Pravachol Clinical Trials and Studies
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Pravachol Clinical Trials and Studies
Pravachol is highly effective in reducing Total-C and LDL-C in patients with heterozygous familial, presumed familial combined, and non-familial (non-FH) forms of primary hypercholesterolemia. 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 is effective in reducing the risk of acute coronary events in hypercholesterolemic patients with and without previous myocardial infarction.
A single daily Pravachol dose administered in the evening (the recommended dosing) is as effective as the same total daily dose given twice a day. Once daily administration in the evening appears to be marginally more effective than once daily administration in the morning, perhaps because hepatic cholesterol is synthesized mainly at night. In multicenter, double-blind, placebo-controlled studies of patients with primary hypercholesterolemia, treatment with pravastatin in daily doses ranging from 10 mg to 40 mg consistently and significantly decreased Total-C, LDL-C, and Total-C/HDL-C and LDL-C/HDL-C ratios; modestly decreased VLDL-C and plasma TG levels; and produced increases in HDL-C of variable magnitude.
TABLE 1 Primary Hypercholesterolemia Study Dose Response of Pravastatin Once Daily Administration At Bedtime
| Dose | Total-C | LDL-C | HDL-C | TG |
| 10 mg | -16% | -22% | + 7% | -15% |
| 20 mg | -24% | -32% | + 2% | -11% |
| 40 mg | -25% | -34% | +12% | -24% |
* Mean percent change from baseline after 8 weeks.
In another Pravachol clinical trial, patients treated with Pravachol 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).
Prevention of Coronary Heart Disease
In the Pravachol Primary Prevention Study (West of Scotland Coronary Prevention Study- WOS)1, the effect of Pravachol on fatal and non-fatal coronary heart disease (CHD) was assessed in 6595 men 45-64 years of age, without a previous MI, and with LDL-C levels between 156-254 mg/dl (4-6.7 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.
Pravachol significantly reduced the rate of first coronary events (either CHD death or non-fatal MI) by 31% [248 events in the placebo group (CHD death = 44, non-fatal MI = 204) vs. 174 events in the Pravachol group (CHD death = 31, non-fatal MI = 143), p = 0.0001]. The risk reduction with Pravachol 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.
Pravachol also significantly decreased the risk for undergoing myocardial revascularization procedures (coronary artery bypass graft surgery or coronary angioplasty) 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.
Atherosclerosis and Myocardial Infarction
In the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC I2) study, the effect of Pravachol therapy on coronary atherosclerosis was assessed by coronary angiography in patients with coronary disease and moderate hypercholesterolemia (baseline LDL-C range = 130-190 mg/dl). In this double-blind, multicenter, controlled Pravachol clinical trial, angiograms were evaluated at baseline and at three years in 264 patients. Although the difference between Pravachol and placebo for the primary endpoint (per-patient change in mean coronary artery diameter), and one of two 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 Regression Growth Evaluation Statin Study (REGRESS), the effect of Pravachol 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 = 160-310 mg/dl). In this double-blind, multicenter, controlled clinical trial, angiograms were evaluated at baseline and at two years in 653 patients (323 treated with pravastatin). progression of coronary atherosclerosis was significantly slowed in the Pravachol 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, the Pravachol, Lipids, and Atherosclerosis in the Carotids Study (PLAC II)4, REGRESS, and in the Kuopio Atherosclerosis Prevention Study (KAPS) (combined N = 1,891) showed that treatment with pravastatin was associated with a significant reduction in the composite event rate of fatal and non-fatal myocardial infarction (46 events or 6.4% for placebo versus 21 events or 2.4% fro Pravachol, p = 0.001). The predominant effect of Pravachol was to reduce the rate of non-fatal myocardial infarction.
In the Cholesterol and Recurrent Events (CARE) study the effect of Pravachol, 40 mg daily, on coronary heart disease death and nonfatal MI was assessed in 4159 patients (3583 men and 576 women) who had experienced a myocardial infarction in the preceding 3-20 months and who had normal (below the 75th 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 cholesterol of 209 mg/dl. LDL cholesterol levels in this patient population ranged from 101 mg/dl-180 mg/dl (mean = 139 mg/dl). At baseline, 84% of patients were receiving aspirin and 82% were taking antihypertensive medications. Treatment with Pravacholsignificantly reduced the rate of first recurrent coronary events (either CHD death or nonfatal MI) by 24% [274 patients with events (13.3%) in the placebo group vs 212 patients with events (10.4%) in the Pravachol group, p=0.003]. The reduction in risk was consistent in both sexes. The risk of undergoing revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) was significantly reduced by 27% (p<0.001) in the Pravachol treated patients [391 (19.6%) vs 294 (14.2%) patients]. Pravachol also significantly reduced the risk for stroke or transient ischemic attack (TIA) by 26% [124 (6.3%) vs 93 (4.7%) patients, p-0.029].
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