nation of a statin and a fibrate would be a rational approach, as fibrates are more effective than statins in
reducing triglycerides and also in increasing high-den- sity
lipoprotein HDL-cholesterol
[12]. However,
combining statins and fibrates has not been recom- mended because episodes of rhabdomyolysis have fol-
lowed concomitant use of lovastatin or simvastatin and gemfibrozil [13 – 16].
Small studies to date suggest that a combination of fluvastatin and bezafibrate [17,18] or gemfibrozil,
[19,20] is well tolerated with no evidence of any clini- cally significant interactions. The Fluvastatin Alone
and in Combination Treatment FACT Study was performed to examine the effects on plasma lipids and
safety of a combination of fluvastatin and bezafibrate in patients with coronary artery disease CAD and mixed
hyperlipidaemia.
2. Patients and methods
2
.
1
. Patients Male and female patients aged between 40 and 70
years with CAD and mixed hyperlipidaemia were eligi- ble to participate in the study. CAD was defined by
stable angina for at least 4 months, and previous my- ocardial infarction or previous coronary vascularisation
procedure. Patients were required to have a serum LDL-cholesterol between 135 and 250 mgdl and serum
triglycerides between 180 and 400 mgdl after 7 weeks of placebo and dietary run-in. In addition, patients had
to show at least 85 compliance with treatment during the run-in period.
Important exclusion criteria were type I, III, IV or V hyperlipidaemia; conditions associated with secondary
hyperlipidaemia, including diabetes mellitus, nephrotic syndrome, hepatobiliary disease, alcoholism, chronic
pancreatitis, autoimmune disease or hyperthyroidism; congestive heart failure; unstable angina, myocardial
infarction, stroke or coronary revascularisation within the preceding 4 months; uncontrolled hypertension; or
body mass index \ 30 kgm
2
.
2
.
2
. Study design The study was a double-blind, randomised, parallel
group, multicentre 45 centres trial carried out in Italy. Eligible patients were instructed to adhere to a hypolip-
idaemic isocaloric diet according to guidelines of the European Atherosclerosis Society throughout the
study. Patients underwent an 8-week placebo run-in period, after which they were randomly allocated to
one of four treatment groups. Patients received daily doses of either 40 mg fluvastatin, 400 mg bezafibrate, 20
mg fluvastatin + 400 mg bezafibrate, or 40 mg fluvas- tatin + 400 mg bezafibrate for 24 weeks. Fluvastatin
was administered once daily o.a.d. in the evening and bezafibrate retard formulation; Boehringer Mannheim
was given o.a.d. in the morning. To maintain blinding, a double-dummy technique was used with patients as-
signed to monotherapy receiving a placebo matching either fluvastatin or bezafibrate.
Any other medication with the potential to interfere with the evaluation of efficacy, safety and tolerability of
trial medication was prohibited during the study; par- ticularly, drugs with known effects on plasma lipids,
steroids, unless administered topically or for post- menopausal hormone replacement therapy, anticoagu-
lants, cyclosporine A, erythromycin, ketoconazole or cytotoxic agents.
Patients were assessed at baseline and then at 4-week intervals. At each visit, serum lipids were measured
including total cholesterol, HDL-cholesterol, LDL- cholesterol and triglycerides. All biochemical analyses
were carried out by a central laboratory Exacta, Verona, Italy. Lipids were analysed using standard
techniques [21 – 23], with LDL calculated according to the Friedewald formula [24] when triglycerides were
5
400 mgdl, or directly determined by means of a homogeneous method N-geneousTM LDL-C; Gen-
zyme Diagnostics, West Malling, UK [25] when triglycerides were \ 400 mgdl. All assays had an intra-
assay coefficient of variation of less than 2 and inter- assay variation of less than 5. Liver function tests
ASAT, ALAT, bilirubin, alkaline phosphatase and creatine-kinase were measured, and the occurrence of
any adverse events recorded at 4-week intervals. Pulse rate and blood pressure were measured at 8-week inter-
vals with an electrocardiogram performed at baseline and after 24 weeks. Routine haematology and a wider
set of safety blood chemistry were carried out at base- line and at the end of the study.
2
.
3
. Statistical methodology Efficacy was primarily assessed by determining the
mean percentage reduction from baseline in LDL- cholesterol measured at the end of the study.
A sample size of 80 subjects for the treatment group was estimated to be required to detect a difference in
mean LDL-cholesterol reduction of 10 or more, with S.D. of 18, power of 80 and a significance level of
0.008 significance levels of 0.05 adjusted for multiple treatment comparison.
The comparability of the four treatment groups with respect to demographics and baseline characteristics
was assessed in a descriptive way considering all ran- domized patients.
Efficacy was analyzed on an intention-to-treat basis, including all randomized patients with at least one
post-treatment assessment for the variable being ana-
lyzed. In case of missing data, the final observation carried forward approach was used.
The statistical analysis was carried out on the per- centage change from baseline applying the analysis of
covariance ANCOVA, PROC GLM of SAS. The statistical model included centre and treatment as fac-
tors, and baseline values as covariate. A statistical test was provided for all six pairwise treatment compari-
sons. The 95 confidence interval of the estimated difference between treatments in percentage change
from baseline was provided for each of these pairwise treatment comparisons.
Standard safety laboratory parameters were assessed by evaluating the incidences of worsening during treat-
ment and of the worst newly occurring events labora- tory value falling outside normal range with respect to
baseline on all randomised patients. The incidence of patients having an adverse experience, related and not
related
to trial
treatment, was
summarised by
treatment.
3. Results
