(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Coronary-Artery-Disease

Statin therapy has been shown to significantly decrease vascular events and overall mortality in primary and secondary prevention trials. This review considers the pharmacology, nonlipid-lowering effects and clinical trial evidence of fluvastatin based on a survey of PubMed entries.. Recent clinical data show that treatment with fluvastatin is associated with a variety of benefits in different high-risk populations along with a good safety profile. Fluvastatin exerts non-lipid lowering-associated pleiotropic effects in both clinical and experimental studies. Furthermore, an extended-release formulation of fluvastatin with a favourable pharmacokinetic profile is available.. Treatment with fluvastatin offers a convenient, safe and evidence-based approach to managing dyslipidaemias and preventing vascular events.

Topics: Coronary Artery Disease; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Lipids; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Animals; Anticholesteremic Agents; Cholesterol, LDL; Clinical Trials as Topic; Coronary Artery Disease; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemia Type II; Indoles; Lipid Peroxidation

Drug-drug interaction between statins metabolised by cytochrome P450 3A4 and clopidogrel have been claimed to attenuate the inhibitory effect of clopidogrel. However, published data regarding this drug-drug interaction are controversial. We aimed to determine the effect of fluvastatin and atorvastatin on the inhibitory effect of dual antiplatelet therapy with acetylsalicylic acid (ASA) and clopidogrel. One hundred one patients with symptomatic stable coronary artery disease undergoing percutaneous coronary intervention and drug-eluting stent implantation were enrolled in this prospective randomised study. After an interval of two weeks under dual antiplatelet therapy with ASA and clopidogrel, without any lipid-lowering drug, 87 patients were randomised to receive a treatment with either fluvastatin 80 mg daily or atorvastatin 40 mg daily in addition to the dual antiplatelet therapy for one month. Platelet aggregation was assessed using light transmission aggregometry and whole blood impedance platelet aggregometry prior to randomisation and after one month of receiving assigned statin and dual antiplatelet treatment. Platelet function assessment after one month of statin and dual antiplatelet therapy did not show a significant change in platelet aggregation from 1st to 2nd assessment for either statin group. There was also no difference between atorvastatin and fluvastatin treatment arms. In conclusion, neither atorvastatin 40 mg daily nor fluvastatin 80 mg daily administered in combination with standard dual antiplatelet therapy following coronary drug-eluting stent implantation significantly interfere with the antiaggregatory effect of ASA and clopidogrel.

Topics: Aged; Angioplasty, Balloon, Coronary; Aspirin; Atorvastatin; Chi-Square Distribution; Clopidogrel; Coronary Artery Disease; Drug Interactions; Drug Therapy, Combination; Drug-Eluting Stents; Fatty Acids, Monounsaturated; Female; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prospective Studies; Prosthesis Design; Pyrroles; Switzerland; Ticlopidine; Time Factors; Treatment Outcome

Case-control Genome-Wide Association Studies (GWAS) have identified single nucleotide polymorphisms (SNPs) at the 9p21 locus as risk factors for coronary artery disease (CAD). The locus does not contain a clear candidate gene. Hence, the results of GWAS have raised an intense interest in delineating the basis for the observed association. We analyzed association of 4 SNPs at the 9p21 locus with the severity and progression of coronary atherosclerosis, as determined by serial quantitative coronary angiograms (QCA) in the well-characterized Lipoprotein Coronary Atherosclerosis Study (LCAS) population. The LCAS is a randomized placebo-control longitudinal follow-up study in patients with CAD conducted to test the effects of fluvastatin on progression or regression of coronary atherosclerosis.. Extensive plasma lipid levels were measured at the baseline and 2 1/2 years after randomization. Likewise serial QCA was performed at the baseline and upon completion of the study. We genotyped the population for 4 SNPs, previously identified as the susceptibility SNPs for CAD in GWAS, using fluorogenic 5' nuclease assays. We reconstructed the haplotypes using Phase 2, analyzed SNP and haplotype effects using the Thesias software as well as by the conventional statistical methods.. Only Caucasians were included since they comprised 90% of the study population (332/371 with available DNA sample). The 4 SNPs at the 9p21 locus were in tight linkage disequilibrium, leading to 3 common haplotypes in the LCAS population. We found no significant association between quantitative indices of severity of coronary atherosclerosis, such as minimal lumen diameter and number of coronary lesions or occlusions and the 9p21 SNPs and haplotypes. Likewise, there was no association between quantitative indices of progression of coronary atherosclerosis and the SNPs or haplotypes. Similarly, we found no significant SNP or haplotype effect on severity and progression of coronary atherosclerosis.. We conclude the 4 SNPs at the 9p21 locus analyzed in this study do not impart major effects on the severity or progression of coronary atherosclerosis. The effect size may be very modest or the observed association of the CAD with SNPs at the 9p21 locus in the case-control GWAS reflect involvement of vascular mechanisms not directly related to the severity or progression of coronary atherosclerosis.

Topics: Adult; Aged; Chromosomes, Human, Pair 9; Coronary Artery Disease; Disease Progression; Fatty Acids, Monounsaturated; Female; Fluvastatin; Follow-Up Studies; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Indoles; Linkage Disequilibrium; Male; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors; Severity of Illness Index; White People

Patients with systemic lupus erythematosus (SLE), with or without end-stage renal failure, are at increased risk of premature cardiovascular disease. Although statin therapy has been found to reduce cardiovascular risk in the general population, its effectiveness in kidney transplant recipients with SLE has not been examined. This study was undertaken to investigate the effect of fluvastatin on cardiac end points in a randomized controlled trial of renal transplant patients with SLE.. Patients with SLE were identified from among participants in the Assessment of Lescol in Renal Transplantation trial, a randomized, double-blind, placebo-controlled study of the effect of fluvastatin (40-80 mg/day) on cardiovascular outcomes in renal transplant recipients. Patients were randomized to either a group receiving fluvastatin or a placebo group for the duration of the 5-6-year trial, and then invited to continue in a 2-year open-label extension during which all participants, regardless of original group, received fluvastatin. Patients were followed up for a total of 7-8 years for assessment of the primary end point of major cardiac events, comprising nonfatal myocardial infarction, cardiac death, and coronary intervention procedures.. Fluvastatin reduced low-density lipoprotein cholesterol levels by 29.2% (95% confidence interval [95% CI] 18.3-40%), from a mean +/- SD of 4.0 +/- 0.9 mmoles/liter to 2.8 +/- 1.1 mmoles/liter, and total cholesterol by 19.6% (95% CI 11.7-27.5%), from 6.4 +/- 0.9 mmoles/liter to 5.1 +/- 1.1 mmoles/liter. Compared with placebo-treated patients, patients randomized to receive fluvastatin exhibited a 73.4% reduction in the risk of major cardiac events (relative risk 26.6 [95% CI 5.9-119.4], P = 0.064).. Our results indicate that the effect of fluvastatin on cardiac events in renal transplant recipients with SLE is similar to that observed with statin therapy in the renal transplant population as a whole.

Topics: Adult; Anticholesteremic Agents; Cholesterol, LDL; Coronary Artery Disease; Death, Sudden, Cardiac; Fatty Acids, Monounsaturated; Fluvastatin; Follow-Up Studies; Humans; Indoles; Kaplan-Meier Estimate; Kidney Transplantation; Lupus Erythematosus, Systemic; Lupus Nephritis; Middle Aged; Morbidity; Myocardial Infarction; Placebos; Postoperative Complications; Proportional Hazards Models; Risk Factors

Patients with metabolic syndrome (MS) and type 2 diabetes (T2DM) show increased risk for coronary artery disease. Lipoprotein metabolism is characterized by elevated triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C) and predominance of atherogenic small, dense low-density lipoprotein (sdLDL), while low-density lipoprotein (LDL) cholesterol is only slightly elevated.. Multicentre, randomized, open-label cross-over study investigating the effect of combination of fluvastatin/fenofibrate (80/200 mg) (F&F) on LDL-subfractions compared with combination of simvastatin/ezetimibe (20/10 mg) (S&E) in patients with MS/T2DM.. Seventy-five patients were randomized, 69 completed the study and LDL-subfractions of 56 patients were analysed. Thirty-eight out of 56 patients (68%) showed a profile dominated by sdLDL. In these, TG and total cholesterol (TC) were elevated compared with non-sdLDL patients. In all patients, reduction of TC and LDL cholesterol (LDL-C) by S&E was stronger than by F&F. The increase of HDL-C was stronger with S&E in the non-sdLDL group, whereas in the sdLDL group, there was no difference between treatments. In non-sdLDL patients, there was no effect on TG or LDL-radius. However, in the sdLDL group, F&F was more effective in reducing TG and increased LDL radius, whereas S&E reduced LDL radius even further.. S&E is more efficient in reducing TC and LDL-C. This is also true for HDL-C increase in non-sdLDL patients. However, in patients with sdLDL, F&F was more efficient in reducing TG and increasing LDL radius.

