Pravastatin Sodium: Package Insert and Label Information (Page 5 of 7)

14 CLINICAL STUDIES

14.1 Prevention of Coronary Heart Disease

In the Pravastatin Primary Prevention Study (WOS), 3 the effect of pravastatin sodium on fatal and nonfatal CHD was assessed in 6595 men 45 to 64 years of age, without a previous MI, and with LDL-C levels between 156 to 254 mg/dL (4 to 6.7 mmol/L). In this randomized, double-blind, placebo-controlled study, patients were treated with standard care, including dietary advice, and either pravastatin sodium 40 mg daily (N = 3302) or placebo (N = 3293) and followed for a median duration of 4.8 years. Median (25 th , 75 th percentile) percent changes from baseline after 6 months of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were −20.3 (−26.9, −11.7), −27.7 (−36.0, −16.9), −9.1 (−27.6, 12.5), and 6.7 (−2.1, 15.6), respectively.

Pravastatin sodium significantly reduced the rate of first coronary events (either CHD death or nonfatal MI) by 31% (248 events in the placebo group [CHD death = 44, nonfatal MI = 204] versus 174 events in the pravastatin sodium group [CHD death = 31, nonfatal MI = 143], p = 0.0001 [see figure below]). The risk reduction with pravastatin sodium was similar and significant throughout the entire range of baseline LDL cholesterol levels. This reduction was also similar and significant across the age range studied with a 40% risk reduction for patients younger than 55 years and a 27% risk reduction for patients 55 years and older. The Pravastatin Primary Prevention Study included only men, and therefore it is not clear to what extent these data can be extrapolated to a similar population of female patients.

Figure
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Pravastatin sodium also significantly decreased the risk for undergoing myocardial revascularization procedures (coronary artery bypass graft [CABG] surgery or percutaneous transluminal coronary angioplasty [PTCA]) by 37% (80 vs 51 patients, p = 0.009) and coronary angiography by 31% (128 vs 90, p = 0.007). Cardiovascular deaths were decreased by 32% (73 vs 50, p = 0.03) and there was no increase in death from non-cardiovascular causes.

14.2 Secondary Prevention of Cardiovascular Events

In the LIPID 4 study, the effect of pravastatin 40 mg daily, was assessed in 9014 patients (7498 men; 1516 women; 3514 elderly patients [age ≥ 65 years]; 782 diabetic patients) who had experienced either an MI (5754 patients) or had been hospitalized for unstable angina pectoris (3260 patients) in the preceding 3 to 36 months. Patients in this multicenter, double-blind, placebo-controlled study participated for an average of 5.6 years (median of 5.9 years) and at randomization had Total-C between 114 and 563 mg/dL (mean 219 mg/dL), LDL-C between 46 and 274 mg/dL (mean 150 mg/dL), TG between 35 and 2710 mg/dL (mean 160 mg/dL), and HDL-C between 1 and 103 mg/dL (mean 37 mg/dL). At baseline, 82% of patients were receiving aspirin and 76% were receiving antihypertensive medication. Treatment with pravastatin significantly reduced the risk for total mortality by reducing coronary death (see Table 5). The risk reduction due to treatment with pravastatin on CHD mortality was consistent regardless of age. Pravastatin significantly reduced the risk for total mortality (by reducing CHD death) and CHD events (CHD mortality or nonfatal MI) in patients who qualified with a history of either MI or hospitalization for unstable angina pectoris.

Table 5: LIPID — Primary and Secondary Endpoints

Number (%) of Subjects

Event

Pravastatin 40 mg (N=4512)

Placebo (N=4502)

Risk Reduction

p -value

Primary Endpoint

CHD mortality

287 (6.4)

373 (8.3)

24%

0.0004

Secondary Endpoints

Total mortality

498 (11.0)

633 (14.1)

23%

< 0.0001

CHD mortality or nonfatal MI

557 (12.3)

715 (15.9)

24%

< 0.0001

Myocardial revascularization procedures (CABG or PTCA)

584 (12.9)

706 (15.7)

20%

< 0.0001

Stroke

All-cause

169 (3.7)

204 (4.5)

19%

0.0477

Non-hemorrhagic

154 (3.4)

196 (4.4)

23%

0.0154

Cardiovascular mortality

331 (7.3)

433 (9.6)

25%

< 0.0001

In the CARE 5 study, the effect of pravastatin, 40 mg daily, on CHD death and nonfatal MI was assessed in 4159 patients (3583 men and 576 women) who had experienced a MI in the preceding 3 to 20 months and who had normal (below the 75 th percentile of the general population) plasma total cholesterol levels. Patients in this double-blind, placebo-controlled study participated for an average of 4.9 years and had a mean baseline Total-C of 209 mg/dL. LDL-C levels in this patient population ranged from 101 to 180 mg/dL (mean 139 mg/dL). At baseline, 84% of patients were receiving aspirin and 82% were taking antihypertensive medications. Median (25 th , 75 th percentile) percent changes from baseline after 6 months of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were −22.0 (−28.4, −14.9), −32.4 (−39.9, −23.7), −11.0 (−26.5, 8.6), and 5.1 (−2.9, 12.7), respectively. Treatment with pravastatin significantly reduced the rate of first recurrent coronary events (either CHD death or nonfatal MI), the risk of undergoing revascularization procedures (PTCA, CABG), and the risk for stroke or TIA (see Table 6).

