Zocor

[simvastatin]

Clinical Studies in Adults Reductions in Risk of CHD Mortality and Cardiovascular Events

In 4S, the effect of therapy with ZOCOR on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol 212-309 mg/ dL (5. 5-8. 0 mmol/ L). In this multicenter, randomized, double-blind, placebo-controlled study, patients were treated with standard care, including diet, and either ZOCOR 20-40 mg/ day (n= 2,221) or placebo (n= 2,223) for a median duration of 5.4 years. After six weeks of treatment with ZOCOR the median (25 th and 75 th percentile) changes in LDL-C, TG, and HDL-C were -39% (-46, -31%), -19% (-31, 0%), and 6% (-3, 17%). Over the course of the study, treatment with ZOCOR led to mean reductions in total-C, LDL-C and TG of 25%, 35%, and 10%, respectively, and a mean increase in HDL-C of 8%.

ZOCOR significantly reduced the risk of mortality by 30%, (p= 0.0003, 182 deaths in the ZOCOR group vs 256 deaths in the placebo group). The risk of CHD mortality was significantly reduced by 42%, (p= 0.00001, 111 vs 189 deaths). There was no statistically significant difference between groups in non-cardiovascular mortality. ZOCOR also significantly decreased the risk of having major coronary events (CHD mortality plus hospital-verified and silent non-fatal myocardial infarction [MI]) by 34%, (p< 0.00001, 431 vs 622 patients with one or more events).

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The risk of having a hospital-verified non-fatal MI was reduced by 37%. ZOCOR significantly reduced the risk for undergoing myocardial revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37%, (p< 0.00001, 252 vs 383 patients). Furthermore, ZOCOR significantly reduced the risk of fatal plus non-fatal cerebrovascular events (combined stroke and transient ischemic attacks) by 28% (p= 0.033, 75 vs 102 patients). ZOCOR reduced the risk of major coronary events to a similar extent across the range of baseline total and LDL cholesterol levels. Because there were only 53 female deaths, the effect of ZOCOR on mortality in women could not be adequately assessed. However, ZOCOR significantly lessened the risk of having major coronary events by 34% (60 vs 91 women with one or more event).

The randomization was stratified by angina alone (21% of each treatment group) or a previous MI. Because there were only 57 deaths among the patients with angina alone at baseline, the effect of ZOCOR on mortality in this subgroup could not be adequately assessed. However, trends in reduced coronary mortality, major coronary events and revascularization procedures were consistent between this group and the total study cohort. Additionally, in this study, 1,021 of the patients were 65 and older. Cholesterol reduction with simvastatin resulted in similar decreases in relative risk for total mortality, CHD mortality, and major coronary events in these elderly patients, compared with younger patients.

Lilja JJ, Kivisto KT, Neuvonen PJ. Clin Pharmacol Ther 1998; 64( 5): 477-83.

The Heart Protection Study (HPS) was a large, multi-center, placebo-controlled, double-blind study with a mean duration of 5 years conducted in 20,536 patients (10,269 on ZOCOR 40 mg and 10,267 on placebo). Patients were allocated to treatment using a covariate adaptive method 3 which took into account the distribution of 10 important baseline characteristics of patients already enrolled and minimized the
imbalance of those characteristics across the groups. Patients had a mean age of 64 years (range 40-80 years), were 97% Caucasian and were at high risk of developing a major coronary event because of existing coronary heart disease (65%), diabetes (Type 2, 26%; Type 1, 3%), history of stroke or other cerebrovascular disease (16%), peripheral vessel disease (33%), or hypertension in males 65 years of age and older (6%). At baseline, 3,421 patients (17%) had LDL-C levels below 100 mg/ dL, of whom 953 (5%) had LDL-C levels below 80 mg/ dL; 7,068 patients (34%) had levels between 100 and 130 mg/ dL; and 10,047 patients (49%) had levels greater than 130 mg/ dL. The HPS results showed that ZOCOR 40 mg/ day significantly reduced: total and CHD mortality; non-fatal myocardial infarctions, stroke, and revascularization procedures (coronary and non-coronary) (see Table 1).