Topics: Anticholesteremic Agents; Azetidines; Cholesterol, LDL; Coronary Artery Disease; Drug Administration Schedule; Drug Therapy, Combination; Ezetimibe; Fatty Acids, Monounsaturated; Female; Fenofibrate; Fluvastatin; Humans; Indoles; Male; Metabolic Syndrome; Middle Aged; Simvastatin; Treatment Outcome

The aim of this study was to evaluate the effect of treatment with statins on the progression of coronary atherosclerotic plaques of a nonculprit vessel by serial volumetric virtual histology (VH) intravascular ultrasound (IVUS).. Recent clinical trials have demonstrated a reduction of atherosclerotic plaque, yet whether statin therapy affects the change in components of plaque remains unknown.. This study was a nonrandomized and nonblinded design. Eighty patients with stable angina pectoris were divided into either the fluvastatin group (n = 40) or the control group (n = 40) according to their total or low-density lipoprotein (LDL) cholesterol level. The volume of each plaque component (dense calcium, fibrous tissue, fibro-fatty, or necrotic core) was evaluated at baseline and at 12-month follow-up.. The LDL cholesterol and high-sensitivity C-reactive protein (hsCRP) levels in the fluvastatin group were significantly decreased at time of follow-up. In VH IVUS findings, fibro-fatty volume was significantly decreased (baseline 80.1 +/- 57.9 mm(3) vs. follow-up 32.5 +/- 27.7 mm(3), p < 0.0001) and fibrous tissue volume was increased (baseline 146.5 +/- 85.6 mm(3) vs. follow-up 163.3 +/- 94.5 mm(3), p < 0.0001) in the fluvastatin group. In the control group, the volumes of all plaque components without fibrous tissue were significantly increased. Change in fibro-fatty volume has a significant correlation with a change in LDL cholesterol level (R = 0.703, p < 0.0001) and change in hsCRP level (R = 0.357, p = 0.006).. One-year lipid-lowering therapy by fluvastatin showed significant regression of plaque volume and alterations in atherosclerotic plaque composition with a significant reduction of fibro-fatty volume.

Topics: Aged; Biomarkers; C-Reactive Protein; Calcinosis; Cholesterol, LDL; Coronary Artery Disease; Disease Progression; Fatty Acids, Monounsaturated; Female; Fibrosis; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Japan; Male; Middle Aged; Necrosis; Predictive Value of Tests; Prospective Studies; Severity of Illness Index; Time Factors; Treatment Outcome; Ultrasonography, Interventional; User-Computer Interface

The present study was designed to test the hypothesis that fluvastatin might improve arterial stiffness, as assessed with pulse wave velocity (PWV), in patients with coronary artery disease (CAD) and hyperlipidemia over the long term.. Ninety-three patients were randomly assigned to either fluvastatin (group A, n=50) or bezafibrate (group B, n=43) and followed for 5 years. There was no difference in the clinical findings between the 2 groups. In group A, there was a progressive reduction in the brachial-ankle PWV along with a decrease in serum low-density lipoprotein-cholesterol (LDL-C) and C-reactive protein (CRP) by 12 months after fluvastatin, and the improvement was maintained until 5 years after treatment. In group B, despite identical lowering of the serum lipid, PWV was progressively increased. In group A, the percentage change in PWV correlated significantly with that of the serum CRP (r=0.49, p<0.001), but not with that of the serum LDL-C after treatment.. The beneficial vascular effects of fluvastatin persisted for a long period in patients with CAD and hyperlipidemia. Its anti-inflammatory action might contribute to the favorable effects on arterial stiffness.

Topics: Aged; Aorta; Bezafibrate; Blood Flow Velocity; Coronary Artery Disease; Fatty Acids, Monounsaturated; Female; Fluvastatin; Follow-Up Studies; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Indoles; Linear Models; Male; Middle Aged; Multivariate Analysis; Prospective Studies; Pulsatile Flow; Risk Factors; Treatment Outcome

Mild renal impairment is an important risk factor for late cardiovascular complications. This substudy of the Lescol Intervention Prevention Study (LIPS) assessed the effect of fluvastatin on outcome of patients who had renal dysfunction and those who did not. Complete data for creatinine clearance calculation (Cockcroft-Gault formula) were available for 1,558 patients (92.9% of the LIPS population). Patients were randomized to fluvastatin or placebo after successful completion of a first percutaneous coronary intervention. Follow-up time was 3 to 4 years. The effect of baseline creatinine clearance on coronary atherosclerotic events (cardiac death, nonfatal myocardial infarction, and coronary reinterventions not related to restenosis) was evaluated. Baseline creatinine clearance (logarithmic transformation) was inversely associated with an incidence of adverse events among patients who received placebo (hazard ratio 0.99, 95% confidence interval 0.982 to 0.998, p = 0.01). However, no association was noted between creatinine clearance and the incidence of adverse events among patients who received fluvastatin (hazard ratio 1.0, 95% confidence interval 0.99 to 1.0, p = 0.63). No further deterioration in creatinine clearance was observed during follow-up, regardless of baseline renal function or allocated treatment. Occurrence of adverse events was not related to changes in renal function during follow-up. Fluvastatin therapy markedly decreased the risk of coronary atherosclerotic events after percutaneous intervention in patients who had lower values of creatinine clearance at baseline. The benefit of fluvastatin was unrelated to any effect on renal function.

Topics: Age Factors; Aged; Angioplasty, Balloon, Coronary; Coronary Artery Disease; Creatinine; Europe; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Kidney Diseases; Lipoproteins; Male; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Severity of Illness Index; Sex Factors

We sought to determine the effects of PCSK9 variants on plasma low-density lipoprotein cholesterol (LDL-C) levels, severity of coronary atherosclerosis, and response to statin therapy in the Lipoprotein Coronary Atherosclerosis Study (LCAS) population.. Mutations in PCSK9 cause autosomal-dominant hypercholesterolemia. We hypothesized that PCSK9 variants could affect plasma LDL-C in individuals with polygenic hypercholesterolemia.. We sequenced all 12 exons and boundaries to detect novel polymorphisms, and genotyped 372 subjects in LCAS and 319 subjects in a second independent population for six polymorphisms, including novel leucine repeats, by fluorescently tagged markers. We reconstructed haplotypes using a Bayesian algorithm.. Permutation test results showed statistically significant differences in global haplotype distribution among the tertiles of LDL-C (odds ratio [OR]: 2.36, 95% confidence interval [CI]: 1.90 to 4.32, p = 0.005) and minimum lumen diameter of coronary lesions (OR: 1.83, 95% CI: 1.01 to 3.55, p = 0.045). Regression analysis identified haplotype 3 as an independent determinant of LDL-C levels (adjusted R2 = 2.2%, F = 9.37, p = 0.002). Haplotype structure analysis identified E670G as the determinant variant, exerting a dose effect (GG > EG > EE) and accounting for 3.5% of plasma LDL-C variability (F = 14.6, p < 0.001). Plasma total cholesterol, apolipoprotein B, and lipoprotein (a) levels were also associated with the E670G variant. Distributions of the E670G genotypes in an independent normolipidemic and the hyperlipidemic LCAS populations were significantly different (F = 7.2, p = 0.027). No significant treatment-by-genotype interactions were detected. The false positive report probability was between 2% and 8%.. Haplotype 3 encompassing the E670G variant is an independent determinant of plasma LDL-C levels and the severity of coronary atherosclerosis.

