Efficacy and tolerability of fluvastatin extended-release delivery system: a pooled analysis

CLINICAL THERAPEUTICSVVOL. 23, NO. 2,200l

Efficacy and Tolerability of Fluvastatin Extended-Release Delivery System: A Pooled Analysis Christie M. Ballantyne, MD,’ Franc0 Pazzucconi, MD,2 Xavier Pintb, MD, PhD,3 John P. Reckless, MD,4 Evan Stein, MD, PhD,s James McKenney, PharmD,6 Michele Bortolini, MD,’ and Yann Tong Chiung, PhD8 ‘Baylor Colleg e of Medicine, Houston, Texas, 20spedale Niguarda Ca’Granda, Centro E Grossi-Paoletti, Padiglione Vergani, Piazza Ospedale Maggiore, Milan, Italy, 3Ciutat Sanitaria i Universitaria de Bellvitge, Unidad de Arteriosclerosis, Servicio de Medicina Interna, Hospitalet de Llobregat, Barcelona, Spain, 4Royal United Hospital, Bath, United Kingdom, sMedical Research Laboratories, Highland Heights, Kentucky, 6National Clinical Research Inc, Richmond, Virginia, ‘Novartis Pharma AG, Basel, Switzerland, and 8Novartis Pharmaceuticals Corporation, East Hanover New Jersey

ABSTRACT

Background: At high doses, the pharmacokinetics of fluvastatin immediate-release (IR) are nonlinear, possibly due to saturation of hepatic uptake. Fluvastatin delivery to the liver in a slower but sustained fashion would be expected to avoid hepatic saturation without elevating systemic drug levels. Objective: This pooled analysis compared the efficacy and tolerability of extendedrelease (XL) 80-mg and IR 40-mg formulations of fluvastatin in lowering low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels and raising high-density lipoprotein cholesterol (HDL-C) levels in patients with hypercholesterolemia. Methods: Data were pooled from 3 double-blind, randomized, active-controlled, multicenter, parallel-group studies that compared changes in lipid and apolipoprotein levels with fluvastatin XL 80 mg at bedtime (HS) with changes in fluvastatin IR 40 mg HS or BID in patients aged 218 years with primary hypercholesterolemia (consistently elevated LDL-C level [a160 mg/dL] and plasma TG levels 5,400 mg/dL). The primary efficacy variable was percent change in LDL-C from baseline. Results: The pooled analysis provided an intent-to-treat efficacy study population of 1674 patients. At 4 weeks, fluvastatin XL 80 mg HS reduced LDL-C levels by a mean of 36.3% (median 38%), significantly greater than a mean reduction of 25.9% (median 27%) seen with fluvastatin IR 40 mg HS, and an incremental additional mean reduction in LDL-C of 10.4% (P < 0.001). At 4 and 24 weeks, fluvastatin XL 80 mg HS provided an LDL-C reduction equivalent to fluvastatin IR 40 mg BID (P c 0.001 for noninferiority). Significant, dose-related changes in HDL-C, LDL-C:HDL-C ratio, total cholesterol, TG, and apolipoprotein A-I and apolipoprotein B levels also occurred. Mean HDL-C level Accepted for publication October 31. 2000. Printed in the USA. Reproduction

0149-2918/01/$19.00

in whole or part is not permitted.

177

CLINICAL THERAPEUTICS”

increased by 8.7% and median TG level decreased by 19% with fluvastatin XL 80 mg HS (P < 0.001 and P < 0.05vs fluvastatin IR 40 mg HS, respectively). Maximum mean increases in HDL-C level (21%) and median decreases in TG level (31%) with fluvastatin XL 80 mg HS occurred in patients with type IIb dyslipidemia and the highest baseline TG. Adverse events were mild, with similar frequency in all treatment groups. Conclusions: Once-daily administration of fluvastatin XL 80 mg provides enhanced efficacy with an additional 10.4% reduction in LDL-C levels compared with fluvastatin IR 40 mg HS, and superior increases in HDL-C levels, particularly in patients with elevated TG levels (P< 0.05 vs fluvastatin IR 40 mg HS). Fluvastatin XL 80 mg HS has a good tolerability profile and is effective as starting and maintenance lipid-lowering treatment in patients with type II hypercholesterolemia. Key words: fluvastatin, extended-release formulation, hypercholesterolemia, LDL cholesterol, HDL cholesterol, triglycerides. (Clin Ther: 2001;23:177-192)

INTRODUCTION Coronary and peripheral vasculature atherosclerosis is the leading cause of death among men and women worldwide.’ There is now considerable evidence that controlling hypercholesterolemia can reduce the incidence of coronary heart disease (CHD).* The place of statins as firstline therapy in the treatment of elevated cholesterol levels is well established.3 Five large randomized clinical trials with statins have shown significant reductions in the incidence of CHD, with mean lowdensity lipoprotein cholesterol (LDL-C) reductions of 25% to 35%.4-8 Based on

