Effects of colesevelam HC1 on sterol and bile acid excretion in patients with type IIa hypercholesterolemia.

Colesevelam HC1 is a potent bile acid-binding polymer. This study's aim was to determine effects of colesevelam HCl on sterol and bile acid excretion in patients with type IIa hypercholesterolemia. Twenty-four patients (low-density lipoprotein cholesterol, 130 to 220 mg/dL) enrolled in an open-label, parallel-design study, entered an American Heart Association/National Cholesterol Education Program diet for 6 weeks and were randomized to colesevelam HCl, 2.3 or 3.8 g/day for 4 weeks. In an apparent dose-related manner, respective mean serum concentrations HCl of low-density lipoprotein cholesterol decreased by 10% (P < 0.01) and 13% (P = 0.05), mean total cholesterol levels decreased by 4.9% (P = 0.05) and 6.1% (P = 0.09), and total fecal bile acid excretion showed median changes of +324% (P < 0.05) and +316% (P < 0.05). Colesevelam HCl did not affect fecal neutral sterol or fecal fatty acid excretion; however, 24-hr urinary mevalonic acid levels significantly increased in both treatment groups (P < 0.05). The cholesterol-lowering action of colesevelam HCl appears to be mediated through increased bile acid excretion.

Long-term efficacy and safety of cerivastatin 0.8 mg in patients with primary hypercholesterolemia.

BACKGROUND: Statins are the agents of choice in reducing elevated plasma low-density lipoprotein cholesterol (LDL-C). HYPOTHESIS: Cerivastatin 0.8 mg has greater long-term efficacy in reducing LDL-C than pravastatin 40 mg in primary hypercholesterolemia. METHODS: In this double-blind, parallel-group, 52-week study, patients (n = 1,170) were randomized (4:1:1) to cerivastatin 0.8 mg, cerivastatin 0.4 mg, or placebo daily. After 8 weeks, placebo was switched to pravastatin 40 mg. Patients with insufficient LDL-C lowering after 24 weeks were allowed open-labeled resin therapy. RESULTS: Cerivastatin 0.8 mg reduced LDL-C versus cerivastatin 0.4 mg (40.8 vs. 33.6%, p <0.0001) or pravastatin 40 mg (31.5%, p<0.0001), and brought 81.8% of all patients, and 54.1% of patients with atherosclerotic disease, to National Cholesterol Education Program (NCEP) goals. Cerivastatin 0.8 mg improved mean total C (-29.0%), triglycerides (-18.3%), and high-density lipoprotein cholesterol (HDL-C) (+9.7%) (all p < or = 0.013 vs. pravastatin 40 mg). Higher baseline triglycerides were associated with greater reductions in triglycerides and elevations in HDL-C with cerivastatin. Cerivastatin was well tolerated; the most commonly reported adverse events were arthralgia, headache, pharyngitis, and rhinitis. Symptomatic creatine kinase > 10x the upper limit of normal (ULN) occurred in 1, 1.5, and 0% of patients receiving cerivastatin 0.8 mg, cerivastatin 0.4 mg, and pravastatin 40 mg, respectively. Repeat hepatic transaminases >3 x ULN occurred in 0.3-0.5, 0.5, and 0% of patients, respectively. CONCLUSION: In long-term use, cerivastatin 0.8 mg effectively and safely brings the majority of patients to NCEP goal.

Low-dose combination therapy with colesevelam hydrochloride and lovastatin effectively decreases low-density lipoprotein cholesterol in patients with primary hypercholesterolemia.