Topics: Adult; Aged; Anticholesteremic Agents; Cholesterol; Cholesterol, HDL; Chromosome Aberrations; Coronary Artery Disease; DNA Mutational Analysis; Fatty Acids, Monounsaturated; Female; Fluvastatin; Gene Frequency; Genes, Dominant; Genetic Markers; Genetic Variation; Genotype; Haplotypes; Humans; Hyperlipoproteinemia Type II; Indoles; Lipoprotein(a); Male; Middle Aged; Multifactorial Inheritance; Pharmacogenetics; Polymorphism, Single Nucleotide; Predictive Value of Tests; Prognosis; Proprotein Convertase 9; Proprotein Convertases; Serine Endopeptidases; Treatment Outcome; Triglycerides

The effect of atorvastatin and fluvastatin on antioxidative enzymatic activity was studied in CHD risk patients. The study comprised 35 patients (20 men and 15 women) aged 35-47 years, who were allotted into two groups: I--18 patients were administered fluvastatin (Lescol) in a dose of 40 mg once daily at bed time for 6 weeks and II--17 patients were administered atorvastatin (Sortis) in a dose of 10 mg once daily at bed time for 6 weeks. The control group consisted of 12 clinically healthy subjects, aged 34-42 years. SOD-1, GSH-Px and CAT activity in erythrocytes was measured. Greater increase of low erythrocyte antioxidative enzymatic activity was observed in atorvastatin than in fluvastatin group.

Topics: Adult; Antioxidants; Atorvastatin; Coronary Artery Disease; Erythrocytes; Fatty Acids, Monounsaturated; Female; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Middle Aged; Primary Prevention; Pyrroles; Treatment Outcome

The study comprised 35 patients with mixed hyperlipidaemia and coronary heart disease (CHD) risk factors (overweight or obesity, low physical activity, family history). Seventeen patients were administered atorvastatin in a dose of 10 mg and 18 -fluvastatin in a dose of 40 mg once daily at bed time for 6 weeks. The control group consisted of 12 clinically healthy subjects with no CHD risk factors. Blood samples for testing were collected from cubital vein of patients after hypolipaemic diet prior to and 6 weeks after drugs application and once in control group. Malondialdehyde (MDA) concentrations in erythrocytes and plasma were determined by the method of Placer et al. MDA concentrations in erythrocytes and plasma were significantly higher (p < 0.05) in patients than in healthy subjects. After 6-week atorvastatin therapy MDA concentrations in erythrocytes and plasma decreased to the values observed in healthy subjects. In fluvastatin group erythrocyte and plasma MDA concentrations were unchanged and still significantly higher in comparison to the healthy subjects. Atorvastatin, contrary to fluvastatin, decreases lipid peroxidation in CHD risk patients.

Topics: Adult; Anticholesteremic Agents; Antioxidants; Atorvastatin; Coronary Artery Disease; Fatty Acids, Monounsaturated; Female; Fluvastatin; Free Radical Scavengers; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Primary Prevention; Pyrroles; Treatment Outcome

We assessed the impact of long-term fluvastatin treatment on adverse atherosclerotic cardiac events (cardiac death, myocardial infarction, and revascularization excluding repeat interventions due to restenosis in the first 6 months) in 847 patients (fluvastatin [n = 417] or placebo [n = 430]) with average cholesterol levels treated with stents in the Lescol Intervention Prevention Study (LIPS). During the 4-year follow-up period, fluvastatin significantly decreased total cholesterol and low-density lipoprotein cholesterol levels and decreased the risk of first adverse atherosclerotic cardiac events by 30% compared with placebo (95% confidence interval -49 to -3.4, p = 0.03).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticholesteremic Agents; Brazil; Canada; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Coronary Artery Disease; Drug Administration Schedule; Europe; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Indoles; Longitudinal Studies; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Radiography; Severity of Illness Index; Stents; Treatment Outcome; Triglycerides

To study the differences between fluvastatin and pravastatin regarding LDL susceptibility to oxidation, plasma levels of total cholesterol (TC), HDL-C, LDL-C and triglycerides (TG) in hypercholesterolemic patients with established coronary heart disease (CHD).. A double-blind randomized parallel study was conducted that included 41 hypercholesterolemic outpatients with CHD treated at the Instituto de Cardiologia do Rio Grande do Sul. The inclusion criteria were LDL-C above 100 mg/dL and triglycerides below 400 mg/dL based on 2 measures. After 4 weeks on a low cholesterol diet, those patients that fullfilled the inclusion criteria were randomized into 2 groups: the fluvastatin group (fluvastatin 40 mg/day) and the pravastatin group (pravastatin 20 mg/day), for 24 weeks of treatment. LDL susceptibility to oxidation was analyzed with copper-induced production of conjugated dienes (Cu2+) and water-soluble free radical initiator azo-bis (2'-2'amidinopropanil) HCl (AAPH). Spectroscopy nuclear magnetic resonance was used for determination of lipids.. After 24 weeks of drug therapy, fluvastatin and pravastatin significantly reduced LDL susceptibility to oxidation as demonstrated by the reduced rate of oxidation (azo and Cu) and by prolonged azo-induced lag time (azo lag). The TC, LDL-C, and TG reduced significantly and HDL-C increased significantly. No differences between the drugs were observed.. In hypercholesterolemic patients with CHD, both fluvastatin and pravastatin reduced LDL susceptibility to oxidation.

Topics: Adult; Aged; Antioxidants; Coronary Artery Disease; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Lipids; Lipoproteins, LDL; Male; Middle Aged; Oxidation-Reduction; Pravastatin

The Lescol Intervention Prevention Study (LIPS) was the first randomized trial to show a significant reduction in the risk of cardiac events in patients started on fluvastatin immediately after a successful percutaneous coronary intervention. The benefit was independent of baseline cholesterol levels. The results suggest that all patients should be discharged on lipid-lowering therapy after a percutaneous coronary intervention. Currently, this is seldom done.

Topics: Angioplasty, Balloon, Coronary; Coronary Artery Disease; Double-Blind Method; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Prospective Studies

Sterol regulatory elements binding factor-1a (SREBF-1a) and SREBF cleavage activating protein (SCAP) regulate lipids homeostasis. Polymorphisms in SREBF-1a and SCAP could affect plasma levels of lipids and risk of atherosclerosis. We determined association of SREBF-1a -36del/G and SCAP 2386A/G genotypes with plasma levels of lipids, severity and progression/regression of coronary atherosclerosis, and response to treatment with fluvastatin in a well-characterized Lipoprotein Coronary Atherosclerosis Study population. Plasma lipids and quantitative indices of coronary atherosclerosis were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo in 372 subjects. Fluvastatin reduced plasma levels of total cholesterol by 16%, LDL-C by 25%, and ApoB by 16% and increased plasma levels of HDL-C by 9% and apoA-1 by 7%. Distributions of SREBF-1a SCAP genotypes were 60 GG, 172 del-G and 140 del-del and 88 GG, 188 GA and 96 AA, respectively. There were no significant differences in baseline plasma levels of lipids or indices of severity of atherosclerosis among the genotypes of each gene. There was a strong graded genotype-treatment interaction between SREBF-1a genotypes and change in apoA-I levels in response to fluvastatin (16.5% increase in GG, 10.5% in del/G, and 0.4% in del/del groups). Modest interactions between SREBF-1a genotypes and changes in HDL-C, and apoC-III levels in response to fluvastatin were also present. No genotype-treatment interaction for progression or regression of coronary atherosclerosis was detected. There were no significant interactions between SCAP genotypes and response to therapy. Thus we detected a strong graded interaction between SREBF-1a -36del/G genotypes and response of plasma apoA-I to treatment with fluvastatin.

Topics: Anticholesteremic Agents; Apolipoprotein A-I; CCAAT-Enhancer-Binding Proteins; Coronary Artery Disease; Disease Progression; DNA-Binding Proteins; Fatty Acids, Monounsaturated; Fluvastatin; Genotype; Humans; Indoles; Intracellular Signaling Peptides and Proteins; Lipids; Membrane Proteins; Polymorphism, Genetic; Sterol Regulatory Element Binding Protein 1; Transcription Factors

Human serum paraoxonase (PON1) is a high-density lipoprotein (HDL)-associated enzyme that is responsible for the protective effect of HDL against oxidation of low-density lipoprotein (LDL). PON1 has a Glu to Arg polymorphism at codon 192 (CGA-->CAA) which is designated R/Q192. The R/Q192 polymorphism has been associated with coronary artery disease (CAD) in several, but not all, case-control studies. We prospectively studied the association of the Q/R192 genotypes with the severity, progression and regression of CAD, plasma lipid levels, clinical events and response to treatment with fluvastatin in a well-characterized cohort. Genotypes were determined by polymerase chain reaction (PCR) and restriction mapping with AlwI enzyme in 356 subjects in the Lipoprotein and Coronary Atherosclerosis Study (LCAS). Fasting plasma lipids were measured and quantitative coronary angiograms were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo. A total of 177 (50%), 142 (40%) and 37 (10%) subjects had Q/Q, Q/R and R/R genotypes, respectively. Baseline and final plasma levels of HDL, LDL, triglyceride and other lipoproteins, lesion-specific minimum lumen diameters (MLD), mean MLD, number of coronary lesions and total occlusions at baseline and follow-up and clinical event rates were not significantly different among the genotypes. There was no genotype-treatment interaction with respect to plasma lipid levels and angiographic indices of CAD. The Q/R192 variants of PON1 are not associated with severity, progression or regression of coronary atherosclerosis, plasma lipid levels, clinical events, or response to treatment with fluvastatin. Thus, the Q/R192 polymorphism is not a major risk factor in susceptibility to CAD in the LCAS population.

