Prevention of Cardiovascular Events
The American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol management guideline recommends statins as first-line therapy for prevention of atherosclerotic cardiovascular disease (ASCVD) in adults. There is extensive evidence demonstrating that statins can substantially reduce ASCVD risk when used for secondary prevention or primary prevention (in high-risk patients). Because the relative reduction in ASCVD risk is correlated with the degree of low-density lipoprotein (LDL)-cholesterol lowering, the maximum tolerated statin intensity should be used to achieve optimum ASCVD benefits. According to the ACC/AHA guidelines, pravastatin may be used for primary or secondary prevention in adults when moderate-intensity statin therapy is indicated.
(See Prevention of Cardiovascular Events under Dosage and Administration: Dosage.)Nonstatin therapies do not provide acceptable ASCVD risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD. For additional details on prevention of ASCVD, and also consult the most recent ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (available at http://www.cardiosource.org or http://my.americanheart.org).
Pravastatin is used as an adjunct to nondrug therapies (i.e., lifestyle modifications) in patients with hypercholesterolemia without clinical evidence of coronary heart disease (CHD) to reduce the risk of myocardial infarction (MI), to reduce the risk of undergoing myocardial revascularization procedures, and to reduce the risk of cardiovascular mortality (with no increase in death from noncardiovascular causes).
The ACC/AHA cholesterol management guideline recommends statins as first-line therapy for primary prevention in patients 21 years of age and older without clinical ASCVD who have primary, severe elevations in LDL-cholesterol concentration (190 mg/dL or greater); patients 40-75 years of age with type 1 or 2 diabetes mellitus; and patients 40-75 years of age with LDL-cholesterol concentrations of 70-189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher. Before initiating statin therapy for primary prevention in patients without clinical ASCVD or diabetes mellitus, it is reasonable for clinicians and patients to discuss the potential for ASCVD risk reduction benefits, adverse effects, and drug interactions, as well as patient preferences for treatment.
In a randomized, placebo-controlled study (West of Scotland Coronary Prevention Study [WOSCOPS]) in men with moderate hypercholesterolemia and no history of MI, therapy with pravastatin sodium (40 mg daily) for a median of 4.9 years lowered plasma total and LDL-cholesterol by 20 and 26%, respectively, and reduced the incidence of MI and death from cardiovascular causes by approximately 31%; the risk of undergoing myocardial revascularization procedures also was reduced by 37%. Unlike some prior studies of cholesterol-lowering therapy, an increased risk of death from noncardiovascular causes was not observed in patients receiving pravastatin therapy in this study.
Despite favorable findings from the WOSCOPS study, clinical benefit (i.e., reduction in CHD-related morbidity or all-cause mortality) was not observed in a randomized, open-label study, the lipid lowering trial (LLT), in a subset of patients from the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). In this study (ALLHAT-LLT) in patients 55 years of age or older with well-controlled hypertension and moderately elevated LDL-cholesterol concentrations, the incidence of all-cause mortality or CHD-related adverse events (i.e., CHD death, nonfatal MI, stroke, congestive heart failure) was similar among patients receiving pravastatin sodium (40 mg daily) or usual care (i.e., moderate LDL-cholesterol lowering according to the discretion of the patient's primary care physician) for a mean duration of 4.8 years. The lack of clinical benefit may be attributable to the modest difference in total and LDL-cholesterol reduction between pravastatin and usual care recipients (17 versus 8% reduction in total cholesterol and 28 versus 11% reduction in LDL-cholesterol, respectively) compared with the differences reported in other statin trials. This modest difference may have resulted from poor adherence to initially prescribed therapy; at year 6 of follow-up, only 70% of patients randomized to receive pravastatin sodium were still taking the protocol-specified dosage (40 mg daily), while 28.5% of patients randomized to receive usual care were receiving antilipemic therapy (26.1% with a statin). Despite the reported lack of clinical benefit, the study results are consistent with previous findings indicating that lesser degrees of cholesterol lowering are associated with less clinical benefit. Adherence to treatment should be particularly emphasized when antilipemic therapy is implemented in routine clinical practice in order to achieve adequate reductions in LDL-cholesterol concentrations.
Pravastatin is used as an adjunct to nondrug therapies (i.e., lifestyle modifications) in patients with clinical evidence of CHD to reduce the risk of total mortality by reducing coronary death, to reduce the risk of MI, to reduce the risk of undergoing myocardial revascularization procedures, and to reduce the risk of stroke or transient ischemic attack (TIA).