178

the evidence from these clinical trials, the standard starting dose for agents in this class of drugs has been set to achieve LDL-C reductions at least in this range. Although the main focus of treatment has been directed at lowering LDL-C levels, other lipid parameters are also important, and high-risk patients with hypertension or diabetes frequently have associated abnormalities of triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) levels. Low levels of HDLC, defined in the US National Cholesterol Education Program (NCEP) guidelines as ~35 mg/dL, are often the predominant lipid abnormality among patients with CHD.9 Numerous epidemiologic studies have shown a strong inverse relationship between HDL-C levels and CHD, and a study by Rubins et allo has shown that increasing HDL-C levels may thus be beneficial in reducing CHD events. Fluvastatin is a synthetic competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase available as an immediate-release (IR) capsule. It is an effective and well-tolerated treatment for primary hypercholesterolemia, resulting in mean LDL-C reductions of ~36% over long-term treatment when given as 40 mg BID.” Fluvastatin also produces significant reductions in TG levels, apolipoprotein (apo) B levels, LDLC:HDL-C ratio, and very-low-density lipoprotein cholesterol levels and increases in HDL-C levels.” The clinical benefit of fluvastatin is reflected in the concomitant reduction in frequency of clinically relevant coronary events, including cardiac death, angina pectoris, and myocardial infarction,‘2~13 and the retardation of atherosclerosis progression.14 An extended-release (XL) 80-mg formulation of fluvastatin (80-mg matrix

C.M. BALLANTYNE

ET AL.

Table I. Summary of 3 phase III studies that assessed efficacy and tolerability extended-release (XL) versus immediate-release (IR). No. of Patients

Study Olsson et ali’

Data on filei

Data on filei

Treatment

Randomized

Pluvastatin XL 80 mg HS Pluvastatin IR 40mgHS Pluvastatin IR 40 mg BID

346

Pluvastatin XL 80 mg HS Pluvastatin IR 40 mg HS

370

Pluvastatin XL 80 mg HS Pluvastatin IR 40 mg HS Pluvastatin IR 40mgBID

141

No. of Centers

Tteatment Duration

51

24 weeks

of fluvastatin

Population

174

White (Czech Republic, Germany, Italy, The Netherlands, Poland, Spain,

175

United

Sweden,

Switzerland, Kingdom)

30

24 weeks

Mixed population (United States)

29

24 weeks

Mixed population (United States, Canada, Australia, South Africa, Turkey)

185

146 155

HS = at bedtime.

tablet)* with an 8-hour release rate for oncedaily administration has been developed. It was recently approved by the US Food and Drug Administration as an adjunct to diet to reduce elevated total cholesterol (TC), LDL-C, TG, and apo B levels and to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson type IIa or IIb). Three phase III studies of 24 weeks’ treatment have been conducted to assess the long-term efficacy and tolerability of the XL 80-mg formulation of fluvastatin, compared with fluvastatin IR 40 mg administered at bedtime (HS) or BID, in pa*Trademark: Lescol@ XL (Novartis Switzerland).

Pharma,

Basel,

tients with primary hypercholesterolemia with or without moderate hypertriglyceridemia (Fredrickson type IIa or IIb) (Table I).15-t7 In the present study, a pooled analysis was performed on data from these 3 trials, with an emphasis on lipid changes in the overall study population as well as in different clinically relevant subgroups.

METHODS Patients The phase III program evaluating the 80-mg dose of the XL formulation of fluvastatin consisted of 3 phase III studies. Study participants were aged ~18 years with primary hypercholesterolemia (Fred-

179

CLINICAL THERAPEUTICS”

rickson type IIa or IIb) and showed a consistently elevated LDL-C level (~160 mg/dL) and a plasma TG level 5400 mg/dL at each of 2 visits during the dietary lead-in period. All patients were following a low-saturated fat and lowcholesterol diet initiated ~4 weeks before the lead-in period (European Atberosclerosis Society or NCEP Step I or II). The main exclusion criteria were homozygous familial hypercholesterolemia; types I, III, IV, or V or secondary hyperlipoproteinemia; diabetes mellitus; body mass index >35 kg/m*; pregnancy or lactation; or hepatic or renal impairment. Also excluded were patients who had had myocardial infarction; major surgery or angioplasty during the previous 6 months; unstable congestive heart failure (severe [New York Heart Association functional class IV], complicated, uncontrolled by treatment, or rapidly progressing); unstable angina pectoris or severe stable angina (based on intensity of pain/discomfort and level of exertion at which symptoms occurred); poorly controlled (still requiring drug-regimen adjustments to achieve optimal goals) or uncontrolled (despite maximal multiregimen doses) hypertension; or prior or current muscle disease. Study Design The 3 studies had a double-blind, randomized, active-controlled, multicenter, parallel-group design (Table I). The studies were performed in accordance with the Declaration of Helsinki and its subsequent amendments. Local ethics committees approved the study protocols, and all patients gave written informed consent. The primary efficacy variable was percent change in LDL-C level from baseline. Secondary efficacy variables were changes