Topics: Aged; Anticholesteremic Agents; Aryldialkylphosphatase; Cohort Studies; Coronary Angiography; Coronary Artery Disease; Disease Progression; Esterases; Fatty Acids, Monounsaturated; Female; Fluvastatin; Genotype; Humans; Indoles; Lipids; Male; Middle Aged; Polymorphism, Genetic; Prospective Studies; Severity of Illness Index

Our objectives were to determine whether angiotensin-1 converting enzyme (ACE) insertion/deletion (I/D) polymorphism was associated with the severity of coronary artery disease (CAD) and its progression/regression in response to fluvastatin therapy in the Lipoprotein and Coronary Atherosclerosis Study (LCAS) population.. Genetic factors are involved in susceptibility to CAD. Angiotensin-1 converting enzyme I/D polymorphism, which accounts for half of the variance of plasma and tissue levels of ACE, has been implicated in susceptibility to CAD and myocardial infarction (MI).. Angiotensin-1 converting enzyme genotypes were determined by polymerase chain reaction (PCR). Fasting plasma lipids were measured and quantitative coronary angiograms were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo.. Ninety-one subjects had DD, 198 ID and 75 II genotypes. The mean blood pressure, minimum lumen diameter (MLD), number of coronary lesions and total occlusions were not significantly different at baseline or follow-up among the genotypes. There was a significant genotype-by-treatment interaction for total cholesterol (p = 0.018), low-density lipoprotein cholesterol (LDL-C) (p = 0.005) and apolipoprotein (apo) B (p = 0.045). In response to fluvastatin therapy, subjects with DD, compared with those with ID and II genotypes, had a greater reduction in total cholesterol (19% vs. 15% vs. 13%), LDL-C (31% vs. 25% vs. 21%) and apo B (23% vs. 15% vs. 12%). Definite progression was less (14%) and regression was more common (24%) in DD as compared with those with ID (32% and 17%) and II (33% and 3%) genotypes (p = 0.023). Changes in the mean MLD and lesion-specific MLD also followed the same trend.. Angiotensin-1 converting enzyme I/D polymorphism is associated with the response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin. Subjects with DD genotype had a greater reduction in LDL-C, a higher rate of regression and a lower rate of progression of CAD.

Topics: Adult; Aged; Cholesterol, LDL; Chromosome Aberrations; Chromosome Deletion; Coronary Artery Disease; Disease Progression; Fatty Acids, Monounsaturated; Female; Fluvastatin; Genetic Predisposition to Disease; Genotype; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lipids; Male; Middle Aged; Myocardial Infarction; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Treatment Outcome

A series of pro-oxidant and antioxidant enzymes, such as the NADPH oxidase system, maintain the redox state in the vessel wall. A major component of NADPH oxidase is p22(phox), which is implicated in atherosclerosis. We prospectively studied the association of the histidine (H)(72)-->tyrosine (Y) mutation in p22(phox) with the severity and progression/regression of coronary artery disease (CAD), plasma lipid levels, clinical events, and response to treatment with fluvastatin in a well-characterized population. Genotypes were determined by polymerase chain reaction and restriction digestion with RsaI enzyme in 368 subjects in the Lipoprotein and Coronary Atherosclerosis Study (LCAS). Fasting plasma lipids and quantitative coronary angiograms were obtained at baseline and 2.5 years after randomization to fluvastatin or placebo. Subjects with CC genotype (n=157) were identified by the presence of 396-bp and 113-bp products on gel electrophoresis. Those with TT (n=39) were identified by the presence of 316-bp, 113-bp, and 80-bp products, and those with CT (n=172) by the presence of 396-bp, 316-bp, 113-bp, and 80-bp products. Baseline and final plasma levels of lipids and the baseline severity of CAD were not significantly different among the genotypes. In the placebo group, subjects with the mutation had a 3- to 5-fold greater loss in mean minimum lumen diameter (MLD) (TT: -0.15+/-0.15; CT: -0.17+/-0.26; and CC: -0.03+/-0.22 mm; P=0. 006) and lesion-specific MLD (TT: -0.15+/-0.06; CT: -0.18+/-0.03; and CC: -0.06+/-0.03 mm; P=0.038) than those without. Progression was also more (TT: 8/17 [47%]; CT: 35/73 [48%]; and CC: 17/62 [27%]) and regression less (TT: 0/17 [0%]; CT: 1/73 [1%]; and CC: 11/72 [18%]) common in those with the mutation (P=0.002). The C(242)T mutation in p22(phox), involved in maintaining the redox state in the vessel wall, is associated with progression of coronary atherosclerosis in the LCAS population.

Topics: Adult; Aged; Alleles; Anticholesteremic Agents; Blood Vessels; Coronary Artery Disease; Disease Progression; Fatty Acids, Monounsaturated; Fluvastatin; Genetic Variation; Genotype; Humans; Indoles; Lipids; Membrane Transport Proteins; Middle Aged; Mutation; NADPH Dehydrogenase; NADPH Oxidases; Phosphoproteins; Prospective Studies; Randomized Controlled Trials as Topic; Reactive Oxygen Species

We sought to examine the association of apolipoprotein (apo) E genotypes with baseline plasma lipid levels and severity of coronary artery disease (CAD), as well as the response to treatment with fluvastatin in the Lipoprotein and Coronary Atherosclerosis Study (LCAS).. Apo E genotypes have been associated with plasma lipid levels and CAD. However, the influence of apo E genotypes on the response of plasma lipids and CAD progression or regression to statin treatment in patients with mildly to moderately elevated cholesterol remains unknown.. Apo E genotypes were determined by polymerase chain reaction and restriction mapping. Plasma lipids were measured at baseline and 12 weeks after therapy with fluvastatin or placebo in 320 subjects. In 287 subjects, quantitative coronary angiography was performed at baseline and after 2.5 years of treatment.. Subjects with the 3/3 genotype had greater reductions in total cholesterol (20.4% vs. 15.4%, p = 0.01) and low density lipoprotein (LDL) cholesterol (28.8% vs. 22.7%, p = 0.03) than did the subjects with the 3/4 or 4/4 genotype. In contrast, subjects with the 2/3 genotype (n = 10) had a greater increase in high density lipoprotein cholesterol (19.1%) than did the subjects with the 3/3 genotype (4.3%, p = 0.002) and those with the 3/4 or 4/4 genotype (7.0%, p = 0.02). Subjects with the 3/4 or 4/4 genotype had an increased frequency of previous angioplasty, but other measures of baseline CAD severity and baseline lipids did not differ significantly among the genotypes, nor did CAD progression or clinical events.. Although subjects with the epsilon4 allele had less reduction in LDL cholesterol with fluvastatin, they had similar benefit in terms of CAD progression.

