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, fluvastatin 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).
Fluvastatin is used as an adjunct to nondrug therapies (i.e., lifestyle modifications) in patients with clinical evidence of coronary heart disease (CHD) to reduce the risk of undergoing coronary revascularization procedures.
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 myocardial infarction [MI], stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack [TIA], or peripheral arterial disease presumed to be of atherosclerotic origin) unless contraindicated.
In a randomized, double-blind, placebo-controlled study (Lescol Intervention Prevention Study [LIPS]) in 1677 patients with stable or unstable angina or silent ischemia who had undergone a first percutaneous coronary intervention (PCI) therapy with fluvastatin (40 mg twice daily), initiated within a mean of 3 days following PCI and continued for a median of 3.9 years, resulted in a 22% reduction in the relative risk and a 5.3% reduction in the absolute risk of fatal or nonfatal major adverse cardiac events (e.g., cardiac death, nonfatal MI, new or repeat PCI or coronary artery bypass grafting [CABG] procedure). Reduction in the risk of adverse cardiac events also was observed in geriatric patients (older than 65 years of age). Revascularization procedures (repeat PCI or CABG) involving the originally instrumented site comprised most of the initial recurrent adverse cardiac events; these procedures were performed in 143 or 171 patients receiving fluvastatin or placebo, respectively, within the first 6 months following the initial procedure. Treatment with fluvastatin also was associated with a 32% reduction in the risk of late revascularization procedures (i.e., PCI or CABG occurring at the original site more than 6 months following the initial procedure, or at another site).
In another randomized, double-blind, placebo-controlled study (Fluvastatin Angiographic Restenosis [FLARE] study) in patients with symptomatic or ischemia-producing coronary lesions who required balloon angioplasty, therapy with fluvastatin (40 mg twice daily) was associated with a lower incidence of death and nonfatal MI (1.4% in fluvastatin-treated patients versus 4% in placebo-treated patients).
Reducing Progression of Coronary Atherosclerosis
Fluvastatin is used as an adjunct to nondrug therapies (e.g., dietary management) to slow the progression of coronary atherosclerosis in hypercholesterolemic patients with CHD. In a placebo-controlled trial in men and women with angiographically documented CHD and mildly to moderately elevated serum LDL-cholesterol concentrations, progression of coronary atherosclerosis was slowed in patients treated with fluvastatin as measured by within-patient, per-lesion changes in minimum lumen diameter of qualifying lesions (primary end point), percent diameter stenosis, and the formation of new lesions over the 2.5-year follow-up period.
Beneficial effects of fluvastatin on angiographic progression of coronary atherosclerosis (change in minimum lumen diameter) were independent of patient gender and consistent across a range of baseline LDL-cholesterol concentrations. However, changes in minimum lumen diameter were greater among patients with low baseline high-density lipoprotein (HDL)-cholesterol (i.e., less than 35 mg/dL) than in those with normal to high HDL-cholesterol concentrations (i.e., 35 mg/dL or greater). In addition, fluvastatin-treated patients with low baseline HDL-cholesterol concentrations had improved event-free survival, as evidenced by a lower rate of time to first clinical event (i.e., percutaneous transluminal coronary angioplasty [PTCA], CABG, definite or probable MI, unstable angina requiring hospitalization, or death of any cause) compared with no benefit among patients with normal or high HDL-cholesterol concentrations.
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 fluvastatin 20-40 mg daily to be a low-intensity statin (producing approximate LDL-cholesterol reductions of less than 30%) and fluvastatin 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.
Patients with Chronic Kidney Disease
The potential benefits of fluvastatin in patients with chronic kidney disease, a population at high risk of cardiovascular disease, were evaluated in the Assessment of Lescol in Renal Transplantation (ALERT) study, a randomized, double-blind, placebo-controlled study that was conducted in approximately 2100 renal transplant patients. Results of the study showed no substantial effect of fluvastatin on the primary end point of major adverse cardiac events (defined as cardiac death, nonfatal MI, or coronary intervention procedure) compared with placebo, although fluvastatin appeared to reduce the risk of cardiac death and nonfatal MI.
Primary Hypercholesterolemia or Mixed Dyslipidemia
Fluvastatin 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 (heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIa or IIb). Fluvastatin also is used as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, and apo B concentrations in the management of heterozygous familial hypercholesterolemia in boys and girls (who are at least 1 year postmenarchal) 10-16 years of age 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 fluvastatin 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.
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.
Reductions in total and LDL-cholesterol produced by usual dosages of fluvastatin substantially exceed those of placebo but appear to be less than those produced by monotherapy with usual dosages of other antilipemic agents. Mean reductions in total cholesterol, LDL-cholesterol, apolipoprotein B (apo B), and triglyceride concentrations of 13-27, 17-36, 18-28, and 7-18%, respectively, have been reported in controlled studies in patients with primary hypercholesterolemia or mixed dyslipidemia who received 20-80 mg of fluvastatin daily for at least 6 weeks. Modest and variable increases in HDL-cholesterol concentrations (2-10%) also were observed in these patients. In a subgroup of patients with primary mixed dyslipidemia (defined as baseline triglyceride concentrations of at least 200 mg/dL), therapy with fluvastatin was associated with 16-27, 22-35, 18-28, and 17-23% reductions in total cholesterol, LDL-cholesterol, apo B, and triglyceride concentrations, respectively, and 6-9% increases in HDL-cholesterol concentrations. In a long-term (98-week), open label, dose-titration study, LDL-cholesterol reductions of 25, 31, and 34% were observed with 20, 40, and 80 mg, respectively, of fluvastatin.