TABLE 1
Summary of Heart Protection Study Results
Endpoint ZOCOR (N= 10,269)

n (%) *
Placebo (N= 10,267)
n (%) *
Risk Reduction (%) (95% CI) p-Value

Primary
Mortality 1,328 (12.9) 1,507 (14.7) 13 (6-19) p= 0.0003

CHD mortality 587 (5. 7) 707 (6.9) 18
(8-26)
p= 0.0005

Secondary
Non-fatal MI 357 (3.5) 574 (5.6) 38
(30-46)
p< 0.0001

Stroke 444 (4.3) 585 (5.7) 25
(15-34)
p< 0.0001

Tertiary
Coronary revascularization 513 (5) 725 (7.1) 30 (22-38) p< 0.0001

Peripheral and other non-coronary
revascularization
450 (4.4) 532 (5.2) 16
(5-26)
p= 0.006

* n = number of patients with indicated event
Two composite endpoints were defined in order to have sufficient events to assess relative risk reductions across a range of baseline characteristics (see Figure 1). A composite of major coronary events (MCE) was comprised of CHD mortality and non-fatal MI (analyzed by time-to-first event; 898 patients treated with ZOCOR had events and 1,212 patients on placebo had events). A composite of major vascular events (MVE) was comprised of MCE, stroke and revascularization procedures including coronary, peripheral and other non-coronary procedures (analyzed by time-to-first event; 2,033 patients treated with ZOCOR had events and 2,585 patients on placebo had events).

Significant relative risk reductions were observed for both composite endpoints (27% for MCE and 24% for MVE, p< 0.0001).
Furthermore, treatment with ZOCOR produced significant relative risk reductions for all components of the composite endpoints. The risk reductions produced by ZOCOR in both MCE and MVE were evident and consistent regardless of cardiovascular disease related medical history at study entry (i. e., CHD alone; or peripheral vascular disease, cerebrovascular disease, diabetes or treated hypertension, with or without CHD), gender, age, creatinine levels up to the entry limit of 2.3 mg/ dL, baseline levels of LDL-C, HDL-C, apolipoprotein B and A-1, baseline concomitant cardiovascular medications (i. e., aspirin, beta blockers, or calcium channel blockers), smoking status, alcohol intake, or obesity. Diabetics showed risk reductions for MCE and MVE due to ZOCOR treatment regardless of baseline HbA1c levels or obesity with the greatest effects seen for diabetics without CHD.

D. R. Taves, Minimization

a new method of assigning patients to treatment and control groups. Clin. Pharmacol. Ther. 15 (1974), pp. 443-453

Figure 1
The Effects of Treatment with ZOCOR on Major Vascular Events and Major Coronary Events in HPS

0.4 0. 6 0.8 1. 0 1.2 0. 4 0. 6 0. 8 1.0 1. 2
Characteristics N Placebo Placebo
Major Vascular Events Major Coronary Events
Incidence (%)
ZOCOR
Incidence (%)
ZOCOR

Risk Ratio ( 95% CI ) Risk Ratio ( 95% CI )

Favors Favors Favors Favors
ZOCOR Placebo ZOCOR Placebo

All patients 19.8 8. 7 25.2 11.8 20, 536
Without CHD 16.1 5. 1 20.8 8.0 7, 150 With CHD 21.8 10. 7 27.5 13.9 13, 386

Diabetes mellitus 20.2 9. 4 25.1 12.6 5, 963 Without CHD 13.8 5. 5 18.6 8.4 3, 982
With CHD 33.4 17. 4 37.8 21.0 1, 981
Without diabetes mellitus 19.6 8. 5 25.2 11.5 14, 573
Peripheral vascular disease 26.4 10. 9 32.7 13.8 6, 748 Without CHD 24.7 7. 0 30.5 10.1 2, 701
With CHD 27.6 13. 4 34.3 16.4 4, 047
Cerebrovascular disease 24.7 10. 4 29.8 13.3 3, 280 Without CHD 18.7 5. 9 23.6 8.7 1, 820
With CHD 32.4 16. 2 37.4 19.0 1, 460
Gender Female 14.4 5. 2 17.7 7.8 5, 082
Male 21.6 9. 9 27.6 13.1 15, 454
Age (years) 40 to < 65 16.9 6. 2 22.1 9.2 9, 839
65 to < 70 20.9 9. 5 27.2 13.1 4, 891 70 23.6 12. 4 28.7 15.2 5, 806

