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
3
.
1
. Patients A total of 333 patients were randomised to receive
fluvastatin alone n = 80, bezafibrate alone n = 86, 20 mg fluvastatin + bezafibrate n = 85, 40 mg fluvas-
tatin + bezafibrate n = 82. Table 1 shows that there were no important differ-
ences between the groups with respect to demographics and baseline measurements. The groups were compara-
ble with respect to CAD, with approximately one-half the patients 55 having angina pectoris, 51 having a
history of myocardial infarction, and 30 having previ- ous coronary revascularisation. There was also no dif-
ference between the groups with respect to previous management of hyperlipidaemia, with 60 of patients
having used a lipid-lowering diet and 54 having taken lipid-lowering drugs prior to the study. The most com-
mon previous lipid-lowering drugs were statins 38 of all patients, and fibrates 28. Resins, fish oils, or
probucol were each used in B 5 of all patients.
A total of 293 88 of patients completed the 24- week treatment period with fourteen, eight, eight and
ten patients discontinuing prematurely in the fluvastatin fluva, bezafibrate beza, 20 mg fluva + beza and 40
mg fluva + beza groups, respectively Table 2.
3
.
2
. Efficacy Table 3 shows the percentage decrease from baseline
in lipid parameters. LDL-Cholesterol decreased in all groups from baseline value within 4 weeks of starting
therapy. However, decreases of \ 20 were only ob-
Table 1 Demographics and baseline characteristics
a
Randomised patients 400 mg Bezafibrate
40 mg Fluvastatin 40 mg Fluvastatin+400 mg
20 mg Fluvastatin+400 mg bezafibrate n = 85
n = 80 n = 86
bezafibrate n = 82 80.5
Sex male 78.8
70.0 76.3
55 9 8 56 9 8
Age in years mean 9 S.D. 55 9 9
57 9 8 BMI kgm
2
mean 9 S.D. 27.0 9 2.4
26.4 9 2.2 26.3 9 2.5
26.9 9 2.8 52
53 Family history of CV disease
54 74
Smoking 26
16 Current
18 28
54 49
Ex smoker 52
41 35
31 20
Never smoked 30
Alcohol 26
28 No units per week
32 32
5 14 U per week
64 70
63 60
\ 15 U per week
5 8
8 4
Lipid profile mean
9
S.D. 286.5 9 37.0
282.4 9 38.6 274.2 9 36.1
277.6 9 36.3 Total cholesterol mgdl
188.9 9 34.8 179.2 9 32.2
LDL-cholesterol mgdl 186.1 9 33.8
192.1 9 36.4 39.5 9 8.1
42.5 9 10.1 HDL-cholesterol mgdl
40.5 9 7.7 42.1 9 8.7
4.9 9 1.1 4.4 9 1.3
LDL-HDL-cholesterol 4.7 9 1.1
4.7 9 1.2 253.0 9 56.8
257.0 9 65.0 262.7 9 64.4
Triglycerides mgdl 258.8 9 71.0
Blood pressure mmHg
133.2 9 11.7 136 9 14.6
Systolic BP mean 9 S.D. 135.5 9 15.2
135.8 9 14.2 80.4 9 7.3
Diastolic BP mean 9 S.D. 82.8 9 8.2
83.5 9 8.6 81.9 9 7.7
69.9 9 8.0 69.7 9 8.5
Heart rate b.p.m. mean 9 S.D. 69.2 9 8.4
70.6 9 9.6
a
BMI, Body mass index; CV, cardiovascular; BP, blood pressure; b.p.m., beats per minute.
Table 2 Premature discontinuations
40 mg Fluvastatin 400 mg Bezafibrate
20 mg Fluvastatin+400 mg 40 mg Fluvastatin+400 mg
n = 86 n = 80
bezafibrate n = 85 bezafibrate n = 82
Total number of patients 8 9.3
14 17.5 8 9.4
10 12.2 Reason for discontinuation
3 3
6 5
Adverse events 1
– Concomitant diseases
– –
– –
3 1
Withdrawal consent –
1 Dose violation
– 1
3 2
3 2
Lost to follow up 1
Other 2
1 2
Table 3 Percentage change in lipid parameters from baseline to 24-week endpoint
40 mg Fluvastatin 20 mg Fluvastatin+400 mg
Least-squares means 400 mg Bezafibrate
40 mg Fluvastatin+400 mg bezafibrate n = 85
bezafibrate n = 82 95 confidence interval
n = 86 n = 80
− 22.5
a
−26.2, −18.9 LDL-cholesterol
− 9.6 −13.2,−6.1
− 23.3
a
−26.9,−19.8 −
23.6
a
−27.4,−19.9 −
9.8 −12.4, −7.2 −
19.9
a
−22.6, −17.3 −
17.3
a
−20.0, −14.6 −
20.4
a
−23.1, −17.6 Total cholesterol
0.3 −3.8, 4.5 HDL-cholesterol
17.4
b
13.4, 21.4 20.9
b
16.9, 24.9 21.9
b
17.8, 26.1 Triglycerides
− 6.0 −14.2, 2.3
− 25.1
b
−33.0, −17.3 −
35.7
b
−43.6,−27.7 −
37.7
b,c
−45.9, −29.4
a
PB0.001 versus 400 mg bezafibrate.