BACKGROUND: Colesevelam hydrochloride is a novel, lipid-lowering agent that binds bile acids with high affinity. A multicenter, randomized, double-blind, placebo-controlled, parallel-design study was conducted to assess the efficacy and tolerability of combination low-dose colesevelam and lovastatin treatment in patients with primary hypercholesterolemia. HYPOTHESIS: Combination therapy with low doses of colesevelam and lovastatin decreases low density (LDL) cholesterol with minimal adverse events. METHODS: Following a 4- to 6-week dietary lead in, 135 patients were randomized into five groups for a 4-week treatment period: placebo, colesevelam 2.3 g at dinner, lovastatin 10 mg at dinner, the combination of colesevelam and lovastatin given at dinner (dosed together), and combination treatment with colesevelam given at dinner and lovastatin administered at bedtime (dosed apart). RESULTS: Combination colesevelam and lovastatin treatment decreased LDL cholesterol by 34% (60 mg/dl, p < 0.0001) and 32% (53 mg/dl, p < 0.0001) when colesevelam and lovastatin were dosed together or dosed apart, respectively. Both combination therapies were superior to either agent alone (p < 0.05). Decreases in LDL cholesterol exceeded the combined decreases observed for colesevelam alone (13 mg/dl, 7%) and lovastatin alone (39 mg/dl, 22%). Both combination treatments reduced total cholesterol by 21% (p < 0.0001) and apolipoprotein B by 24% (p < 0.0001). Neither combination treatment significantly altered high-density lipoprotein cholesterol or triglycerides. Adverse side effects were not significantly different among randomized groups. CONCLUSIONS: Combination colesevelam and lovastatin was efficacious and well tolerated, resulting in additive decreases in LDL cholesterol levels whether or not both agents were administered simultaneously.

Influence of gender on the pharmacokinetics, safety, and tolerability of cerivastatin in healthy adults.

The pharmacokinetics, safety, and tolerability of cerivastatin, a synthetic HMG-CoA reductase inhibitor were studied in 49 healthy volunteers. In this double-blind, parallel group, multiple-dose study, volunteers were randomized as age-matched, male-female pairs and stratified into younger (18-65 years, premenopausal females) or older (65-85 years, postmenopausal females) groups. Thirty-two (16 female, 16 male) subjects received 0.2 mg cerivastatin daily for 7 days; 17 received placebo. Between all males and females, no differences in cerivastatin pharmacokinetics were observed. The AUCnorm in older females was 21% higher than in older males, while the AUCnorm in younger females was 26% lower than in younger males. The Cmax in older females was 30% higher than in age-matched males or younger males and females. All other pharmacokinetic parameters, including half-life, tmax, accumulation ratios, and steady state plasma levels were similar in all treatment groups. The most common adverse events, including headache (4), dyspepsia (4), and rash (4), were equally distributed between groups. Treatment-emergent elevations (< 2 x ULN) in creatine kinase occurred in one subject. Transaminase elevations occurred in nine subjects, most were less than 3 x ULN, and were equally distributed between groups. In conclusion, cerivastatin was well tolerated. The minor differences in the pharmacokinetics of cerivastatin 0.2 mg between genders does not require modification of dosage.

Efficacy and safety of cerivastatin 0.8 mg in patients with hypercholesterolaemia: the pivotal placebo-controlled clinical trial. Cerivastatin Study Group.

This pivotal, multicentre, double-blind, parallel-group study evaluated the efficacy and safety of cerivastatin 0.8 mg. Patients with primary hypercholesterolaemia were randomized, after 10 weeks' dietary stabilization on an American Heart Association (AHA) Step I diet, to treatment with cerivastatin 0.8 mg (n = 776), cerivastatin 0.4 mg (n = 195) or placebo (n = 199) once daily for 8 weeks. Cerivastatin 0.8 mg reduced mean low density lipoprotein-cholesterol (LDL-C) by 41.8% compared with cerivastatin 0.4 mg (-35.6%, P < 0.0001) or placebo. In 90% of patients receiving cerivastatin 0.8 mg LDL-C was reduced by 23.9 -58.4% (6th - 95th percentile). Overall attainment of the National Cholesterol Education Program (NCEP) goal was achieved by 84% of patients receiving cerivastatin 0.8 mg and by 59% of those with coronary heart disease (CHD). In the sub-population meeting the NCEP criteria for pharmacological therapy for LDL-C reduction, 74.6% of patients, including the 59% with CHD, reached the goal with cerivastatin 0.8 mg. Cerivastatin 0.8 mg also reduced mean total cholesterol by 29.9%, apolipoprotein B by 33.2% and median triglycerides by 22.9% (all P < 0.0001). Mean high density lipoprotein-cholesterol (HDL-C) and apolipoprotein A1 were elevated 8.7% (P < 0.0001) and 4.5% (P < 0.0001), respectively, by cerivastatin 0.8 mg. Reductions of triglyceride and elevation in HDL-C were dependent upon triglyceride baseline levels; in patients having baseline triglyceride levels 250 - 400 mg/dl, cerivastatin 0.8 mg reduced median triglycerides by 29.5% and elevated HDL-C by 13.2%. Cerivastatin 0.8 mg was well tolerated. The most commonly reported adverse events included headache, pharyngitis and rhinitis (4 - 6%). Symptomatic creatine kinase elevations > 10 times upper limit of normal occurred in 0%, 1% and 0.9% of patients receiving placebo, cerivastatin 0.4 mg or cerivastatin 0.8 mg, respectively. Cerivastatin 0.8 mg is an effective and safe treatment for patients with primary hypercholesterolaemia who need aggressive LDL-C lowering in order to achieve NCEP-recommended levels.