Topics: Anticholesteremic Agents; Apolipoproteins E; Cholesterol; Coronary Artery Disease; Disease Progression; Fatty Acids, Monounsaturated; Female; Fluvastatin; Genotype; Humans; Indoles; Male; Middle Aged; Remission Induction

Inflammation plays a key role in susceptibility to coronary atherosclerosis and response to therapy. A diverse array of factors modulates inflammation, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and CD14 receptors on the surface of macrophages. Genes encoding for inflammatory markers have variants that regulate their expression and are potential risk factors for atherosclerosis. We prospectively analyzed the possible association of CD14 -260C/T, TNF-alpha -308G/A, and IL-6 -174G/C variants, located in the promoter regions, with the severity, progression, and response to therapy of coronary atherosclerosis in a well-characterized cohort. We studied 375 subjects enrolled in the Lipoprotein and Coronary Atherosclerosis Study (LCAS). Genotypes were determined by polymerase chain reaction (PCR) and restriction mapping. Fasting plasma lipids and quantitative coronary angiograms were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo. Distributions of genotypes were--for CD14: 100 CC, 184 CT, and 86 TT; IL-6: 152 GG, 153 GC, and 62 CC; and TNF-alpha: 244 GG, 110 GA, and 17 AA. The CD14 CC genotype was associated with incidence of new coronary occlusion (P=0.026); TNF-alpha AA genotype with history of myocardial infarction (MI, P=0.04), and A allele with total occlusions at baseline (P=0.027), and systolic blood pressure (P=0.046); and IL-6-174 CC genotype with baseline minimum lumen diameter (P=0.043) and reduction in lipoprotein(a) with fluvastatin (P=0.03). Otherwise, no association between the genotypes and the biochemical, angiographic, and clinical phenotypes was detected, and neither were genotype-treatment interactions. Functional variants of CD14 -260C/T, TNF-alpha -308G/A, and IL-6 -174G/C, implicated in the susceptibility to infection, are unlikely to confer major risk for susceptibility to coronary atherosclerosis and its progression or response to therapy in the LCAS population.

Topics: Adult; Aged; Anticholesteremic Agents; Coronary Artery Disease; Fatty Acids, Monounsaturated; Female; Fluvastatin; Genetic Predisposition to Disease; Humans; Indoles; Infections; Inflammation; Interleukin-6; Lipids; Lipopolysaccharide Receptors; Male; Middle Aged; Prospective Studies; Treatment Outcome; Tumor Necrosis Factor-alpha

Monocytes are recruited as the principal inflammatory cells into the atherosclerotic lesion. In a previous study we demonstrated that a low HDL-cholesterol and the apo E4 allele are associated with an increased proportion of blood monocytes that are characterized by a high expression of Fcgamma-RIIIa (CD16), a dim expression of the lipopolysaccharide (LPS) receptor (CD14) and a high expression of beta1- and beta2-integrins (Rothe et al. Arterioscler Thromb Vasc Cell Biol 1996;16:1437-1447). In this study, 79 hypercholesterolemic patients were treated either with the HMG CoA reductase inhibitor fluvastatin in combination with diet or with placebo and diet in a double-blind and randomized multicenter study, and monitored for the potential effects on the phenotype of peripheral blood monocytes. At baseline, in the whole group of hypercholesterolemic patients the population size of these more mature monocytes (CD14dimCD16+) was positively correlated to triglyceride (P = 0.003) and total serum cholesterol levels (P = 0.012) confirming our previous study. Fluvastatin treatment for 52 weeks was associated with a 24.2% reduction in LDL-cholesterol (P < 0.001) as well as a 40.7% decrease in the expression density of CD14 on all monocytes (P = 0.027). A 24.5% decrease (P < 0.001) of the population of less differentiated CD14brightCD16- monocytes and an 83.1% increase (P = 0.029) of the population of more differentiated CD14dimCD16+ monocytes further confirmed this modification of the phenotype of peripheral blood monocytes. The positive pre-study correlation of the CD14dimCD16+ monocyte subset to the serum cholesterol concentration, but inverse changes of both parameters under fluvastatin therapy, in conclusion indicate that fluvastatin exerts an as yet uncharacterized immunomodulatory effect on either monocyte maturation and differentiation, or extravasation which may also depend on the endothelial phenotype that is independent of the change in serum lipids.

Topics: Adult; Aged; Combined Modality Therapy; Coronary Artery Disease; Diet; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Flow Cytometry; Fluvastatin; Follow-Up Studies; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Leukocytes, Mononuclear; Linear Models; Lipids; Male; Middle Aged; Phagocytes; Phenotype

Mutations in human lipoprotein lipase (LPL) gene are potential risk factors for susceptibility to coronary artery disease (CAD). The objectives of this study were to determine the influence LPL mutations Asn291Ser and Ser447Ter on plasma lipid levels, regression and progression of CAD, clinical events rate, and response to fluvastatin therapy in the Lipoprotein and Coronary Atherosclerosis Study (LCAS) population. LCAS is a double blind, randomized, placebo-controlled study designed to test the influence of fluvastatin on progression or regression of CAD. The Asn291Ser and Ser447Ter genotypes were determined by polymerase chain reaction (PCR) and restriction enzyme digestion. Fasting plasma lipid profiles were measured and quantitative coronary angiography was performed at baseline and 2.5 years following randomization. Fatal and non-fatal cardiovascular events during the follow-up period were recorded. A total of 4% (14/363) and 18% (62/352) of the subjects had the Asn291Ser and Ser447Ter mutations, respectively. Overall, there was no statistically association between the Asn291Ser and Ser447Ter mutations and the baseline or final mean plasma levels of lipids, number of coronary lesions, total occlusions, the mean minimal lumen diameter (MLD) stenoses and the clinical events rate. However, patients with the Ser447Ter variant had a slightly higher baseline high density lipoprotein-cholesterol (HDL-C) level (46.2 +/- 12 vs 43.2 +/- 11, P = 0.057), less increase in plasma HDL levels in response to fluvastatin therapy (3 vs 11%, P = 0.056) and a higher cardiovascular events rate (23 vs 13%, P = 0.056). Thus, the Ser447Ter variant had a modest influence on plasma HDL levels and the rate of cardiovascular events. These changes were of borderline statistical significance. Neither the Ser447Ter nor the Asn291Ser mutation had a major impact on susceptibility to CAD, progression or regression of CAD, clinical events rate or response to fluvastatin therapy in LCAS population.

Topics: Adult; Aged; Amino Acids; Anticholesteremic Agents; Cholesterol, LDL; Coronary Angiography; Coronary Artery Disease; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Fluvastatin; Genotype; Humans; Indoles; Lipids; Lipoprotein Lipase; Male; Middle Aged; Mutation; Myocardial Infarction; Polymerase Chain Reaction; Treatment Outcome

Studies of lipid-lowering therapy are usually conducted in patients with severely elevated cholesterol levels. However, most individuals who develop clinically significant coronary artery disease (CAD) have total cholesterol levels <240 mg/dL and low-density lipoprotein (LDL) cholesterol levels similar to individuals who do not develop significant CAD. The Lipoprotein and Coronary Atherosclerosis Study (LCAS) was conducted to determine whether lipid-lowering therapy with fluvastatin would reduce the progression or induce the regression of coronary atherosclerotic lesions and/or reduce new lesion formation in patients with CAD and mildly to moderately elevated LDL cholesterol. The LCAS was the first angiographically monitored trial of this 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. All 429 men and women (mean age, 58.8 years) had angiographic evidence of CAD and LDL cholesterol levels of 115-190 mg/dL (mean 145.6 mg/dL). Patients were randomized to fluvastatin 20 mg twice daily or placebo. Patients whose prerandomization LDL cholesterol was > or = 160 mg/dL also received open-label cholestyramine. Lipid-lowering therapy with fluvastatin significantly slowed CAD progression. After 2.5 years, the mean LDL cholesterol decreased by 23.9% in all fluvastatin-treated patients (+/-cholestyramine) and by 22.5% in patients treated with fluvastatin monotherapy. There was significantly less lesion progression in fluvastatin versus placebo-treated patients (p <0.01). There also were fewer clinical events in fluvastatin-treated patients. Findings suggest that fluvastatin may improve arterial and arteriolar function within a few weeks of beginning therapy.

Topics: Adult; Aged; Cholesterol, LDL; Coronary Artery Disease; Disease Progression; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Middle Aged

Despite the potential for reduced morbidity and mortality, aggressive intervention against mild to moderate hypercholesterolemia in patients with coronary heart disease (CHD) remains controversial and infrequently practiced. Eligible patients in the 2.5-year Lipoprotein and Coronary Atherosclerosis Study were men and women aged 35 to 75 years with angiographic CHD and mean low-density lipoprotein (LDL) cholesterol of 115 to 190 mg/dl despite diet. Patients (n = 429; 19% women) were randomized to fluvastatin 20 mg twice daily or placebo. One fourth of patients were also assigned open-label adjunctive cholestyramine up to 12 g/day because prerandomization LDL cholesterol remained > or = 160 mg/dl. The primary end point, assessed by quantitative coronary angiography, was within-patient per-lesion change in minimum lumen diameter (MLD) of qualifying lesions. Across 2.5 years, mean LDL cholesterol was reduced by 23.9% in all fluvastatin patients (+/- cholestyramine) (146 to 111 mg/dl) and by 22.5% in the fluvastatin only subgroup (137 to 106 mg/dl). Primary end point analysis (340 patients) showed significantly less lesion progression in all fluvastatin versus all placebo patients, deltaMLD -0.028 versus -0.100 mm (p <0.01), and for fluvastatin alone versus placebo alone, deltaMLD -0.024 versus -0.094 mm (p <0.02). A consistent angiographic benefit with treatment was seen whether baseline LDL cholesterol was above or below 160 or 130 mg/dl. Beneficial trends with treatment were also consistently seen in clinical event rates but were not statistically significant. Thus, lipid lowering by fluvastatin in patients with mildly to moderately elevated LDL cholesterol significantly slowed CHD progression.