LDL-cholesterol (mg/ dL) < 100 16.4 7. 5 21.0 9.8 3, 421
100 to < 130 18.9 7. 9 24.7 11.9 7, 068 130 21.6 9. 7 26.9 12.4 10, 047

HDL-cholesterol (mg/ dL) < 35 22.6 10. 2 29.9 14.4 7, 176
35 to < 43 20.0 8. 9 25.1 11.7 5, 666 43 17.0 7. 3 20.9 9.4 7, 694

Baseline

N= number of patients in each subgroup. The inverted triangles are point estimates of the relative risk, with their 95% confidence intervals represented as a line. The area of a triangle is proportional to the number of patients with MVE or MCE in the subgroup relative to the number with MVE or MCE, respectively, in the entire study population. The vertical solid line represents a relative risk of one. The vertical dashed line represents the point estimate of relative risk in the entire study population.

Angiographic Studies

In the Multicenter Anti-Atheroma Study, the effect of simvastatin on atherosclerosis was assessed by quantitative coronary angiography in hypercholesterolemic patients with coronary heart disease. In this randomized, double-blind, controlled study, patients were treated with simvastatin 20 mg/ day or placebo. Angiograms were evaluated at baseline, two and four years.

The co-primary study endpoints were mean change per-patient in minimum and mean lumen diameters, indicating focal and diffuse disease, respectively. Simvastatin significantly slowed the progression of lesions as measured in the Year 4 angiogram by both parameters, as well as by change in percent diameter stenosis. In addition, simvastatin significantly decreased the proportion of patients with new lesions and with new total occlusions.

Modifications of Lipid Profiles

Primary Hypercholesterolemia (Fredrickson type lla and llb)
ZOCOR has been shown to be highly effective in reducing total-C and LDL-C in heterozygous familial and non-familial forms of hypercholesterolemia and in mixed hyperlipidemia. A marked response was seen within 2 weeks, and the maximum therapeutic response occurred within 4-6 weeks. The response was maintained during chronic therapy. Furthermore, improving lipoprotein levels with ZOCOR improved survival in patients with CHD and hypercholesterolemia treated with 20-40 mg/ day for a median of 5.4 years.
In a multicenter, double-blind, placebo-controlled, dose-response study in patients with familial or non-familial hypercholesterolemia, ZOCOR given as a single dose in the evening (the recommended dosing)
was similarly effective as when given on a twice-daily basis. ZOCOR consistently and significantly decreased total-C, LDL-C, total-C/ HDL-C ratio, and LDL-C/ HDL-C ratio. ZOCOR also decreased TG and increased HDL-C.
The results of studies depicting the mean response to simvastatin in patients with primary hypercholesterolemia and combined (mixed) hyperlipidemia are presented in Table 2.

TABLE 2
Mean Response in Patients with Primary Hypercholesterolemia and Combined (mixed) Hyperlipidemia
(Mean Percent Change from Baseline After 6 to 24 Weeks)

TREATMENT N TOTAL-C LDL-C HDL-C TG *

Lower Dose Comparative Study
(Mean % Change at Week 6)

ZOCOR 5 mg q. p. m.
ZOCOR 10 mg q. p. m.
109
110
-19
-23
-26
-30
10
12
-12
-15

Scandinavian Simvastatin Survival Study (Mean % Change at Week 6)
Placebo
ZOCOR 20 mg q. p. m.
2223
2221
-1
-28
-1
-38
0
8
-2
-19
Upper Dose Comparative Study (Mean % Change Averaged at
Weeks 18 and 24)

ZOCOR 40 mg q. p. m.
ZOCOR 80 mg q. p. m.
433
664
-31
-36
-41
-47
9
8
-18
-24

Multi-Center Combined Hyperlipidemia Study
(Mean % Change at Week 6)

Placebo
ZOCOR 40 mg q. p. m.
ZOCOR 80 mg q. p. m.