Colesevelam hydrochloride (cholestagel): a new, potent bile acid sequestrant associated with a low incidence of gastrointestinal side effects.

OBJECTIVES: To compare colesevelam hydrochloride (Cholestagel), a nonabsorbed hydrogel with bile acid-sequestering properties, with placebo for its lipid-lowering efficacy, its effects on laboratory and clinical safety parameters, and the incidence of adverse events. METHODS: Following diet and placebo lead-in periods, placebo or colesevelam was administered at 4 dosages (1.5, 2.25, 3.0, or 3.75 g/d) for 6 weeks with morning and evening meals to men and women with hypercholesterolemia (low-density lipoprotein cholesterol level >4.14 mmol/L [>160 mg/dL]). Patients returned to the clinic every 2 weeks throughout the treatment period for lipid parameter measurements and adverse event assessments. Samples were collected for serum chemistry profiles, hematologic studies, coagulation studies, and vitamin level assessment at baseline and after 6 weeks of treatment. RESULTS: Among the 149 patients randomized, 137 completed the study. Low-density lipoprotein cholesterol concentrations decreased in a dosage-dependent manner by 0.11 mmol/L (4.2 mg/dL) (1.8%) in the 1.5-g/d colesevelam treatment group and up to 1.01 mmol/L (39 mg/dL) (19.1%) in the 3.75-g/d colesevelam treatment group. Low-density lipoprotein cholesterol concentrations at the end of treatment were significantly reduced from baseline levels in the 3.0- and 3.75-g/d colesevelam treatment groups (P = .01 and P<.001, respectively). Total cholesterol levels demonstrated a similar response to colesevelam treatment, with an 8. 1% decrease from baseline in the 3.75-g/d treatment group (P<.001). High-density lipoprotein cholesterol levels rose significantly in the 3.0- and 3.75-g/d colesevelam treatment groups, by 11.2% (P=.006) and 8.1% (P=.02), respectively. Median triglyceride levels did not change from baseline, nor were there any significant differences between treatment groups. The incidence of adverse events was similar among all groups. CONCLUSIONS: Colesevelam therapy is effective for lowering low-density lipoprotein cholesterol concentrations in persons with moderate hypercholesterolemia. It lacks the constipating effect of other bile acid sequestrants, demonstrating the potential for increased compliance.

Pharmacodynamics, safety, tolerability, and pharmacokinetics of the 0.8-mg dose of cerivastatin in patients with primary hypercholesterolemia.