Topics: Adult; Aged; Cholesterol, LDL; Coronary Angiography; Coronary Artery Disease; Disease Progression; Double-Blind Method; Enzyme Inhibitors; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Indoles; Male; Middle Aged; Retrospective Studies; Treatment Outcome

Few direct clinical data are available regarding whether cholesterol-lowering therapy should be extended to patients with coronary heart disease (CHD) and normal or only slightly elevated plasma cholesterol concentrations. The one published angiographic trial designed to examine this question found no benefit. Additional prospective data will be provided by the Lipoprotein and Coronary Atherosclerosis Study (LCAS), a randomized, double-blind, placebo-controlled trial of fluvastatin therapy (20 mg twice daily) monitored by both quantitative coronary angiography (QCA) and, in a subset of patients, positron-emission tomography (PET). Eligible subjects in LCAS were men and women 35-75 years of age with low-density lipoprotein (LDL) cholesterol of 115-190 mg/dL on stable dietary therapy and with angiographic evidence by caliper measurement of at least one coronary atherosclerotic lesion causing 30-75% diameter stenosis. Among the 429 patients randomized (mean age 58.8, 81% male), mean baseline LDL cholesterol was only 145.6 mg/dL. Any patient with mean prerandomization LDL cholesterol of 160 mg/dL or higher also received open-label adjunctive cholestyramine. The primary endpoint is within-patient per-lesion change in minimum lumen diameter (MLD) as measured by QCA at baseline and 2.5-year follow-up. All evaluable lesions had MLD at least 0.8mm less than the reference lumen diameter at either baseline or follow-up and MLD at least 25% of the reference lumen diameter at baseline. Data obtained on myocardial perfusion changes (99 patients underwent initial PET), special lipid particles, and coagulation factors may help define which patients with CHD and relatively low LDL cholesterol will benefit from lipid-lowering treatment.

Topics: Adult; Aged; Anticholesteremic Agents; Blood Coagulation Factors; Coronary Angiography; Coronary Artery Disease; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Lipids; Male; Middle Aged; Multicenter Studies as Topic; Multivariate Analysis; Patient Selection; Prospective Studies; Random Allocation; Randomized Controlled Trials as Topic; Regression Analysis; Research Design; Severity of Illness Index; Tomography, Emission-Computed

High-risk patients with dyslipidemias resistant to diet and single-agent pharmacotherapy may require combination therapy to achieve target levels of low density lipoprotein, triglycerides, and high density lipoprotein. Combinations of fibrates and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors are effective, but because of safety concerns related to myopathy and rhabdomyolysis, it is important to consider the possibility of pharmacokinetic interactions when such combinations are used. In this study, the area under the curve, maximum plasma concentration, and time to maximum concentration for fluvastatin and gemfibrozil are compared, when used alone and in combination, in patients with hyperlipidemia and either coronary or carotid atherosclerosis, or a family history of coronary artery disease. A total of 17 patients were studied in a random sequence, open-label, crossover study of fluvastatin at 20 mg twice daily, gemfibrozil at 600 mg twice daily, and the combination of the 2 drugs. No significant difference was observed in area under the curve, maximum plasma concentration, and time to maximum concentration when comparing the combination with each drug alone. These pharmacokinetic data add support to the clinical observations that the combination of fluvastatin and gemfibrozil is both effective and safe.

Topics: Anticholesteremic Agents; Arteriosclerosis; Carotid Stenosis; Coronary Artery Disease; Coronary Disease; Cross-Over Studies; Drug Combinations; Fatty Acids, Monounsaturated; Female; Fluvastatin; Gemfibrozil; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Indoles; Lipoproteins, HDL; Lipoproteins, LDL; Male; Middle Aged; Pilot Projects; Placebos; Safety; Triglycerides

Familial hypercholesterolemia carries a markedly increased risk of coronary artery disease. Reduction of plasma low density lipoprotein cholesterol (LDL-C) levels to the normal range may prevent premature atherosclerosis and usually requires a combination of cholesterol-lowering drugs such as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors plus resins or fibrates. The current, 60-week, open-label investigation involved 22 patients whose plasma LDL-C had not reached the target level for prevention of coronary artery disease in 3 previous studies using fluvastatin alone and in combination with other cholesterol-lowering medications. At the beginning of the current study, patients were stabilized on fluvastatin monotherapy at 40 mg/day. After 6 weeks, the daily treatment changed to a combination of fluvastatin 40 mg/day in the evening and bezafibrate 400 mg/day in the morning. After a further 6 weeks, a lunchtime dose of cholestyramine 8 g/day was added, to form triple cholesterol-lowering therapy. Efficacy was determined by plasma lipid/lipoprotein analysis. Baseline levels were assessed after 4 weeks of placebo treatment, prior to active treatment, in the first fluvastatin study. Safety analyses included liver and renal function tests, creatine phosphokinase levels and blood counts. Compliance was determined by counting the fluvastatin capsules, bezafibrate tablets, and cholestyramine sachets returned by the patients at each visit. The triple-drug combination used in this study was more effective than the double therapy and resulted in stabilization of the LDL-C:high density lipoprotein cholesterol (HDL-C) ratio, at a reduction from baseline ranging from -40.4 to -52.5%.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Anticholesteremic Agents; Bezafibrate; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cholestyramine Resin; Coronary Artery Disease; Creatine Kinase; Drug Combinations; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemia Type II; Indoles; Kidney; Liver; Male; Middle Aged; Patient Compliance; Placebos; Safety; Triglycerides

A total of 429 subjects (79 women and 350 men), aged 35-75 years, have been enrolled in a randomized clinical trial of fluvastatin therapy for hypercholesterolemia. The progression and regression of atherosclerotic lesions will be assessed by quantitative angiography and positron emission tomography (PET) after 2.5 years of treatment. Patients were included in the trial if they had angiographically documented lesions that occluded 30-75% of the diameter of a major coronary vessel. Of the 429 subjects, 99 were also studied by PET at rest and during static exercise of sustained handgrip combined with administration of dipyridamole. All subjects were instructed in an American Heart Association/National Cholesterol Education Program (AHA/NCEP) Step I or Step II diet. Of the total, 107 subjects (25%) had low density lipoprotein cholesterol (LDL-C) > or = 160 mg/dL and were given cholestyramine, 8 g/day. All subjects were randomized to placebo or fluvastatin, the newest 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor to be introduced into the U.S. market. Fluvastatin is entirely synthetic and is similar in efficacy to the other available HMG-CoA reductase inhibitors. Its pharmaceutical profile (i.e., low systemic exposure) makes fluvastatin a good candidate for use in combination lipid-lowering therapy. The majority of subjects were recruited through a community campaign and the remainder through cardiac catheterization laboratories and the medical records of hospitals in the Texas Medical Center. Approximately 8,500 prospects from the community campaign were screened and 272 were randomized, a conversion rate of approximately 3%.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Angioplasty, Balloon, Coronary; Anticholesteremic Agents; Cholesterol, LDL; Cholestyramine Resin; Combined Modality Therapy; Coronary Artery Disease; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lipoproteins; Male; Middle Aged; Severity of Illness Index; Time Factors

Randomized control trials of statins have not demonstrated significant benefits in outcomes of heart failure (HF). However, randomized control trials may not always be generalizable. The aim was to determine whether statin and statin type-lipophilic or -hydrophilic improve long-term outcomes in Africans with HF.. This was a retrospective longitudinal study of HF patients aged ≥18 years hospitalized at a tertiary healthcare center between January 1, 2009 and December 31, 2013 in Ghana. Patients were eligible if they were discharged from first admission for HF (index admission) and followed up to time of all-cause, cardiovascular, and HF mortality or end of study. Multivariable time-dependent Cox model and inverse-probability-of-treatment weighting of marginal structural model were used to estimate associations between statin treatment and outcomes. Adjusted hazard ratios were also estimated for lipophilic and hydrophilic statin compared with no statin use. The study included 1488 patients (mean age 60.3±14.2 years) with 9306 person-years of observation. Using the time-dependent Cox model, the 5-year adjusted hazard ratios with 95% CI for statin treatment on all-cause, cardiovascular, and HF mortality were 0.68 (0.55-0.83), 0.67 (0.54-0.82), and 0.63 (0.51-0.79), respectively. Use of inverse-probability-of-treatment weighting resulted in estimates of 0.79 (0.65-0.96), 0.77 (0.63-0.96), and 0.77 (0.61-0.95) for statin treatment on all-cause, cardiovascular, and HF mortality, respectively, compared with no statin use.. Among Africans with HF, statin treatment was associated with significant reduction in mortality.