125
123
124

1
-25
-31

2
-29
-36

3
13
16

-4
-28
-33 *
median percent change

In the Upper Dose Comparative Study, the mean reduction in LDL-C was 47% at the 80-mg dose. Of the 664 patients randomized to 80 mg, 475 patients with plasma TG 200 mg/ dL had a median reduction in TG of 21%, while in 189 patients with TG > 200 mg/ dL, the median reduction in TG was 36%. In these studies, patients with TG > 350 mg/ dL were excluded. In the Multi-Center Combined Hyperlipidemia Study, a randomized, 3-period crossover study, 130 patients with combined hyperlipidemia (LDL-C> 130 mg/ dL and TG: 300-700 mg/ dL) were treated with placebo, ZOCOR 40, and 80 mg/ day for 6 weeks. In a dose-dependent manner ZOCOR 40 and 80 mg/ day, respectively, decreased mean LDL-C by 29 and 36% (placebo: +2%) and median TG levels by 28 and 33% (placebo: 4%), and increased mean HDL-C by 13 and 16% (placebo: 3%) and apolipoprotein A-I by 8 and 11% (placebo: 4%). Hypertriglyceridemia (Fredrickson type lV) The results of a subgroup analysis in 74 patients with type lV hyperlipidemia from a 130-patient double-blind, placebo-controlled, 3-period crossover study are presented in Table 3. The median baseline values (mg/ dL) for the patients in this study were: total-C = 254, LDL-C = 135, HDL-C = 36, TG = 404, VLDL-C = 83, and non-HDL-C = 215.

TABLE 3
Six-week, Lipid-lowering Effects of Simvastatin in Type lV Hyperlipidemia
Median Percent Change (25 th and 75 th percentile) from Baseline

TREATMENT N Total-C LDL-C HDL-C TG VLDL-C Non-HDL-C
Placebo 74 +2
(-7, +7)
+1
(-8, +14)
+3
(-3, +10)
-9
(-25, +13)
-7
(-25, +11)
+1
(-9, +8)

ZOCOR 40 mg/ day 74 -25
(-34, -19)
-28
(-40, -17)
+11
(+ 5, +23)
-29
(-43, -16)
-37
(-54, -23)
-32
(-42, -23)

ZOCOR 80 mg/ day 74 -32
(-38, -24)
-37
(-46, -26)
+15
(+ 5, +23)
-34
(-45, -18)
-41
(-57, -28)
-38
(-49, -32)

Dysbetalipoproteinemia (Fredrickson type lll)
The results of a subgroup analysis in 7 patients with type lll hyperlipidemia (dysbetalipoproteinemia) (apo E2/ 2) (VLDL-C/ TG> 0.25) from a 130-patient double-blind, placebo-controlled, 3-period crossover

study are presented in Table 4. In this study the median baseline values (mg/ dL) were: total-C = 324, LDL-C = 121, HDL-C = 31, TG = 411, VLDL-C = 170, and non-HDL-C = 291.

TABLE 4
Six-week, Lipid-lowering Effects of Simvastatin in Type lll Hyperlipidemia
Median Percent Change (min, max) from Baseline

TREATMENT N Total-C LDL-C + IDL HDL-C TG VLDL-C+ IDL Non-HDL-C
Placebo 7 -8
(-24,+ 34)
-8
(-27,+ 23)
-2
(-21,+ 16)
+4
(-22,+ 90)
-4
(-28,+ 78)
-8
(-26,-39)

ZOCOR 40 mg/ day 7 -50
(-66,-39)
-50
(-60,-31)
+7
(-8,+ 23)
-41
(-74,-16)
-58
(-90,-37)
-57
(-72,-44)