Cerivastatin is a third generation hydroxy-methyl-glutaryl-Co-enzyme A (HMG-CoA) reductase inhibitor proven to lower low-density lipoprotein (LDL) cholesterol 28% to 31% in patients with primary hypercholesterolemia when given at 0.3 mg/day. This study evaluates the safety, tolerability, pharmacodynamics, and pharmacokinetics of cerivastatin 0.8 mg once daily for 4 weeks. In this randomized, double-blind, placebo-controlled parallel group trial conducted at 2 study centers, 41 patients (63% women) with primary hypercholesterolemia were placed on an American Heart Association Step 1 diet for 4 weeks. Single-blind placebo was administered for the final 2 weeks, before randomization. Patients received cerivastatin 0.8 mg (n = 28) or placebo (n = 13) once each evening for 28 days. Cerivastatin at 0.8 mg daily was well tolerated. No discontinuations occurred during the study. Adverse events were mild and transient. One cerivastatin-treated patient experienced asymptomatic creatinine kinase, 8x the upper limit of normal (ULN) elevation on the last day of the study, which resolved 6 days after the completion of the study. Cerivastatin 0.8 mg daily significantly reduced LDL cholesterol compared with placebo (-44.0 +/- 2.0% vs 2.2 +/- 2.8%, p <0.0001); total cholesterol (-30.8 +/- 1.4% vs 2.6 +/- 2.1%, p <0.0001), triglycerides (-11.2 +/- 5.9% vs 15.9 +/- 8.6%, p <0.02), but did not significantly alter high-density lipoprotein (HDL) cholesterol (3.2 +/- 2.1% vs -1.2 +/- 3.1%, p = NS). The pharmacokinetics of the 0.8-mg dose revealed dose proportional elevations in the 24-hour area under the curve and maximum plasma concentration relative to 0.3- and 0.4-mg doses with no change in time to maximum concentration or the elimination half-life in plasma. The increased efficacy and lack of clinically significant laboratory abnormalities or adverse events demonstrates a need for a large long-term study to confirm the safety and efficacy of this dose of cerivastatin.

Efficacy and safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia: a randomized controlled trial.

CONTEXT: Heterozygous familial hypercholesterolemia (HeFH) is a common disorder associated with early coronary artery disease, especially in men. The age at which drug therapy should be started is still controversial, as is the use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). OBJECTIVE: To assess the lipid-lowering efficacy, biochemical safety, and effect on growth and sexual development of lovastatin in adolescent boys with HeFH. DESIGN: One-year, double-blind, placebo-controlled, balanced, 2-period, 2-arm randomized trial. In the first period (24 weeks), lovastatin was increased at 8 and 16 weeks and the dosage remained stable during the second period (24 weeks). The study was conducted between 1990 and 1994. SETTING: Fourteen pediatric outpatient clinics in the United States and Finland. PATIENTS: Boys aged 10 to 17 years with HeFH. Of 132 randomized subjects (67 intervention, 65 placebo), 122 (63 intervention, 59 placebo) and 110 (61 intervention, 49 placebo) completed the first and second periods, respectively. INTERVENTION: Lovastatin, starting at 10 mg/d, with a forced titration at 8 and 16 weeks to 20 and 40 mg/d, respectively, or placebo. MAIN OUTCOME MEASURES: The primary efficacy outcome measure was low-density lipoprotein cholesterol (LDL-C). Primary safety measures were growth and sexual development. RESULTS: Compared with placebo, LDL-C levels of patients receiving lovastatin decreased significantly (P<.001) by 17%, 24%, and 27% receiving dosages of 10, 20, and 40 mg/d, respectively, and remained 25 % lower than baseline at 48 weeks. Growth and sexual maturation assessed by Tanner staging and testicular volume were not significantly different between the lovastatin and placebo groups at 24 weeks (P = .85) and 48 weeks (P = .33); neither were serum hormone levels or biochemical parameters of nutrition. However, the study was underpowered to detect significant differences in safety parameters. Serum vitamin E levels were reduced with lovastatin treatment consistent with reductions in LDL-C, the major carrier of vitamin E in the circulation. CONCLUSIONS: This study in adolescent boys with HeFH confirmed the LDL-C-reducing effectiveness of lovastatin. Comprehensive clinical and biochemical data on growth, hormonal, and nutritional status indicated no significant differences between lovastatin and placebo over 48 weeks, although further study is required.

Garlic powder and plasma lipids and lipoproteins: a multicenter, randomized, placebo-controlled trial.