180

from baseline in the following lipid parameters: TC, HDL-C, TG, LDL-C:HDL-C ratio, apo A-I, and apo B. After the 4-week diet/placebo lead-in period and fulfillment of the entry criteria, patients were randomized in 2 studies to 1 of 3 treatment groups: fluvastatin XL 80 mg HS, fluvastatin IR 40 mg HS, or fluvastatin IR 40 mg BID (HS and before or with breakfast). In 1 study,15 patients were randomized to fluvastatin XL 80 mg or IR 40 mg HS. The dosage forms (tablets for fluvastatin XL or capsules for fluvastatin IR) required the use of double-dummy blinding procedures. Patients were assessed at the beginning of the diet/placebo period and 2 weeks later (weeks 4 and -2), at the beginning of the active-treatment period (week 0), at weeks 2 and 4, and every 4 weeks for the following 24 weeks. In all 3 studies, an extra visit was also allowed at week -1 to assess patients who had not previously met the entry criteria. Tolerability was assessed by continuously evaluating new and worsening adverse events, as well as laboratory abnormalities, including notable alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations (>3 times upper limit of normal [ULN] on 2 consecutive visits) and creatine kinase (CK) elevations (210 times ULN), standard safety measures such as electrocardiogram abnormalities, and rate of dropout due to adverse events or laboratory abnormalities. Causation and severity of adverse events were assessed by the investigators while blinded to treatment allocation during the course of the study according to predefined guidelines, which included a 3point scale of increasing severity (mild, moderate, severe) and 2 options for causal relationship (suspected, not suspected). In particular, a severe adverse event was de-

CM.

BALLANTYNE

ET AL.

fined as any event causing severe discomfort or inability to continue in the trial or requiring cessation of study treatment, treatment of the event, or hospitalization. A suspected adverse event implied a reasonable temporal relationship of the event to study drug administration, a known or expected response pattern to the study drug, and insufficient explanation for the observed event by other drugs or therapeutic interventions or underlying conditions.

Statistical Analysis Overall efficacy of fluvastatin XL 80 mg HS was assessed by a pooled analysis of the 3 phase III trials and was compared with that of fluvastatin IR 40 mg HS or BID. The raw data from the original database of the 3 trials were pooled in a straightforward fashion, and statistical methods used for the analysis of each individual study were applied to the pooled analysis. The sample size in the 2 trials that included a fluvastatin IR 40-mg BID group was based on the null hypothesis that the treatment effect of fluvastatin XL 80 mg HS on percentage reduction in LDL-C from baseline was not ~5% less than that of fluvastatin IR 40 mg BID, versus the alternative hypothesis that the difference between the 2 groups was ~5%. In these studies, sample size was adequate to provide ~90% power to the noninferiority test. In each of the 3 studies, the power to detect a difference between fluvastatin XL 80 mg HS and fluvastatin IR 40 mg HS of ~6% was also ~90%. A 2-way analysis of variance with treatment and trial as factors was used to compare least-squares mean percent change from baseline in lipid variables between treatment groups. For the week-24 analyses of all lipid variables (ie, all random-

ized patients for whom measurements were recorded both at baseline and at week 24), a 2-sided test for the differences between treatment groups was used. Two-sided 95% CIs were calculated for between-treatment differences for all efficacy variables. For all efficacy variables except apo A-I and apo B, baseline was defined as the mean of the value at week 0 and the most recent previous value. For apo A-I and apo B, week 0 values, the only measurement obtained before treatment, were used as the baseline. The median percent change from baseline in TG at week 24 was compared between 2 treatment groups by testing the null hypothesis that median, was equal to median, versus the alternative hypothesis that median, was different from median,, where median, and median, denote the true population medians for the 2 treatment groups, respectively. The Wilcoxon ranksum test was used to obtain the P value for the null hypothesis. The null hypothesis was rejected if P was ~0.05. The analysis was performed for all randomized patients overall and by baseline TG levels (~200 mg/dL, 200-299 mg/dL, and 2300 mg/dL). LDL-C goal achievements at week 24 were assessed using the Fisher exact test comparing the proportion of patients achieving treatment goal between the treatment groups for each risk category in the overall population and in subgroups by baseline LDL-C. RESULTS

EfJicw A total of 1692 patients were randomized in the 3 trials; demographic characteristics were similar between the groups. Patients’ mean age was -56 years (range,

181

CLINICAL THERAPEUTICS”

18 to 87 years); 74% were aged ~65 years, 92% were white, and 53% were women (Table II). The pooled analysis of the 3 trials provided an intent-to-treat efficacy study population of 1674 patients, of whom 849 were randomized to fluvastatin XL 80 mg HS, 500 to fluvastatin IR 40 mg HS, and 325 to fluvastatin IR 40 mg BID.

Low-Density

Lipoprotein

Cholesterol

The LDL-C-lowering effect of fluvastatin was apparent after 2 weeks of treatment, and the full effect was observed within 4 weeks of treatment initiation. After 4 weeks of treatment with fluvastatin XL 80 mg HS, LDL-C levels were reduced by a mean of 36.3% (from 195.7 mg/dL at baseline to 124.5 mg/dL), significantly greater reductions than obtained with fluvastatin IR 40 mg HS (25.9%; from 196.7 mg/dL to 145.8 mg/dL), an incremental additional reduction in mean LDL-C of 10.4% (P < 0.001; 95% CI, -11.7 to -9.1) (Table III). The benefits were sustained at 24 weeks (Table IV). At both 4 and 24 weeks, fluvastatin XL 80 mg HS provided as much LDL-C reduction as fluvastatin IR 40 mg BID. Patients treated with fluvastatin XL 80 mg achieved consistently higher responder rates. After 4 weeks, more than half the patients in the fluvastatin XL 80-mg HS group (58%) and the fluvastatin IR 40-mg BID group (59%) achieved LDL-C reductions ~35% compared with only 20% of the fluvastatin IR 40-mg HS group. Moreover, LDL-C reductions of ~40% were achieved by 40% of patients in the fluvastatin XL 80-mg HS group, 43% of patients in the fluvastatin IR 40-mg BID group, and only 9% of patients in the fluvastatin IR 40-mg HS group (Figure 1).