The ACC/AHA cholesterol management guideline recommends statins as first-line therapy for secondary prevention in patients 21-75 years of age who have clinical ASCVD (i.e., acute coronary syndromes, history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, peripheral arterial disease presumed to be of atherosclerotic origin) unless contraindicated.
Several clinical trials designed to evaluate the benefits of pravastatin for secondary prevention of cardiovascular disease in patients with established CHD, including prior MI and angina pectoris, have reported improvements in cardiovascular risk status, as evidenced by reductions in the risks of total mortality and nonfatal coronary events. In the Cholesterol and Recurrent Events (CARE) study, therapy with pravastatin sodium (40 mg daily) in patients with prior MI and average cholesterol concentrations (baseline total, LDL-, and high-density lipoprotein [HDL]-cholesterol concentrations averaging 209, 139, and 39 mg/dL, respectively), was associated with a 24% reduction in fatal or nonfatal coronary events (i.e., CHD death, nonfatal MI) compared with placebo after an average follow-up period of approximately 5 years. Therapy with pravastatin also reduced the risk of undergoing myocardial revascularization procedures (e.g., coronary artery bypass grafting, percutaneous transluminal coronary angioplasty) by 27% and the risk of stroke or TIA by 26% (risk reduction of 31% for stroke alone). The reduction in the incidence of combined coronary events (coronary death, nonfatal MI, revascularization procedures, stroke or TIA) reported in the CARE trial also was observed in women, in geriatric patients (65 years of age and older), in patients with diabetes mellitus, and in those who had undergone coronary revascularization. Treatment with pravastatin also was associated with a reduction in overall mortality when compared with placebo. In the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study, therapy with pravastatin sodium (40 mg daily) in patients with a history of MI or hospitalization for unstable angina and normal or elevated total cholesterol concentrations resulted in reductions in overall mortality (22%), CHD mortality (24%), MI (29%), stroke (19%), and coronary revascularization procedures (20%) compared with placebo after an average follow-up period of 6.1 years.
Recent findings indicate that intensive antilipemic therapy may be more effective than moderate antilipemic therapy in reducing the risk of cardiovascular events in patients with acute coronary syndrome. In a randomized, double-blind, active-control study (Pravastatin or Atorvastatin Evaluation and Infection Therapy [PROVE-IT]) in over 4000 patients hospitalized for an acute coronary syndrome within the preceding 10 days, treatment with intensive antilipemic therapy (atorvastatin 80 mg daily) or moderate antilipemic therapy (pravastatin sodium 40 mg daily) for 2 years reduced LDL-cholesterol concentrations to a median of 62 or 95 mg/dL, respectively. Compared with the moderate regimen, treatment with the intensive regimen resulted in a 16% reduction in the composite risk of primary endpoints, including a 14% reduction in the need for revascularization procedures and a 29% reduction in the risk of recurrent unstable angina. Atorvastatin therapy also was associated with reductions in the endpoints of death from any cause (28%) and of death or MI (18%) compared with pravastatin therapy, but these differences were not statistically significant. Results of this study suggest that among patients who have recently had an acute coronary syndrome, an intensive antilipemic regimen provides greater protection against death or major cardiovascular events than does a standard regimen, and patients benefit from early and continued lowering of LDL-cholesterol to levels substantially below currently recommended target levels.
Reducing Progression of Coronary Atherosclerosis
Pravastatin is used as an adjunct to nondrug therapies (e.g., dietary management) in patients with clinical evidence of CHD to slow the progression of coronary atherosclerosis.
Pravastatin has been shown to slow the progression and/or induce regression of atherosclerosis in both coronary and carotid arteries by reducing intimal-medial wall thickness. In several double-blind, placebo-controlled studies (i.e., the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries [PLAC I] and the Regression Growth Evaluation Statin Study [REGRESS] in men and women with clinical evidence of CHD and/or angina pectoris and normal to moderately elevated lipoprotein concentrations), progression of atherosclerosis at 2-3 years (measured as the mean per-patient changes from baseline in mean and minimal coronary artery lumen diameters, percent diameter stenosis, and formation of new lesions) was reduced in patients who received pravastatin sodium (40 mg daily) compared with that in those receiving placebo.
