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| |  Fluvastatin Slows Progression of Atherosclerosis in CHD Patients NEW ORLEANS, Nov. 11, 1996 -- AMERICAN HEART ASSOCIATION MEETING -- For the first time, a trial with angiographic endpoints demonstrated the benefits of cholesterol-lowering treatment in patients with mildly and moderately elevated low-density lipoprotein cholesterol (LDL-C) levels (as low as 115 mg/dl) and coronary heart disease (CHD), according to a study presented this week at the annual meeting of the American Heart Association. The Lipoprotein and Coronary Atherosclerosis Study (LCAS), demonstrated that therapy with the cholesterol-lowering drug fluvastatin sodium, an HMG-CoA reductase inhibitor, produced regression and slowed progression of atherosclerosis in patients with CHD and mild to moderate LDL-C elevations. "The findings of this study are important because the majority of patients with CHD have LDL-C elevations in the mild to moderate range," said Antonio M. Gotto, Jr., M.D., D.Phil., Chief, Internal Medicine Service, Methodist Hospital and Chairman, Department of Medicine, Baylor College of Medicine, in Houston, Texas, and the principal investigator of LCAS. Previous angiographic trials with HMG-CoA reductase inhibitors, also called statins, have demonstrated the benefits of lowering moderate to severely elevated LDL-C. However, prior to LCAS, effects of cholesterol-lowering treatment in patients with mildly elevated LDL-C have been controversial. As a result, appropriate treatment may not be commonly prescribed for all patients with CHD and LDL-C levels in this range, which is above the National Cholesterol Education Program (NCEP) goal of 100 mg/dl. "Many physicians have been reluctant to treat patients with relatively low LDL-C elevations without conclusive evidence that these patients would receive therapeutic benefit from treatment with cholesterol-lowering drugs. LCAS provides information physicians need in order to assess which patients can benefit from treatment," said Dr. Gotto. Slowing the Progression of Atherosclerosis Fluvastatin patients exhibited significantly less atherosclerotic progression than placebo patients: minimum lumen diameter decreased only 0.028 mm with fluvastatin versus 0.100 mm with placebo. LCAS demonstrated similar treatment benefit among both men and women treated with fluvastatin. In addition, regression of atherosclerosis occurred in nearly twice as many fluvastatin patients as placebo patients (14.6 versus 8.3 percent) and progression occurred less frequently (28.7 versus 39.1 percent of patients). Angiographic benefit was consistent in patients with LDL-C levels less than 160 mg/dl and in patients with LDL-C 160 mg/dl or greater. Clear benefits were also demonstrated in patients with pretreatment LDL-C less than 130 mg/dl. The Harvard Atherosclerosis Reversibility Project (HARP) is the only previously reported angiographic trial designed to assess the effects of lipid-regulating therapy in patients with normal to mildly elevated cholesterol. Alone among reported regression trials, HARP, a study of 79 patients, failed to show angiographic coronary benefit despite achievement of a mean LDL-C of 86 mg/dl with treatment. Investigators concluded that patients with mildly elevated LDL-C have minimal, if any, angiographic benefit. In LCAS, the number of patients with new lesions was reduced by 40.5 percent with fluvastatin. New lesions occurred in 22 fluvastatin patients and 37 placebo patients. At 12 weeks, LDL-C was reduced 26.5 percent in patients randomized to fluvastatin, and at the end of 2.5 years, LDL-C was reduced 23.9 percent from baseline. The angiographic benefit indicates that this LDL-C reduction was sufficient to reduce progression -- and in some instances -- induce regression in patients with mild to moderate elevations. "These data clearly indicate that the percent reduction in LDL-C is not the determining factor for therapeutic benefit from lipid lowering, as has been suggested," said Dr. Gotto. Atherosclerosis is a progressive, degenerative disease in which cholesterol, smooth muscle cells and blood components build up in the inner walls of arteries and form atherosclerotic plaque. The formation of these lesions causes narrowing of the arterial lumen, resulting in the obstruction of blood flow. The obstruction of blood flow to the heart can result in tissue damage or tissue death. Progression of atherosclerosis is associated with higher morbidity and mortality from CHD. Clinical Benefits Although the study was not designed specifically to