182

As shown in Table V, after stratification by risk status at study entry according to NCEP guidelines, t8 for primary prevention, 85% of patients with <2 risk factors for CHD and 61% of patients with ~2 risk factors for CHD treated with fluvastatin XL 80 mg HS achieved their respective target LDL-C levels of < 160 mg/dL and ~130 mg/dL at 24 weeks, compared with 68% and 38% of those receiving fluvastatin IR 40 mg HS (P < 0.05). In the subgroup of patients with moderate elevations of LDL-C at baseline (s 190 mg/dL), the percentages of primary-prevention patients achieving their target LDL-C with fluvastatin XL 80 mg HS were 95% and 75% in the respective NCEP risk categories, compared with 87% and 5 1% with fluvastatin IR 40 mg HS (P < 0.05) (Table V). In patients with CHD treated with fluvastatin XL 80 mg HS, 19% achieved the NCEP goal of LDL-C s 100 mg/dL, compared with 2% treated with fluvastatin IR 40 mg HS (P < 0.05).

High-Density

Lipoprotein

Cholesterol

Fluvastatin XL 80 mg HS was effective in raising HDL-C levels. In patients overall, HDL-C increased by a mean of 8.7% after 24 weeks’ treatment with fluvastatin XL 80 mg HS, compared with 5.9% with fluvastatin IR 40 mg HS (P < 0.001) and 7.4% with fluvastatin IR 40 mg BID. As shown in Figure 2A, the increase in HDL-C was related to baseline TG levels, rising from 6.6% in patients in the fluvastatin XL 80-mg HS group with baseline TG ~200 mg/dL, to 12.1% in patients with baseline TG 200-299 mg/dL, to 2 1.1% in patients with baseline TG 2300 mg/dL (P < 0.05 vs fluvastatin IR 40 mg HS in the 200-299-mg/dL and a300-mg/dL groups). The difference between fluva-

CM. BALLANTYNE

ET AL.

Table II. Summary of patient demographic and clinical characteristics at baseline for all randomized patients. Fluvastatin IR

Fluvastatin XL Variable

80 mg HS (n = 857)

40 mg HS (n = 505)

40 mg BID (n = 330)

57.0 f 11.2

56.6 + 11.9

55.7 + 10.6

As Mean f SD, y

21-87

18-85

20-82

235 (27.4)

137 (27.1)

70 (21.2)

406 (47.4)

227 (45.0) 278 (55.0)

157 (47.6)

451 (52.6)

White

783 (9 1.4)

465 (92.1)

306 (92.7)

Black

34 (4.0)

15 (3.0)

Other

40 (4.7) 691 (80.6)

25 (5.0)

2 (0.6) 22 (6.7)

413 (81.8)

279 (84.5)

334 (39.0) 114 (13.3)

194 (38.4) 73 (14.4)

147 (44.5)

271 (31.6)

139 (27.5)

99 (30.0)

368 (42.9) n = 849

209 (4 1.4)

161 (48.8)

195.7 + 36.1

196.7 + 38.8

282.2 + 37.8

282.7 + 39.6 51.9 + 12.3

283.1 * 40.1

51.8 * 11.9 173.6 f 68.1

171.1 + 65.7

172.6 f 69.0

4.0 + 1.2 151.2 f 24.7

151.0 f 25.9

180.2 + 27.7

180.4 f 31.3

Range, y No. (%) of patients aged 265 y Sex, no. (%) Male Female

173 (52.4)

Race, no. (%)

Mean body mass index ~30 kg/m*, no. (%) History of CHD, no. (%) r2 CHD risk factors without CHD, no. (%) Proportion no. (%) Prior treatment with HMG-CoA inhibitors, no. (%) Mean + SD lipid values, mg/dL* LDL-C TC HDL-C TG LDL-C:HDL-C Apo A-I’ Apo B+

41 (12.3)

with type IIb dyslipidemia,

ratio

reductase n=500

4.0 2 1.3

n = 325 197.4 + 37.3 51.0 f 11.5 4.0 f 1.3 149.5 * 25.1 180.9 + 29.0

XL = extended-release; HS = at bedtime; IR = immediate-release; CHD = coronary heart disease; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A: LDL-C = low-density lipoprotein cholesterol; TC = total cholesterol; HDL-C = high-density lipoprotein cholesterol; TG = triglycerides; apo = apolipoprotein. *Categories included only patients in the intent-to-treat analysis (n = 1674); risk factors were defined as in the US National Cholesterol Education Program guidelines’8 (age a45 years in men, a55 years or premature menopause without estrogen-replacement therapy in women; family history of premature CHD; current cigarette smoking; hypertension [r140/90 mm Hg or taking antihypertensive medication]; low HDL-C [<35 mg/dL]; diabetes mellitus; high HDL-C [a60 mg/dL] counted as a negative risk factor). +n = 818, 477, and 301 for fluvastatin XL 80 mg HS, fluvastatin IR 40 mg HS, and fluvastatin IR 40 mg BID, respectively.