Table 6: CARE — Primary and Secondary Endpoints
*
The risk reduction due to treatment with pravastatin was consistent in both sexes.

Number (%) of Subjects

Event

Pravastatin 40 mg (N=2081)

Placebo (N=2078)

Risk Reduction

p -value

Primary Endpoint

CHD mortality or nonfatal MI *

212 (10.2)

274 (13.2)

24%

0.003

Secondary Endpoints

Myocardial revascularization procedures (CABG or PTCA)

294 (14.1)

391 (18.8)

27%

< 0.001

Stroke or TIA

93 (4.5)

124 (6.0)

26%

0.029

In the PLAC I 6 study, the effect of pravastatin therapy on coronary atherosclerosis was assessed by coronary angiography in patients with coronary disease and moderate hypercholesterolemia (baseline LDL-C range: 130 to 190 mg/dL). In this double-blind, multicenter, controlled clinical trial, angiograms were evaluated at baseline and at 3 years in 264 patients. Although the difference between pravastatin and placebo for the primary endpoint (per-patient change in mean coronary artery diameter) and 1 of 2 secondary endpoints (change in percent lumen diameter stenosis) did not reach statistical significance, for the secondary endpoint of change in minimum lumen diameter, statistically significant slowing of disease was seen in the pravastatin treatment group (p = 0.02).

In the REGRESS 7 study, the effect of pravastatin on coronary atherosclerosis was assessed by coronary angiography in 885 patients with angina pectoris, angiographically documented coronary artery disease, and hypercholesterolemia (baseline total cholesterol range: 160 to 310 mg/dL). In this double-blind, multicenter, controlled clinical trial, angiograms were evaluated at baseline and at 2 years in 653 patients (323 treated with pravastatin). Progression of coronary atherosclerosis was significantly slowed in the pravastatin group as assessed by changes in mean segment diameter (p = 0.037) and minimum obstruction diameter (p = 0.001).

Analysis of pooled events from PLAC I, PLAC II, 8 REGRESS, and KAPS 9 studies (combined N = 1891) showed that treatment with pravastatin was associated with a statistically significant reduction in the composite event rate of fatal and nonfatal MI (46 events or 6.4% for placebo versus 21 events or 2.4% for pravastatin, p = 0.001). The predominant effect of pravastatin was to reduce the rate of nonfatal MI.

14.3 Primary Hypercholesterolemia ( Fredrickson Types IIa and IIb)

Pravastatin sodium is highly effective in reducing Total-C, LDL-C, and TG in patients with heterozygous familial, presumed familial combined, and non-familial (non-FH) forms of primary hypercholesterolemia, and mixed dyslipidemia. A therapeutic response is seen within 1 week, and the maximum response usually is achieved within 4 weeks. This response is maintained during extended periods of therapy. In addition, pravastatin sodium is effective in reducing the risk of acute coronary events in hypercholesterolemic patients with and without previous MI.

A single daily dose is as effective as the same total daily dose given twice a day. In multicenter, double-blind, placebo-controlled studies of patients with primary hypercholesterolemia, treatment with pravastatin in daily doses ranging from 10 to 40 mg consistently and significantly decreased Total-C, LDL-C, TG, and Total-C/HDL-C and LDL-C/HDL-C ratios (see Table 7).

In a pooled analysis of 2 multicenter, double-blind, placebo-controlled studies of patients with primary hypercholesterolemia, treatment with pravastatin at a daily dose of 80 mg (N = 277) significantly decreased Total-C, LDL-C, and TG. The 25 th and 75 th percentile changes from baseline in LDL-C for pravastatin 80 mg were −43% and −30%. The efficacy results of the individual studies were consistent with the pooled data (see Table 7).

Treatment with pravastatin sodium modestly decreased VLDL-C and pravastatin sodium across all doses produced variable increases in HDL-C (see Table 7).

Table 7: Primary Hypercholesterolemia Studies: Dose Response of Pravastatin Sodium Once Daily Administration
*
A multicenter, double-blind, placebo-controlled study.
Pooled analysis of 2 multicenter, double-blind, placebo-controlled studies.

Dose

Total-C

LDL-C

HDL-C

TG

Mean Percent Changes From Baseline After 8 Weeks *

Placebo (N = 36)

−3%

−4%

+1%

−4%

10 mg (N = 18)

−16%

−22%

+7%

−15%

20 mg (N = 19)

−24%

−32%

+2%

−11%

40 mg (N = 18)

−25%

−34%

+12%

−24%

Mean Percent Changes From Baseline After 6 Weeks

Placebo (N = 162)

0%

−1%

−1%

+1%

80 mg (N = 277)

−27%

−37%

+3%

−19%

In another clinical trial, patients treated with pravastatin in combination with cholestyramine (70% of patients were taking cholestyramine 20 or 24 g per day) had reductions equal to or greater than 50% in LDL-C. Furthermore, pravastatin attenuated cholestyramine-induced increases in TG levels (which are themselves of uncertain clinical significance).

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