detect differences in clinical events, LCAS demonstrated a trend toward benefit consistent with results from trials of other statins. Compared to placebo, combined all-cause mortality and total cardiac events (myocardial infarction, percutaneous transluminal coronary angioplasty [PTCA], coronary artery bypass grafting [CABG], angina requiring hospitalization) decreased by 32.8 percent in patients with baseline LDL-C < 160 mg/dl. In this population, he number of patients requiring coronary invasive revascularization procedures (PTCA, CABG, atherectomy, transcatheter revascularization or coronary stent) decreased 33.6 percent, while a 35.8 percent reduction was seen in the number of patients requiring any revascularization procedure (coronary, peripheral or cartoid). Although the Cholesterol and Recurrent Events CARE trial -- a trial that restricted enrollment to patients with similar cholesterol levels -- demonstrated reduction of CHD events, the benefits were not shown in patients with LDL-C of less than 125 mg/dl. With an estimated 485,000 CABG procedures and 369,000 PTCA procedures performed each year in the U.S. at an estimated cost of $24,000 and $16,225, respectively, per procedure, the potential reduction in revascularization procedures among patients treated with fluvastatin could have a favorable impact on health care expenditures. Positron-emission tomography (PET) performed in a subset of patients (79 analyzed), showed improvement in myocardial perfusion. PET scanning is a diagnostic technique based on the detection of positively charged particles (positrons) that are emitted by labeled substances (radioisotopes) introduced into the body. PET scanning produces three-dimensional images that allow physicians to examine metabolic changes in the body. In LCAS, fewer than 20 percent of patients were treated with a statin prior to enrollment in the trial. "The level of prior therapy with a statin shown in LCAS provides greater understanding of the actual treatment patterns in practice today," said Dr. Gotto. "The data from LCAS confirming the coronary benefits of statins support the need for more aggressive treatment for patients with established CHD. Further education about the benefits of these drugs will be necessary to ensure that patients who may benefit from therapy are treated appropriately." About LCAS Conducted at Baylor College of Medicine in Houston, Texas, LCAS was a randomized, double-blind, placebo-controlled trial of fluvastatin using 20 mg, twice daily. In order to provide treatment to placebo patients at known risk, open-label cholestyramine was added to the 25 percent of the study population whose baseline LDL-C was ( 160 mg/dl. The primary endpoint was within patient, per-lesion change in minimum lumen diameter as measured by quantitative coronary angiography at baseline and 2.5-year follow-up. Eligible subjects were men and women 35 to 75 years of age with LDL-C of 115-190 mg/dl on stable dietary therapy and with angiographic evidence of at least one coronary atherosclerotic lesion causing 30 to 75 percent diameter stenosis. Among the 429 patients randomized (mean age 58.8 years, 81.4 percent male), mean baseline LDL-C was 145.9 mg/dl. LCAS is the first large-scale clinical trial to monitor the effectiveness of fluvastatin on the progression of atherosclerosis, as observed through coronary angiography. As demonstrated in previous trials, angiographic changes are predictive of clinical coronary events. About Fluvastatin Sodium Fluvastatin is indicated as an adjunct to diet in the treatment of elevated total cholesterol and LDL-C levels in patients with primary hypercholesterolemia whose response to dietary modification and other nonpharmacological measures has not been adequate. Adverse reactions to fluvastatin are generally mild and similar to placebo. Common adverse effects are fatigue, nausea, diarrhea, dyspepsia, abdominal pain and rash. Although rare, instances of rhabdomyolysis (inflammation of the muscles) and myopathy have been reported with fluvastatin and with other drugs in this class. Statins are considered to be the most effective and well-tolerated drugs in lowering LDL-C levels. Statins work by partially blocking the synthesis of cholesterol in the liver. This decreased synthesis increases LDL receptor activity and uptake of LDL-C into liver cells, thereby decreasing the concentration of LDL-C and total cholesterol in the blood. Fluvastatin is manufactured by Sandoz Pharmaceuticals Corporation, headquartered in East Hanover, New Jersey.
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