183

CLINICAL

statin XL 80 mg and fluvastatin IR 40 mg HS was more striking in patients with elevated TG levels. By comparison, HDL-C increases with fluvastatin IR 40 mg HS in the respective TG subgroups were 5.5%, 7.0%, and 10.4%. HDL-C increases were 6.2%, 9.9%, and 8.2% with fluvastatin IR 40 mg BID. In patients with HDL-C levels ~35 mg/dL and TG levels 9200 mg/dL,

THERAPEUTICS”

the mean increase in HDL-C was 16% with fluvastatin XL 80 mg HS. Triglycerides After 24 weeks of treatment, the median percent decreases in TG levels in the overall population were 19% in the fluvastatin XL 80-mg HS group (P < 0.05 vs

Table III. Least-squares means (SE) and median reductions in low-density cholesterol levels achieved with fluvastatin after 4 weeks. Fluvastatin

Fluvastatin XL Parameter Least-squares

mean

lipoprotein

IR

80 mg HS

40 mg HS

40 mg BID

(n = 835)

(n = 492)

(n = 315)

-36.3

Median

(0.43)*

-25.9

-38

(0.53)

-35.9

-27

(0.70)’ -38

XL = extended-release; HS = at bedtime; IR = immediate-release. ‘P < 0.001 versus fluvastatin IR 40 mg HS for superiority (2-way analysis of variance with treatment and trial as factors). +P c 0.001 versus fluvastatin IR 40 mg BID for noninferiority (2-way analysis of variance with treatment and trial as factors).

Table IV. Least-squares to week 24.

means (SE) for percent change in lipid parameters

Fluvastatin Parameter

LDL-C:HDL-C

40 mg HS

40 mg BID

(n = 750)

(n = 450)

(n = 272)

(0.49)*

8.7% (0.50):

HDL-C ratio

IR

80 mg HS

-33.7%

LDL-C

Fluvastatin

XL

from baseline

-24.6% 5.9%

(0.61) (0.62)

-33.3% 7.4%

(0.82) (0.83)

-38.1%

(0.54)*

-28.1%

(0.67)

-37.4%

(0.90)

TC

-23.9%

(0.37)*

-17.4%

(0.46)

-24.1%

(0.62)

TG

-14.0%

(1.05)+

-9.6%

(1.30)

-15.4%

(1.76)

Apo A-I Apo B

8.2% (0.47)+ -25.3%

(0.46)*

6.2% -18.3%

(0.59) (0.57)

7.1% -25.2%

(0.79) (0.77)

XL = extended-release; HS = at bedtime; IR = immediate-release; LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol; TC = total cholesterol; TG = triglycerides; apo = apolipoprotein. *P < 0.001 compared with fluvastatin IR 40 mg HS (2-way analysis of variance [ANOVA] with treatment and trial as factors). +P < 0.01 compared with fluvastatin IR 40 mg HS (2-way ANOVA with treatment and trial as factors). ‘P < 0.05 compared with fluvastatin IR 40 mg HS (2-way ANOVA with treatment and trial as factors).

184

C.M. BALLANTYNE

ET AL.

n

Fluvastatin IR 40 mg HS (n = 492) Fluvastatin IR 40 mg BID (n = 315) 0 Fluvastatin XL 80 mg HS (n = 835)

n

80 g

60

B c 40 .g z a 20

72 74

l-.I__i 59 58

43 40

39

20

9

n-

I

a40%

’

235%

-i

230%

Reduction in LDL-C

Figure

1. Patients achieving reductions in low-density lipoprotein cholesterol (LDL-C) level according to treatment group after 4 weeks of treatment. IR = immediaterelease; HS = at bedtime; XL = extended-release.

Table V. Percentage of patients achieving their National Cholesterol Education Program target low-density lipoprotein cholesterol (LDL-C) levels* at week 24.

Treatment Whole study population+ Fluvastatin XL 80 mg HS Fluvastatin IR 40 mg HS Fluvastatin IR 40 mg BID Patients with moderate hypercholesterolemia (LDL-C < 190 mg/dL) at baseline Fluvastatin XL 80 mg HS Fluvastatin IR 40 mg HS Fluvastatin IR 40 mg BID

<2 Risk Factors

22 Risk Factors

Established Coronary Heart Disease

85%$ n = 336 68% n=211 75% n= 106

61%* n= 112 38% n = 69 69% n = 39

19%$ n = 300 2% n= 170 18% n= 126

95%$ n= 178 87% n= 110 90% n=51

75%$ n = 61 51% n = 47 78% n = 23

25%$ n= 169 3% n = 93 26% n = 72

XL = extended-release; HS = at bedtime; IR = immediate-release. *Treatment targets are LDL-C ~160 mg/dL for patients with no atherosclerotic disease and <2 risk factors; LDL-C ~130 mg/dL for patients with no atherosclerotic disease and r2 risk factors; and LDL-C ~~100mg/dL for patients with atherosclerotic disease. tn = number of patients in each risk category in each treatment group. $P < 0.05 versus fluvastatin IR 40 mg HS (2-sided Fisher’s exact test).