Topics: Aged; Atorvastatin; Atrial Fibrillation; Black People; Cardiomyopathy, Dilated; Cardiovascular Diseases; Cause of Death; Comorbidity; Coronary Artery Disease; Diabetes Mellitus; Fatty Acids, Monounsaturated; Fluvastatin; Ghana; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Indoles; Kaplan-Meier Estimate; Longitudinal Studies; Middle Aged; Mortality; Multivariate Analysis; Probability; Proportional Hazards Models; Renal Insufficiency, Chronic; Retrospective Studies; Rosuvastatin Calcium; Simvastatin; Treatment Outcome

Although statins are generally well-tolerated drugs, recent cases of autoimmune hepatitis (AIH) associated with their use have been reported. A 59-year-old Japanese man reported with liver damage, which appeared one month after beginning treatment with fluvastatin and continued after discontinuation of the drug. Although drug-induced liver injury was possible, positive autoantibody tests (antinuclear antibodies >1/1280, anti-mitochondrial M2 antibodies 21 index value) also suggested autoimmune liver disease. Liver biopsy findings were consistent with an overlap of autoimmune hepatitis and primary biliary cirrhosis. Treatment with prednisone and ursodeoxycholic acid led to a good response. In this patient, manifestation of AIH and primary biliary cirrhosis overlap syndrome was possibly triggered by statin use. Autoimmune liver disease should be considered as a possible diagnosis in patients with evidence of prolonged liver damage after discontinuation of statins.

Topics: Anti-Inflammatory Agents; Antibodies, Antinuclear; Anticholesteremic Agents; Autoantibodies; Coronary Artery Disease; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Fluvastatin; Hepatitis, Autoimmune; Humans; Indoles; Liver Cirrhosis, Biliary; Male; Middle Aged; Mitochondria; Prednisone; Ursodeoxycholic Acid

Topics: Azetidines; Cholesterol; Coronary Artery Bypass; Coronary Artery Disease; Drug Therapy, Combination; Ezetimibe; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hypercholesterolemia; Hypolipidemic Agents; Indoles; Lipoprotein(a); Male; Postoperative Complications; Prognosis; Reference Values; Risk Factors; Secondary Prevention; Treatment Outcome

HMG-CoA reductase inhibitors (statins) are widely used to treat hypercholesterolemia. Among the adverse effects associated with these drugs are statin-associated myopathies, ranging from asymptomatic elevation of serum creatine kinase to fatal rhabdomyolysis. Fluvastatin-induced fatal rhabdomyolysis has not been previously reported. We describe here a patient with liver cirrhosis who experienced fluvastatin-induced fatal rhabdomyolysis. This patient had been treated with simvastatin (20 mg/day) for coronary artery disease and was switched to fluvastatin (20 mg/day) 10 days before admission. He was also taking aspirin, betaxolol, candesartan, lactulose, and entecavir. Rhabdomyolysis was complicated and continued to progress. He was treated with massive hydration, urine alkalization, intravenous furosemide, and continuous renal replacement therapy for acute renal failure, but eventually died due to rhabdomyolysis complicated by hepatic failure. In conclusion, fluvastatin should be used with caution in patients with liver cirrhosis, especially with other medications metabolized with CYP2C9.

Topics: Coronary Artery Disease; Fatal Outcome; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Liver Cirrhosis; Male; Middle Aged; Rhabdomyolysis; Simvastatin

Topics: Calcinosis; Coronary Artery Disease; Fatty Acids, Monounsaturated; Fibrosis; Fluorobenzenes; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Necrosis; Observer Variation; Predictive Value of Tests; Pyrimidines; Radiography; Rosuvastatin Calcium; Severity of Illness Index; Simvastatin; Sulfonamides; Time Factors; Treatment Outcome; Ultrasonography, Interventional; User-Computer Interface

To evaluate the impact of the extent of coronary disease (single- or multivessel) and of fluvastatin treatment on the incidence of long-term cardiac atherosclerotic complications in the Lescol Intervention Prevention Study (LIPS).. A total of 1063 patients with single-vessel disease and 614 patients with multivessel disease were randomized to receive fluvastatin (40 mg bid) or placebo for at least 3 years following a first successful percutaneous coronary intervention. The incidence of cardiac atherosclerotic events (cardiac death, non-fatal myocardial infarction, and coronary re-interventions not related to restenosis) was evaluated.. Patients with multivessel disease tended to be older and presented a higher prevalence of associated risk factors and cardiovascular antecedents. The presence of multivessel disease markedly increased the risk of cardiac atherosclerotic events compared with single-vessel disease among patients allocated to placebo (RR 1.67 [95% CI: 1.24-2.25]; p<0.001). In patients treated with fluvastatin, however, no significant differences in long-term outcomes were observed between patients with multivessel disease and patients single-vessel disease (RR 1.28 [95% CI: 0.90-1.81]; p=0.2).. Multivessel coronary disease impaired the 4-year outcomes after percutaneous intervention. However, the hazardous effect of multivessel disease was significantly reduced by long-term fluvastatin treatment.

Topics: Angioplasty, Balloon, Coronary; Coronary Artery Disease; Coronary Disease; Fatty Acids, Monounsaturated; Fluvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Proportional Hazards Models; Risk Assessment; Stents

Heart rate recovery is the difference in heart rate at peak exercise and at a specific time interval following the onset of recovery. Attenuated heart rate recovery is an independent predictor of mortality in patients with a history of coronary artery disease. The aim of the present study was to evaluate the effect of a statin on heart rate recovery, particularly in patients with ischemic heart failure and hyperlipidemia. Twenty-nine consecutive hyperlipidemic, stable coronary artery disease patients with heart failure and 19 healthy subjects were enrolled. Heart rate recovery values at the 1st and 3rd minutes and lipid profiles of the patients were evaluated at baseline and following 3 months of treatment with fluvastatin. Compared with healthy subjects, the heart rate recovery values were significantly lower in the heart failure patients in both the 1st and 3rd minutes, respectively (31 +/- 6 versus 19 +/- 7, P < 0.0001; 66 +/- 7 versus 47 +/- 8, P < 0.0001). Heart rate recovery in the 1st and 3rd minutes increased from 19 +/- 7 to 24 +/- 9 and 47 +/- 8 to 57 +/- 11, respectively, following treatment (P < 0.001, P < 0.001). There were no significant correlations among the changes in lipid parameters or HRR in the first and third minutes in the recovery period. The results revealed an improvement in heart rate recovery in heart failure patients by fluvastatin treatment. If this association can be confirmed by other studies, it would be interesting to perform further studies into the mechanism underlying this finding.

Topics: Aged; Anticholesteremic Agents; Coronary Artery Disease; Exercise; Fatty Acids, Monounsaturated; Female; Fluvastatin; Heart Failure; Heart Rate; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Indoles; Lipids; Male; Middle Aged; Parasympathetic Nervous System; Recovery of Function

Topics: Anticholesteremic Agents; Cholesterol, LDL; Coronary Artery Disease; Diabetes Mellitus, Type 2; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Myocardial Infarction; Risk Factors; Secondary Prevention

We investigated whether statin type or dose influenced the inhibition of platelet function induced by clopidogrel in a prospective, open, parallel group study in patients undergoing elective percutaneous coronary intervention. Patients were taking CYP3A4 metabolised atorvastatin (n = 20) or simvastatin (n = 21), non-CYP3A4 metabolised pravastatin (n = 11) or fluvastatin (n = 2), or no statin therapy (n = 5). ADP and TRAP-induced platelet aggregation were measured using optical aggregometry, whole-blood single-platelet counting, and the Ultegra and Plateletworks point-of-care systems. Platelet pro-coagulant activity (annexin V binding and microparticle formation), P-selectin expression and platelet-leukocyte conjugate formation were assessed by flow cytometry. Platelet responses were measured at baseline, 4 h post clopidogrel 300 mg, and after 10 and 28 days with clopidogrel 75 mg daily. Clopidogrel significantly inhibited both ADP and TRAP-induced platelet responses over time, with steady state inhibition achieved by day 10. This was demonstrated by all techniques used. There was no significant effect of statin type or dose on platelet responses by any method at any time-point. In conclusion, statins do not influence the inhibitory effects of clopidogrel on multiple platelet responses, including aggregation, P-selectin expression, platelet-leucocyte conjugate formation and pro-coagulant responses, in patients undergoing elective PCI.