Treatment with pravastatin also has been shown to reduce the rate of progression of atherosclerosis in the carotid arteries. In several randomized, placebo-controlled studies (the Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries [PLAC II], the Kuopio Atherosclerosis Prevention Study [KAPS], the REGRESS subgroup study), hypercholesterolemic patients with or without CHD who received pravastatin sodium (20-40 mg daily) for a median of 2-3 years had less progression of atherosclerosis (as determined by B-mode ultrasound quantification of carotid artery intimal-medial thickness [IMT]) compared with those receiving placebo. Limited data indicate that pravastatin also may slow progression of atherosclerosis in patients with clinical evidence of CHD who have normal cholesterol concentrations.
Recent findings indicate that intensive antilipemic therapy may be more effective than moderate antilipemic therapy in slowing the progression of coronary atherosclerosis in patients with CHD. In a randomized, double-blind, active-control study (Reversal of Atherosclerosis with Aggressive Lipid Lowering [REVERSAL]) in 654 patients with CHD, treatment with intensive antilipemic therapy (atorvastatin 80 mg daily) or moderate antilipemic therapy (pravastatin sodium 40 mg daily) for 18 months reduced LDL-cholesterol concentrations to a mean of 79 or 110 mg/dL, respectively; concentrations of C-reactive protein were reduced by 36.4% in atorvastatin-treated patients and by 5.2% in pravastatin-treated patients. Treatment with the intensive regimen was associated with a substantially lower progression rate (measured by percent change in atheroma volume) compared with treatment with the moderate regimen. Compared with baseline values, patients treated with atorvastatin had no change in atheroma burden, whereas patients treated with pravastatin showed progression of coronary atherosclerosis. It has been suggested that the differences in atherosclerosis progression between atorvastatin and pravastatin may be related to the greater reduction in atherogenic lipoproteins and C-reactive protein concentrations in patients treated with atorvastatin.
Pooled data from several atherosclerosis regression trials in patients with documented CHD, including atherosclerosis and angina pectoris, and mild to moderate hypercholesterolemia indicate that treatment with pravastatin is associated with a reduction in the incidence of clinical events (i.e., death, MI, revascularization procedures) compared with that in patients receiving placebo.
Intensity of Statin Therapy
The ACC/AHA cholesterol management guideline states that the appropriate intensity of a statin should be used to reduce the risk of ASCVD in patients most likely to benefit. Based on the average LDL-cholesterol response observed with specific statins and dosages used in the randomized controlled studies evaluated by the guideline expert panel, ACC/AHA considers pravastatin 10-20 mg daily to be a low-intensity statin (producing approximate LDL-cholesterol reductions of less than 30%) and pravastatin 40-80 mg daily to be a moderate-intensity statin (producing approximate LDL-cholesterol reductions of 30% to less than 50%). Individual patient response may vary in clinical practice.
Combination Antilipemic Therapy
The ACC/AHA cholesterol management guideline states that nonstatin drugs may be useful adjuncts to statin therapy in certain high-risk patients (e.g., patients with ASCVD, LDL-cholesterol concentrations of at least 190 mg/dL, or diabetes mellitus) who have a less-than-anticipated response to statins, are unable to tolerate a less-than-recommended intensity of a statin, or are completely intolerant to statin therapy, particularly if there is evidence from randomized controlled studies suggesting that the addition of the nonstatin drug further reduces ASCVD events. If combination therapy is necessary, selection of the nonstatin drug should be based on the risk and benefit profile (i.e., reduction in ASCVD risk outweighs the drug's potential for adverse effects and drug interactions) and patient preferences.
Pravastatin is used as an adjunct to nondrug therapies (e.g., dietary management) to decrease elevated serum total and LDL-cholesterol, apolipoprotein B (apo B), and triglyceride concentrations, and to increase HDL-cholesterol concentrations in the treatment of primary hypercholesterolemia and mixed dyslipidemia, primary dysbetalipoproteinemia, and/or hypertriglyceridemia. Patients with homozygous familial hypercholesterolemia usually respond poorly to combined dietary management and drug therapy, including regimens containing a statin, in part because these patients have poorly functioning, few, or no LDL receptors. The manufacturer states that efficacy of pravastatin remains to be established in patients with elevated chylomicrons as their primary lipid abnormality.
Nondrug therapies and measures specific for the type of dyslipidemia (therapeutic lifestyle changes) are the initial treatments of choice, including dietary management (e.g., restriction of total and saturated fat and cholesterol intake, addition of plant stanols/sterols and viscous fiber to diet), weight control, an appropriate program of physical activity, and management of potentially contributory disease. Drug therapy is not a substitute for but an adjunct to these nondrug therapies and measures, which should be continued when drug therapy is initiated.