185

CLINICAL THERAPEUTICS”

A

n

‘?; 6

Fluvastatin IR 40 mg HS W Fluvastatin IR 40 mg BID 0 Fluvastatin XL 80 mg HS

25

:1

10 6

i

t

21 15

“=

All

c200

200-299

1 36

a300

Baseline TG (mg/dL)

n

Fluvastatin IR 40 mg HS Fluvastatin IR 40 mg BID 0 Fluvastatin XL 80 mg HS

B

n

Baseline TG (mg/dL) All patients

<200

200-299

2300 21 15

36

Figure 2. (A) Increases in mean high-density lipoprotein cholesterol (HDL-C) and (B) decreases in median triglycerides (TG) in the whole patient population and according to baseline TG level after 24 weeks of treatment with fluvastatin. *P < 0.01 and +P < 0.05versus fluvastatin IR 40 mg HS; 2-way analysis of variance with treatment and trial as factors for comparisons in (A) and Wilcoxon rank-sum test for comparisons in (B). IR = immediate-release; HS = at bedtime; XL = extended-release.

186

C.M. BALLANTYNE ET AL

fluvastatin IR 40 mg HS), 19% in the fluvastatin IR 40-mg BID group, and 12% in the fluvastatin IR 40-mg HS group. Similar to the changes seen for HDL-C levels, the decrease in TG levels was greater in patients with mixed dyslipidemia and was also related to baseline TG levels, with a median reduction in TG of 24% in patients with a baseline TG level 200-299 mg/dL and 31% in patients with a baseline TG level a300 mg/dL after treatment with fluvastatin XL 80 mg HS (Figure 2B).

Other Lipid Parameters Significant and dose-ordered changes in all other lipid variables measured were observed (Table IV). The LDL-C:HDL-C ratio and TC and apo B levels were reduced by 38.1%, 23.9%, and 25.3%, respectively, in the fluvastatin XL 80-mg HS group, compared with reductions of 28.1%, 17.4%, and 18.3%, respectively, in the fluvastatin IR 40-mg HS group (all

P

0.001).

CLINICAL

table elevations in ALT or AST occurred at the last scheduled visit in 1 patient, but transaminase levels returned to normal after study completion. In the remainder, notable or nonconsecutive elevations of ALT or AST normalized while active treatment continued. Two patients, both randomized to fluvastatin IR 40 mg HS, had clinically notable (210 times ULN) but asymptomatic CK values; these values returned to normal after study-drug withdrawal. In 1 of these patients, the notable value of CK was associated with intensive physical activity in the days before the study visit. The frequency of musculoskeletal adverse events suspected and not suspected to be drug related was similar between treatment groups, with only 1 patient in each group discontinuing active therapy because of myalgia.

DISCUSSION The most commonly used approach to increasing the efficacy of an HMG-CoA reductase inhibitor is to double the dose, which typically provides an additional 6% reduction in LDL-C levels. 19,*0For example, in the Expanded Clinical Evaluation of Lovastatin (EXCEL) study,*’ doubling the dose of lovastatin from 20 mg each evening (QPM) to 40 mg QPM increased LDL-C reduction from 24% to 30%, an incremental reduction of 6%. However, that study also showed another potential mechanism for increasing efficacy-by altering delivery. Lovastatin 20 mg BID provided a 34% LDL-C reduction, an additional decrease of 10% compared with 20 mg QPM. In addition, lovastatin 20 mg BID gave significantly greater reductions in LDL-C and TG levels and greater increase in HDL-C levels than 40 mg QPM. The superior efficacy of 20 mg BID

188

THERAPEUTICS”

compared with 40 mg QPM may be explained by more prolonged inhibition of hepatic HMG-CoA reductase and provides part of the rationale for the development of an XL preparation of fluvastatin used in these studies. Because the pharmacokinetics of fluvastatin IR are nonlinear, possibly due to saturation of hepatic uptake, 22*23the maximal dose of 80 mg is administered as 40 mg BID to avoid high systemic drug levels. Fluvastatin delivery to the liver in a slower but sustained fashion would be expected to avoid hepatic saturation, providing greater hepatic availability without elevating systemic drug levels. The XL formulation should also prolong inhibition of hepatic cholesterol synthesis and thus provide efficacy similar to that seen with BID administration. Fluvastatin XL is incorporated into a hydrophilic cellulose matrix, which swells when in contact with intestinal fluid; the drug is released by diffusion over 8 hours. A pharmacokinetic study of the XL formulation in patients with primary hypercholesterolemia demonstrated linear pharmacokinetics with fluvastatin XL 80-320 mg after single and multiple oral dosing once daily.24 This suggests that the more sustained delivery of fluvastatin at these doses circumvents saturable hepatic uptake. At the 80-mg dose, systemic availability of fluvastatin XL was lower than that with an identical dose of the IR formulation given as two 40-mg capsules.25 Systemic exposure with the XL 80-mg tablet is similar to that with 1 IR 40-mg capsule daily. In the present analysis, fluvastatin XL 80 mg HS reduced LDL-C by 36.3% after 4 weeks of treatment, a 10.4% greater incremental reduction than fluvastatin IR 40 mg HS (25.9%) and approximately