Topics: Adult; Aged; Angioplasty, Balloon, Coronary; Atorvastatin; Blood Platelets; Clopidogrel; Coronary Artery Disease; Drug Evaluation; Drug Interactions; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Female; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Pravastatin; Pyrroles; Simvastatin; Ticlopidine

The prospective placebo-controlled LIPS study ("Lescol Intervention Prevention Study") demonstrated a significant cardiovascular protection by fluvastatin in patients with coronary artery disease (stable or unstable angina, silent ischemia), without major hypercholesterolaemia (135-270 mg/dl) following successful completion of their first percutaneous coronary intervention. When compared to the placebo group (n = 833), the fluvastatin group (n = 844) showed a relative risk reduction by 22% (relative risk: 0.78; 95% confidence interval: 0.64-0.95; p = 0.01) of major adverse cardiac events after a median time of follow-up of 3.9 years. This effect is observed independently of baseline total cholesterol, of the presence of diabetes mellitus or the existence of multivessel disease. These results suggest that fluvastatin may favorably influence the restenosis process after percutaneous coronary intervention, even in the absence of severe hypercholesterolaemia.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angioplasty, Balloon; Anticholesteremic Agents; Coronary Artery Disease; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hypercholesterolemia; Indoles; Male; Middle Aged; Myocardial Infarction; Placebos; Postoperative Complications; Prospective Studies

Identification of mutations in the ATP binding cassette transporter (ABCA1) gene in patients with Tangier disease, who exhibit reduced HDL cholesterol (HDL-C) and apolipoprotein A1 (apoA1) levels and premature coronary atherosclerosis, has led to the hypothesis that common polymorphisms in the ABCA1 gene could determine HDL-C and apoA1 levels and the risk of coronary atherosclerosis in the general population. We sequenced a 660-bp 5' fragment of the ABCA1 gene in 24 subjects and identified 3 novel polymorphisms: -477C/T, -419A/C, and -320G/C. We developed assays, genotyped 372 participants in the prospective Lipoprotein Coronary Atherosclerosis Study (LCAS), and determined the association of the variants with fasting plasma lipids and indices of quantitative coronary angiograms obtained at baseline and 2.5 years after randomization to fluvastatin or placebo. Distribution of -477C/T and -320G/C genotypes were 127 CC, 171 CT, and 74 TT and 130 GG, 168 GC, and 75 CC, respectively, and were in complete linkage disequilibrium (P<0.0001). Data for -477C/T are presented. The -419A/C variant was uncommon (present in 1 of 63 subjects). Heterozygous subjects had a modest reduction in HDL-C (P=0.09) and apoA1 (P=0.05) levels and a lesser response of apoA1 to treatment with fluvastatin (P=0.04). The mean number of coronary lesions causing 30% to 75% diameter stenosis was greater in subjects with the TT genotype (3.1+/-2.1) or CT genotype (2.9+/-1.9) than in subjects with the CC genotype (2.2+/-1.8) (P=0.002). Similarly, compared with subjects with the CC genotype, greater numbers of subjects with the TT or CT genotype had >/=1 coronary lesion (P=0.001). No association between the genotypes and progression of coronary atherosclerosis or clinical events was detected. We conclude that ABCA1 genotypes are potential risk factors for coronary atherosclerosis in the general population.

Topics: Adult; Aged; Alleles; Anticholesteremic Agents; Apolipoprotein A-I; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Cholesterol, HDL; Coronary Artery Disease; Disease Progression; DNA; Fatty Acids, Monounsaturated; Female; Fluvastatin; Genotype; Humans; Indoles; Lipids; Male; Middle Aged; Phenotype; Polymorphism, Genetic; Promoter Regions, Genetic; Severity of Illness Index

In vitro and in vivo evidence of a decrease in vascular smooth muscle cell (SMC) migration induced by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has been reported. When added to SMC cultures for 6 hours, the HMG-CoA reductase inhibitors fluvastatin, simvastatin, and pravastatin at 1 micromol/L resulted in a 48%, 50%, and 16% suppression, respectively, of human coronary SMC migration; these reductions mirrored the suppression in oxidative stress induced by 1 micromol/L lysophosphatidylcholine (lyso-PC) of 50%, 53% and 19%, respectively. The hydroxylated metabolites of fluvastatin, M(2) and M(3), at 1 micromol/L also suppressed the enhancement of SMC migration by 58% and 45% and the increase in oxidative stress induced by lyso-PC of 58% and 49%, respectively. Lyso-PC activated phospholipase D and protein kinase C (PKC), and this activation was also suppressed by HMG-CoA reductase inhibitors. The inhibition of phospholipase D and PKC was reversed by 100 micromol/L mevalonate, its isoprenoid derivative, farnesol, and geranylgeraniol but not by 10 micromol/L squalene. Antisense oligodeoxynucleotides at 5 micromol/L to PKC-alpha, but not those to the PKC-beta isoform, suppressed the lyso-PC-mediated increases in SMC migration and oxidative stress. These findings suggest that HMG-CoA reductase inhibitors have direct antimigratory effects on the vascular wall beyond their effects on plasma lipids and that they might exert such antimigratory effects via suppression of the phospholipase D- and PKC (possibly PKC-alpha)-induced increase in oxidative stress, which might in turn prevent significant coronary artery disease.

Topics: Antioxidants; Cell Movement; Cells, Cultured; Coronary Artery Disease; Coronary Vessels; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Isoenzymes; Lysophosphatidylcholines; Mevalonic Acid; Muscle, Smooth, Vascular; Oligonucleotides, Antisense; Oxidative Stress; Phospholipase D; Pravastatin; Protein Kinase C; Protein Kinase C beta; Protein Kinase C-alpha; Protein-Tyrosine Kinases; Simvastatin

In the last decade, large-scale clinical trials have consistently shown that therapy with statins is of great benefit to patients with and at risk of developing coronary artery disease. We assessed, in a sample of patients with coronary artery disease in whom coronary angiography was indicated and hospitalized in the last 10 years, the use of statins at admission.. One hundred patients with stable coronary artery disease were randomly selected per year from 1991 to 2000. The final study population consisted of 1000 patients. The prescription of statins for > or = 6 months before hospital admission was determined from a hospital-wide clinical database.. From 1995, the prevalence of patients treated with statins at hospital admission progressively increased. In 1991, only 2% of patients were treated with statins before hospital admission while in the year 2000, 38% of patients were receiving this treatment. The mean prevalence of patients treated with statins before and after 1995 was 3 vs 22% (p < 0.0001) respectively. The distribution of the demographic and clinical parameters and the prevalence of conventional cardiovascular risk factors were similar in patients treated or not treated with statins.. After 1994, in coincidence with the publication of the results of clinical trials showing the benefit of statins in patients with coronary artery disease, the use of these drugs increased significantly. This finding suggests that the widespread diffusion of the results of the major clinical trials and of guidelines drawn up by medical associations have had a significant impact on statin prescription in patients with coronary artery disease. Nevertheless our data also indicate that, despite overwhelming evidence on the benefits of statin therapy, in current clinical practice cardiologists are not optimally utilizing lipid management and that statins are frequently prescribed without an appropriate analysis of risk factors.

Topics: Aged; Anticholesteremic Agents; Atorvastatin; C-Reactive Protein; Cholesterol, LDL; Coronary Artery Disease; Drug Utilization Review; Fatty Acids, Monounsaturated; Female; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Italy; Male; Middle Aged; Practice Patterns, Physicians'; Pravastatin; Pyrroles; Retrospective Studies; Risk Factors; Simvastatin

Topics: Anticholesteremic Agents; Cholesterol, HDL; Coronary Artery Disease; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lovastatin; Male