b
PB0.001 versus 40 mg fluvastatin.
c
P = 0.031 versus 400 mg bezafibrate.
served in fluvastatin monotherapy and combination with fluvastatin, 20 mg fluva + beza, and 40 mg fluva +
beza all showing significantly greater decreases than beza alone P B 0.001. There was no significant differ-
ence in LDL-cholesterol reduction between fluvastatin monotherapy and either fluva + beza combination
therapies.
Total cholesterol also decreased from baseline within 4 weeks of therapy in all groups. All regimens contain-
ing fluvastatin were significantly better than bezafibrate alone P B 0.001. Mean decreases of \ 20 were seen
in the two fluva + beza groups, although there was no statistically significant difference between fluvastatin
monotherapy and the combination regimens P = 0.171 versus 20 mg fluva + beza; P = 0.119 versus 40 mg
fluva + beza or between the combination regimens themselves P = 0.824. The greatest decrease was ob-
served in the 40 mg fluva + beza group least-squares mean decrease from baseline to 24-week endpoint of
20.4.
HDL-Cholesterol increased from baseline in all groups,
although the increase in the fluvastatin
monotherapy group was relatively small. Both bez- afibrate alone and fluva + beza resulted in significantly
greater increases in HDL-cholesterol compared with fluvastatin alone P B 0.001. The largest increase was
observed in the 40 mg fluva + beza group least-squares mean increase from baseline to 24-week endpoint of
21.9. Triglycerides decreased in all groups from baseline
within 4 weeks. Falls in the fluvastatin alone group were relatively small least-squares mean decrease from
baseline to 24-week endpoint of − 6.0. Although bezafibrate alone resulted in a significant decrease from
baseline 25.1, greater reductions were observed with the combinations 35.7 for 20 mg fluva + beza, 37.7
for 40 mg fluva + beza. The combination of 40 mg fluva + beza was significantly superior to bezafibrate
alone in lowering triglycerides at 24-week endpoint P = 0.031.
3
.
3
. Safety and tolerability All treatments were well tolerated with no important
differences between monotherapy and combination therapy. Adverse events were reported by 28.8, 23.3,
24.7 and 26.8 of patients in the fluvastatin, bez- afibrate, 20 mg fluva + beza, and 40 mg fluva + beza,
respectively. A total of eight patients 10 on fluvas- tatin, six patients 7 on bezafibrate, three patients
3.5 on 20 mg fluva + beza and six patients 7 on 40 mg fluva + beza reported adverse events assessed by
the investigator as being at least possibly related to trial medication Table 4.
No clinically relevant changes in laboratory parame- ters were observed. In particular, no clinically relevant
liver ASAT or ALAT greater then three times the upper limit of normal or muscular CPK greater than
Table 4 Adverse events AEs assessed by the investigator to be at least possibly related to study medication
40 mg Fluvastatin 400 mg Bezafibrate
40 mg Fluvastatin+400 mg 20 mg Fluvastatin+400 mg
bezafibrate n = 82 bezafibrate n = 85
n = 86 n = 80
8 10.0 Total number of patients
6 7.0 3 3.5
6 7.3 7
Total number of AEs 6
13 7
– Influenza-like symptoms
– 1
– 1
– 2
Headache 1
Gastric disorder 3
2 1
– –
1 Abdominal pain
2 Gastritis
– 1
1 Diarrhoea
1 1
Hepatic enzyme increase Cholecystitis
1 1
Arthrosis Contractures
1 2
Muscle weakness Leg cramps or pain
1 1
1 1
Decrease in libido Impotence
2 Coughing
1 1
Pneumonia Erythema multiforme
1 1
Intermittent claudication
four times the upper limit of normal laboratory abnor- malities were reported.
A total of 16 patients 4.8 discontinued medication due to adverse events, of which six, three, three and five
were in the fluvastatin, bezafibrate, 20 mg fluva + beza, 40 mg fluva + beza, respectively. Of these, five patients
prematurely interrupted treatment due to cardiovascu- lar adverse events, such as angina worsening one pa-
tient
on 20
mg fluva + beza,
one on
40 mg
fluva + beza, blood pressure increase one patient on fluvastatin, one on 40 mg fluva + beza or syncope one
patient on 40 mg fluva + beza. No deaths, myocardial infarction, or coronary revascularisation procedures oc-
curred during the study.
4. Discussion