Primary Hypercholesterolemia or Mixed Dyslipidemia
Pravastatin is used as an adjunct to nondrug therapies (e.g., dietary management) in adults to decrease elevated serum total and LDL-cholesterol, apo B, and triglyceride concentrations, and to increase HDL-cholesterol concentrations in the treatment of primary hypercholesterolemia or mixed dyslipidemia (Fredrickson type IIa or IIb). Pravastatin also is used as an adjunct to dietary therapy and therapeutic lifestyle changes in the management of heterozygous familial hypercholesterolemia in children 8 years of age and older who, despite an adequate trial of dietary management, have a serum LDL-cholesterol concentration of 190 mg/dL or greater or a serum LDL-cholesterol concentration of 160 mg/dL or greater and either a family history of premature cardiovascular disease or 2 or more other cardiovascular risk factors. Statins such as pravastatin also are used in combination with fenofibrate to decrease triglyceride concentrations and increase HDL-cholesterol concentrations in patients with mixed dyslipidemia and CHD (or CHD risk equivalents) who are receiving optimal statin therapy; however, no additional benefit on cardiovascular morbidity and mortality has been demonstrated with such combination therapy beyond that already established with statin monotherapy.
Reductions in total and LDL-cholesterol produced by usual dosages of pravastatin sodium substantially exceed those of placebo and appear to be similar to or less than those produced by monotherapy with usual dosages of some other antilipemic agents. Mean reductions in total cholesterol concentrations of 13-27%, LDL-cholesterol concentrations of 21-37%, and triglyceride concentrations of 9-24% have been reported in controlled and uncontrolled studies in patients with primary hypercholesterolemia who received 5-80 mg of pravastatin daily for at least 6 weeks. Modest and variable increases in HDL-cholesterol concentrations (2-12%) also were observed in these patients. In long-term controlled and uncontrolled studies (at least 36 weeks), mean total and LDL-cholesterol reductions of 20-29 and 26-34%, respectively, were observed with 40 mg of pravastatin daily.
Reductions in total and LDL-cholesterol concentrations produced by usual dosages of pravastatin sodium appear to be similar to or less than those produced by monotherapy with most other statins (e.g., atorvastatin, lovastatin, rosuvastatin, simvastatin). In a randomized, multicenter, parallel-group study comparing the efficacy of various statins, patients with hypercholesterolemia who received pravastatin sodium 10-40 mg daily experienced similar or smaller reductions in plasma total and LDL-cholesterol concentrations (13-24 and 19-34%, respectively) than those who received atorvastatin 10-80 mg daily (28-4% and 38-54%, respectively), lovastatin 20-80 mg daily (21-36 and 29-48%, respectively), and simvastatin 10-40 mg daily (21-30 and 28-41%, respectively). However, patients receiving pravastatin sodium dosages of 10-40 mg daily had greater reductions in plasma total and LDL-cholesterol concentrations (13-24 and 19-34%, respectively) than those who received fluvastatin 20-40 mg daily (13-19 and 17-23%, respectively).
Limited data from comparative studies suggest that reductions in total and LDL-cholesterol concentrations produced by pravastatin may be similar to or greater than those of other antilipemic agents (i.e., bile acid sequestrants, niacin, fibric acid derivatives). In 2 placebo-controlled studies comparing 12-24 weeks of pravastatin sodium therapy (40-80 mg daily) with that of cholestyramine (24 g daily in 2 divided doses) in patients with primary hypercholesterolemia, total and LDL-cholesterol reductions with pravastatin (24-30 and 30-39%, respectively) were similar to those with cholestyramine (18-23 and 28-32%, respectively); effects on increasing HDL-cholesterol concentrations also were similar (5-8% for pravastatin versus 5% for cholestyramine). However, pravastatin was more effective than cholestyramine in improving triglyceride concentrations, as evidenced by 13-19% decreases in pravastatin-treated patients and 12-21% increases in cholestyramine-treated patients. Pravastatin appears to be more effective than niacin or gemfibrozil in reducing total and LDL-cholesterol concentrations but less effective than these agents in reducing triglycerides and increasing HDL-cholesterol concentrations. In several randomized, comparative studies in patients with primary types IIa and IIb hyperlipoproteinemia, therapy with pravastatin sodium 40 mg daily produced greater reductions in total and LDL-cholesterol concentrations (23-26 and 30-34%, respectively) than niacin 1-4 g daily in 2 or 3 divided doses (11 and 16%, respectively) or gemfibrozil 600 mg twice daily (14-15 and 16-17%, respectively); however, reductions in triglyceride (4-14%) and increases in HDL-cholesterol concentrations (3-6%) associated with pravastatin therapy were less pronounced than those reported with niacin (32% reduction and 27% increase) or gemfibrozil (37-42% reduction and 13-15% increase).