ZOCOR 80 mg/ day 7 -52
(-55,-41)
-51
(-57,-28)
+7
(-5,+ 29)
-38
(-58,+ 2)
-60
(-72,-39)
-59
(-61,-46)

Homozygous Familial Hypercholesterolemia

In a controlled clinical study, 12 patients 15-39 years of age with homozygous familial hypercholesterolemia received simvastatin 40 mg/ day in a single dose or in 3 divided doses, or 80 mg/ day in 3 divided doses. Eleven of the 12 patients had reductions in LDL-C. In those patients with reductions, the mean LDL-C changes for the 40-and 80-mg doses were 14% (range 8% to 23%, median 12%) and 30% (range 14% to 46%, median 29%), respectively. One patient had an increase of 15% in LDL-C. Another patient with absent LDL-C receptor function had an LDL-C reduction of 41% with the 80-mg dose.

Endocrine Function

In clinical studies, simvastatin did not impair adrenal reserve or significantly reduce basal plasma cortisol concentration. Small reductions from baseline in basal plasma testosterone in men were observed in clinical studies with simvastatin, an effect also observed with other inhibitors of HMG-CoA reductase and the bile acid sequestrant cholestyramine. There was no effect on plasma gonadotropin levels. In a placebo-controlled 12-week study there was no significant effect of simvastatin 80 mg on the plasma testosterone response to human chorionic gonadotropin (hCG).

In another 24-week study, simvastatin 20-40 mg had no detectable effect on spermatogenesis. In 4S, in which 4,444 patients were randomized to simvastatin 20-40 mg/ day or placebo for a median duration of 5.4 years, the incidence of male sexual adverse events in the two treatment groups was not significantly different. Because of these factors, the small changes in plasma testosterone are unlikely to be clinically significant. The effects, if any, on the pituitary-gonadal axis in pre-menopausal women are unknown. Clinical Studies in Adolescents In a double-blind, placebo-controlled study, 175 patients (99 adolescent boys and 76 post-menarchal girls) 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (heFH) were randomized to simvastatin (n= 106) or placebo (n= 67) for 24 weeks (base study).

Inclusion in the study required a baseline LDL-C level between 160 and 400 mg/ dL and at least one parent with an LDL-C level >189 mg/ dL. The dosage of simvastatin (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter. In a 24-week extension, 144 patients elected to continue therapy and received simvastatin 40 mg or placebo. ZOCOR significantly decreased plasma levels of total-C, LDL-C, and Apo B (see Table 5). Results from the extension at 48 weeks were comparable to those observed in the base study.

TABLE 5
Lipid-lowering Effects of Simvastatin in Adolescent Patients with Heterozygous Familial Hypercholesterolemia
(Mean Percent Change from Baseline)

Dosage Duration N Total-C LDL-C HDL-C TG * Apo B

Placebo 24 Weeks 67
% Change from Baseline
(95% CI) 1.6
(-2.2, 5.3)
1.1
(-3.4, 5.5)
3.6
(-0.7, 8.0)
-3.2
(-11.8, 5.4)
-0.5
(-4.7, 3.6)

Mean baseline, mg/ dL
(SD)
278.6
(51.8)
211.9
(49.0)
46.9
(11.9)
90.0
(50.7)
186.3
(38.1)

ZOCOR 24 Weeks 106
% Change from Baseline
(95% CI) -26.5
(-29.6, -23.3)
-36.8
(-40.5, -33.0)
8.3
(4.6, 11.9)
-7.9
(-15.8, 0.0)
-32.4
(-35.9, -29.0)

Mean baseline, mg/ dL
(SD)
270.2
(44.0)
203.8
(41.5)
47.7
(9.0)
78.3
(46.0)
179.9
(33.8)

* median percent change

After 24 weeks of treatment, the mean achieved LDL-C value was 124.9 mg/ dL (range: 64.0-289.0 mg/ dL) in the Zocor 40 mg group compared to 207.8 mg/ dL (range: 128.0-334.0 mg/ dL) in the placebo group. The safety and efficacy of doses above 40 mg daily have not been studied in children with heterozygous familial hypercholesterolemia. The long-term efficacy of simvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

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