12:445450. 22. FeussnerG, Eichmger M, Ziegler R. The influence of simvastatinalone or in combination with gemfibroxil on plasma lipids and lipoproteins in patients with type III hyperlipoproteinemia. ChinInvest 1992;70:1027-1035. 26. Yeshurun D, Abukarshin R, Elias N, Ianii A, Naschitz JE. Treatment of severe,resistant familial combined hyperlipidemia with a berafibrate-Iovastatin combination. C[in 77ter1993;15:355-363.

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