C.M. BALLANTYNE

ET AL.

equal in efficacy to fluvastatin IR 40 mg BID (35.9%). Reductions in LDL-C levels of 240% were achieved in 40% of patients receiving fluvastatin XL 80 mg HS. Thus, in addition to increased efficacy, the availability of fluvastatin as an XL formulation for a once-daily starting dose of 80 mg provides a more convenient approach to dosing, which is likely to improve patient compliance and may improve the cost-effectiveness of therapy. In the present study, baseline LDL-C levels were -200 mg/dL, and many patients had multiple concomitant risk factors for CHD or a history of CHD. According to NCEP guidelines,‘* patients with no atherosclerotic disease and multiple risk factors for CHD should achieve target LDL-C levels
LDL-C level in patients with CHD, which is generally ~160 mg/dL.26 Therefore, a larger proportion of patients with CHD might be expected to receive sufficient LDL-C reductions to achieve NCEP goal in routine practice. Significant dose-ordered increases in HDL-C were seen with fluvastatin XL 80 mg HS (8.7%), compared with fluvastatin IR 40 mg HS (5.9%), and the superior efficacy of the XL formulation was more striking in patients with high TG levels. The greatest mean increase in HDL-C levels (2 1.1%) was observed in those patients with more severe hypertriglyceridemia (TG 2300 mg/dL at baseline) who often present with low baseline HDL-C levels. Dose-dependent increases in HDL-C have been described with lovastatin27 and simvastatin,28 particularly in patients with elevated TG levels. Treatment with fluvastatin led to substantial reductions in TG levels, with a significantly greater decrease in median TG in the fluvastatin XL 80-mg HS group than in the fluvastatin IR 40-mg HS group (P < 0.05). Reductions in TG levels were particularly seen in patients with mixed dyslipidemia. In these patients, median decreases of 24% and 31% were seen in patients with baseline TG levels of 200-299 mg/dL and 2300 mg/dL, respectively, treated with fluvastatin XL 80 mg HS, compared with a median decrease of 17% in patients with TG ~200 mg/dL. This finding confirms that the effects of treatment on HDL-C and TG levels depend not only on dose but also on baseline levels.29 Analysis of the pooled data did not raise any tolerability concerns with fluvastatin XL 80 mg administered as a starting dose, compared with the IR 40-mg dose. Consistent with previously reported

189

CLINICAL THERAPEUTICS”

data,30 the proportion of patients for whom treatment was discontinued because of new or worsening adverse events thought to be related to the study drug was low in all 3 treatment groups. Patients who started treatment with fluvastatin XL 80 mg did not have greater risk of developing clinically relevant muscular or hepatic toxicity than those treated with fluvastatin IR 40 mg initially. Clinically notable CK elevations occurred in only 2 of the study participants, both of whom were randomized to the fluvastatin IR 40 mg HS group. However, in 1 of these 2 patients, the notable CK value was associated with intensive physical activity shortly before the study visit. Moreover, there were significantly fewer instances of clinically notable increases of hepatic enzymes in the fluvastatin XL 80-mg HS group compared with the fluvastatin IR 40-mg BID group.

CONCLUSIONS The 80-mg XL formulation of fluvastatin provides greater incremental reductions in mean LDL-C (10.4%) and increases in HDL-C than expected by a usual doubling of statin dose, with maintained tolerability. Sustained administration of fluvastatin XL 80 mg provided efficacy for LDL-C and HDL-C levels that was at least as great as fluvastatin IR 40 mg BID, in contrast to the large EXCEL study2i with lovastatin that showed that administration BID provided superior efficacy for LDL-C, HDL-C, and TG levels than did the same dose administered QPM. No differences were seen between the XL and IR formulations in the incidence of adverse events. These data support the hypothesis that altering the delivery of fluvastatin can improve efficacy without adversely a&&rig tolerability. Fluva-

190

statin XL 80 mg demonstrated good tolerability and was effective as starting and maintenance lipid-lowering treatment in patients with type II hypercholesterolemia.

ACKNOWLEDGMENTS Christie M. Ballantyne, MD, has received research support from, and is a consultant for, Novartis Pharmaceuticals. John P. Reckless, MD, has spoken on behalf of, and acted as consultant for, Novartis; he has also advised, spoken for, and had research grants from other companies with lipid-lowering treatments. Evan Stein, MD, PhD, has received research support from Novartis for clinical studies and is a consultant for and on the speakers’ bureau for Novartis. James McKenney, PharmD, has received research support from Novartis and has occasionally served as a consultant to Novartis regarding drug-development issues with lipid-modifying drugs. Michele Bortolini, MD, and Yann Tong Chiang, PhD, are employees of Novartis.