Effects on various lipoprotein fractions appear to be similar in patients receiving an equivalent daily dosage (80 mg) of extended-release tablets or conventional capsules. Mean reductions in total cholesterol, LDL-cholesterol, apo B, and triglyceride concentrations of 25, 35, 27, and 19%, respectively, and mean increases in HDL-cholesterol concentrations of 7% have been reported in patients receiving the extended-release formulation for at least 4 weeks. In a subgroup of patients with primary mixed dyslipidemia (defined as triglyceride concentrations of at least 200 mg/dL), therapy with extended-release fluvastatin was associated with 25, 33, 27, and 25% reductions in total cholesterol, LDL-cholesterol, apo B, and triglyceride concentrations, respectively, and 11% increases in HDL-cholesterol concentrations.
Safety and efficacy of fluvastatin in pediatric patients have been evaluated in 2 open-label, uncontrolled, dose-titration studies. In these studies, pediatric patients (9-16 years of age) with heterozygous familial hypercholesterolemia treated with fluvastatin 20-80 mg daily for approximately 2 years had 21-22% reductions in total cholesterol and 27-28% reductions in LDL-cholesterol concentrations. Approximately 83-89% of patients received the maximum dosage of 80 mg daily. At the end of the study, 26-30% of patients achieved a target LDL-cholesterol goal of less than 130 mg/dL. The long-term efficacy of fluvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established. For additional details on management of dyslipidemias in pediatric patients, and also consult the most recent Integrated Guideline for Cardiovascular Health and Risk Reduction in Children and Adolescents (available at http://www.nhlbi.nih.gov).
Reductions in total and LDL-cholesterol concentrations produced by usual dosages of fluvastatin appear to be smaller than those produced by monotherapy with other statins. In a randomized, multicenter, parallel-group study comparing the efficacy of various statins (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin), patients with hypercholesterolemia who received fluvastatin 20-40 mg daily had similar or smaller reductions in total and LDL-cholesterol concentrations (13-19 and 17-23%, respectively) than those receiving atorvastatin 10-80 mg daily (28-42 and 38-54%, respectively), lovastatin 20-80 mg daily (21-36 and 29-48%, respectively), pravastatin 10-40 mg daily (13-24 and 19-34%, respectively), and simvastatin 10-40 mg daily (21-30 and 28-41%, respectively).
Fluvastatin (40 mg daily) reportedly produces smaller reductions in total and LDL-cholesterol concentrations than cholestyramine (16 g daily), with reductions of 22 and 28%, respectively, in fluvastatin-treated patients versus 25 and 35%, respectively, in cholestyramine-treated patients. However, treatment with cholestyramine was associated with a 12% increase in triglyceride concentrations compared with an 11% decrease in fluvastatin-treated patients. Limited data from comparative studies suggest that fluvastatin has efficacy similar to or greater than that of fibric acid derivatives in reducing total and LDL-cholesterol concentrations in patients with primary hypercholesterolemia. In a 12-week, open-label study comparing fluvastatin (40 mg daily) with bezafibrate (400 mg daily) (currently not commercially available in the US), patients with primary types IIa and IIb hypercholesterolemia who received fluvastatin therapy had greater reductions in total and LDL-cholesterol concentrations than those treated with bezafibrate (27 and 45% versus 8 and 4%, respectively). Reductions in triglyceride concentrations (26%) reportedly were similar with the 2 treatments.
The combination of fluvastatin 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 with some antilipemic combinations.
(See Combination Antilipemic Therapy under Uses: Prevention of Cardiovascular Events.)The addition of a bile acid sequestrant to fluvastatin therapy further reduced LDL-cholesterol by 9-12%, resulting in overall LDL-cholesterol reductions of 27-47% in patients receiving fluvastatin 10-40 mg daily and cholestyramine 4-16 g daily. The combination of fluvastatin (20 mg daily) and niacin (3 g daily) for 9 weeks in hypercholesterolemic patients further reduced total and LDL-cholesterol concentrations by 12 and 19%, respectively. In addition, such combined therapy also reduced triglyceride concentrations by an additional 18% and increased HDL-cholesterol concentrations by 23%. In several double-blind studies in a limited number of hypercholesterolemic patients, the combination of fluvastatin (40 mg daily) and fibric acid derivatives (i.e., gemfibrozil 600 mg twice daily or bezafibrate [not commercially available in the US] 400 mg daily) resulted in greater reductions in total cholesterol, LDL-cholesterol, and triglyceride concentrations compared with those achieved with fluvastatin monotherapy. Triple-drug therapy with fluvastatin, cholestyramine, and a fibric acid derivative in patients with severe heterozygous familial hypercholesterolemia has produced further sustained reductions in LDL-cholesterol concentrations compared with those produced by combinations of any 2 of these drugs. The increased risk of adverse muscular effects should be considered when fluvastatin is used in combination with some antilipemic agents (e.g., fibric acid derivatives or niacin at lipid-modifying dosages [at least 1 g daily]).
Fluvastatin has reduced total and LDL-cholesterol concentrations in a few patients with hypercholesterolemia associated with or exacerbated by diabetes mellitus (diabetic dyslipidemia), renal insufficiency, cardiac or renal transplantation, or nephrotic syndrome (nephrotic hyperlipidemia). Fluvastatin also has been shown to decrease proteinuria in patients with immunoglobulin A nephropathy. Additional studies are necessary to determine the role, if any, of fluvastatin therapy in patients with these disorders.
For additional information on the role of fluvastatin 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.