The combination of pravastatin and other antilipemic agents (e.g., bile acid sequestrants, niacin, fibric acid derivatives) generally results in additive antilipemic effects; however, the risk of myopathy and rhabdomyolysis may be increased.
(See Combination Antilipemic Therapy under Uses: Prevention of Cardiovascular Events.)The addition of a bile acid sequestrant to pravastatin therapy further reduced LDL-cholesterol by 14-20%, resulting in overall LDL-cholesterol reductions of 45-51% in patients receiving pravastatin 40 mg daily and cholestyramine 24 g daily. Combining niacin (1-3 g daily in 2 or 3 divided doses) with pravastatin sodium (20-40 mg daily) for 8-18 weeks in hypercholesterolemic patients with or without documented CHD further reduced total cholesterol, LDL-cholesterol, apo B, and triglyceride concentrations by 9, 9-11, 11, and 20-27%, respectively, and increased HDL-cholesterol and apo A concentrations by 3-29 and 11%, respectively. Similar effects also were observed in diabetic patients with hyperlipidemia who received low-dose pravastatin sodium (20 mg daily) and niacin (500 mg 3 times daily) therapy for 4 weeks. Pravastatin (40 mg daily) in combination with gemfibrozil (600 mg twice daily) in patients with primary hypercholesterolemia further reduced triglyceride concentrations by 28% and increased HDL-cholesterol concentrations by 11%. The increased risk of adverse skeletal muscle effects should be considered when pravastatin is used in combination with some antilipemic agents (i.e., fibric acid derivatives, niacin at lipid-modifying dosages [at least 1 g daily]).
Pravastatin is used as an adjunct to nondrug therapies (e.g., dietary management) for the treatment of primary dysbetalipoproteinemia (Fredrickson type III) in patients who do not respond adequately to diet.
Treatment with pravastatin has resulted in substantial reductions in total and LDL-cholesterol, VLDL-cholesterol, triglyceride, and non-HDL-cholesterol concentrations. In several small double-blind, crossover studies in a limited number of patients with primary dysbetalipoproteinemia who received pravastatin 40 mg daily, total cholesterol, LDL-cholesterol, VLDL-cholesterol, triglyceride, and non-HDL-cholesterol concentrations decreased by 31-33, 30-41, 36-44, 12-24, and 36-37%, respectively.
Pravastatin is used as an adjunct to nondrug therapies (e.g., dietary management) in the treatment of elevated serum triglyceride concentrations (Fredrickson type IV). AHA states that although statins have consistently shown benefit in subgroups with or without high triglyceride concentrations, fibric acid derivatives have more commonly been shown to provide greater benefit in subgroups with increased triglyceride concentrations.
Mean reductions in total cholesterol concentrations of 22%, LDL-cholesterol concentrations of 32%, triglyceride concentrations of 21%, and non-HDL-cholesterol concentrations of 27% have been reported in a subgroup analysis of a double-blind, placebo-controlled study in patients with hypertriglyceridemia who received 40 mg of pravastatin daily for a median of 4.9 years. Modest increases in HDL-cholesterol concentrations (7%) also were observed in these patients.
Pravastatin has been shown to slow the progression and/or induce regression of atherosclerosis in a few patients without clinical evidence of CHD who had mild to moderate elevations of LDL-cholesterol.The drug also has reduced transient myocardial ischemia in male patients with clinical evidence of CHD or unstable angina pectoris.
While some statins have been shown to reduce the rate of restenosis following coronary stent implantation, pravastatin has not been shown to reduce the incidence of restenosis in patients undergoing coronary balloon angioplasty.
Pravastatin has reduced total and LDL-cholesterol concentrations in patients with hypercholesterolemia associated with or exacerbated by diabetes mellitus (diabetic dyslipidemia), cardiac or liver transplantation, or nephrotic syndrome (nephrotic hyperlipidemia).
For additional information on the role of pravastatin or other statins in the treatment of lipoprotein disorders, prevention of cardiovascular events, or other uses, see General Principles of Antilipemic Therapy and see Uses in the HMG-CoA Reductase Inhibitors General Statement 24:06.08.