REFERENCES Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global Bureau of Disease Study. Lancer. 1997; 349: 1269-1276. Steinberg D, Gotto AM Jr. Preventing coronary artery disease by lowering cholesterol levels. JAMA. 1999;282:2043-2050. Bucher HC, Griffith LE, Guyatt GH. Systemic review on the risk and benefit of different cholesterol-lowering interventions. Arterioscler Thromb Vast Biol. 1999;19:187-195. Downs JR, Clearfield M, Weis S, et al, for the AFCAPVfexCAPS Research Group. Primary prevention of acute coronary

C.M. BALLANTYNE

ET AL.

events with lovastatin in men and women with average cholesterol levels: Results of AFCAPSITexCAPS. JAMA. 1998;279: 1615-1622. 5. Shepherd J, Cobbe SM, Ford I, et al, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995; 333:1301-1307. 6. Sacks FM, Pfeffer MA, MoyC LA, et al, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335: 1001-1009. 7. The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357. 8. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4s). Lancer. 1994; 344:1383-1389.

11. Langtry HD, Markham A. Fluvastatin: A review of its use in lipid disorders. Drugs. 1999;57:583-606. 12. Riegger G, Abletshauser C, Ludwig M, et al. The effect of fluvastatin on coronary events in patients with symptomatic coronary artery disease during one year of treatment. Atherosclerosis. 1999;144:263-270. 13. Serruys PW, Foley DP, Jackson G, et al. A randomized placebo-controlled trial of fluvastatin for the prevention of restenosis after successful coronary balloon angioplasty: Final results of the Fhtvastatin Angiographic Restenosis (FLARE) trial. Eur Heart J. 1999;20:5849. 14. Herd JA, Ballantyne CM, Farmer JA, et al, for the LCAS Investigators. Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]). Am J Cardiol. 1997;80:278-286. 15. Data on file, Study number XUO-F35 1-E00. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 1999. 16. Data on file, Study number XUO-F353-E00. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 1999.

9. Kannel WB. Range of serum cholesterol values in the population developing coronary artery disease. Am J Cardiol. 1995; 76:69C-77C.

17. Olsson AG, Pauciullo P, Soska V, et al. Comparison of the efficacy and tolerability of fluvastatin extended-release and immediate-release formulations in the treatment of primary hypercholesterolemia: A randomized trial. Clin The,: 2001;23:4541.

IO. Rubins HB, Robins SJ, Collins D, et al, for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999;341: 41@418.

18. Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA. 1993;269:3015-3023.

191

CLINICAL THERAPEUTICS@

19. Illingworth DR, Tobert JA. A review of clinical trials comparing HMG-CoA reductase inhibitors. Clin The,: 1994;16:366385. 20. Pedersen TR, Tobert JA. Benefits and risks of HMG-CoA reductase inhibitors in the prevention of coronary heart disease: A reappraisal. Drug SaJ: 1996;l: 1 l-24. 21. Bradford RH, Shear CL, Chremos AN, et al. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. I. Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia. Arch Zntern Med. 1991;151:4349. 22. Smith HT, Jokubaitis LA, Troendle AJ, et al. Pharmacokinetics of fluvastatin and specific drug interactions. Am J Hypertens. 1993;6(11 pt 2):3758-3828. 23. Tse FL, Jaffe JM, Troendle A. Pharmacokinetics of fluvastatin after single and multiple doses in normal volunteers. J Clin Pharmacol. 1992;32:63&638. 24. Sabia H, Prasad P, Stoltz RR, Rothenberg P. Safety, tolerability and pharmacokinetits of an extended-release formulation of fluvastatin administered once daily to patients with primary hypercholesterolemia. J Cardiovasc Pharmacol. In press. S, Sabia H, Prasad P, 25. Appel-Dingemanse et al. Pharmacokinetics, safety, and toler-

ability of three extended-release formulations of fluvastatin in healthy subjects. Poster presented at: 29th European Symposium on Clinical Pharmacy; October 12-14, 2000; Base], Switzerland. 26. Jacobson TA, Griffiths GG, Varas C, et al. Impact of evidence-based “clinical judgment” on the number of American adults requiring lipid-lowering therapy based on updated NHANES III data. Arch Intern Med. 2000;160:1361-1369. 27. Shear CL, Franklin FA, Stinnett S, et al. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results: Effect of patient characteristics on lovastatin-induced changes in plasma concentrations of lipids and lipoproteins. Circulation. 1992;85: 1293-l 303. 28. Stein E, Plotkin D, Bays H, et al. Effects of simvastatin (40 and 80 mg/day) in patients with mixed hyperlipidemia. Am J Cardiol. 2000;86:40&411. 29. Stein EA, Lane M, Laskarzewski P. Comparison of statins in hypertriglyceridemia. Am J Cardiol. 1998;8 1:66B-69B. 30. Plosker GL, Wagstaff AJ. Fluvastatin: A review of its pharmacology and use in the management of hypercholesterolaemia. Drugs. 1996;5 1:433-459.

Address correspondence to: Christie M. Ballantyne, MD, Baylor College of Medicine, 6565 Fannin, MS A-601, Houston, TX 77030. E-mail: [email protected]

192