BACKGROUND: Garlic powder tablets have been reported to lower serum cholesterol levels. There is widespread belief among the general public that garlic powder tablets aid in controlling cholesterol levels. However, much of the prior data demonstrating the cholesterol-lowering effect of garlic tablets involved studies that were inadequately controlled. OBJECTIVE: To determine the lipid-lowering effect of garlic powder tablets in patients with hypercholesterolemia. METHODS: This was a randomized, double-blind, placebo-controlled, 12-week, parallel treatment study carried out in 2 outpatient lipid clinics. Entry into the study after 8 weeks of diet stabilization required a mean low-density lipoprotein cholesterol level on 2 visits of 4.1 mmol/L (160 mg/dL) or lower and a triglyceride level of 4.0 mmol/L (350 mg/dL) or lower. The active treatment arm received tablets containing 300 mg of garlic powder (Kwai) 3 times per day, given with meals (total, 900 mg/d). This is equivalent to approximately 2.7 g or approximately 1 clove of fresh garlic per day. The placebo arm received an identical-looking tablet, also given 3 times per day with meals. The main outcome measures included levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol after 12 weeks of treatment. RESULTS: Twenty-eight patients (43% male; mean +/- SD age, 58 +/- 14 years) received garlic powder treatment and 22 (68% male; mean +/- SD age, 57 +/- 13 years) received placebo treatment. There were no significant lipid or lipoprotein changes in either the placebo- or garlic-treated groups and no significant difference between changes in the placebo-treated group compared with changes in the garlic-treated patients. CONCLUSION: Garlic powder (900 mg/d) treatment for 12 weeks was ineffective in lowering cholesterol levels in patients with hypercholesterolemia.

Long-term effects of low-density lipoprotein apheresis using an automated dextran sulfate cellulose adsorption system. Liposorber Study Group.

The short-term effectiveness of low-density lipoprotein (LDL) apheresis using a dextran sulfate cellulose adsorption column technique was previously examined in a 9-center, 22-week controlled trial in 64 patients with familial hypercholesterolemia (FH) who did not adequately respond to diet and drug therapy. Forty-nine patients (40 treatment, 9 controls) subsequently received LDL apheresis procedures as part of an optional follow-up phase. This study reports on the long-term safety, lipid lowering, and clinical efficacy of LDL apheresis for the 5-year period that includes both the initial controlled study and follow-up phase. During this time, patients received a total of 3,902 treatments of which 3,314 treatments were given during the follow-up phase. Adverse events were infrequent, occurring in 142 procedures (3.6%). Immediate reduction in LDL cholesterol was 76% both in homozygotes and in heterozygotes. Patients with homozygous FH had a progressive decrease in pretreatment LDL cholesterol level along with an increase in high-density lipoprotein (HDL) cholesterol level. There was no appreciable change in pretreatment lipoprotein level over time in heterozygotes. The rate of cardiovascular events during therapy with LDL apheresis and lipid-lowering drugs was 3.5 events per 1,000 patient-months of treatment compared with 6.3 events per 1,000 patient-months for the 5 years before LDL apheresis therapy. These findings support the long-term safety and clinical efficacy of LDL apheresis in patients with heterozygous and homozygous FH who are inadequately controlled with drug therapy.

Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease.

PURPOSE: This study evaluated the effects of cilostazol on walking distances in patients with intermittent claudication (IC) caused by peripheral arterial occlusive disease. METHODS: The study was a multicenter, randomized, double-blind, placebo-controlled trial. Two hundred thirty-nine patients with IC were randomly assigned to receive cilostazol (100 mg b.i.d.) or a placebo for 16 weeks. All patients underwent serial, variable-grade, constant-speed treadmill testing. Absolute claudication distance (ACD), assessed at the end of the 12-hour dosing interval (trough), was the primary end point. Secondary end points included ACD assessed 3 to 4 hours after dosing (peak) and initial claudication distances (trough and peak). Functional status measures, including the Medical Outcomes Scale (SF-36) and Walking Impairment Questionnaire, were used to assess subjective changes over the 16-week treatment period. Ankle-brachial indexes were calculated from Doppler-measured systolic pressures at every visit with treadmill testing. RESULTS: Patients treated with cilostazol demonstrated significant improvements over the placebo patients in ACD at all three time points tested after baseline (weeks 8, 12, and 16). Peak treadmill testing at weeks 8 and 12 also showed significant improvement in walking distances for cilostazol-treated patients over placebo-treated patients. At week 16, patients in the cilostazol group had a 96.4-meter (47%) increase in ACD compared with 31.4 meters (12.9%) for the placebo group (p < 0.001). In the SF-36, significant improvement was observed in the physical component subscale and the composite physical component score. In the Walking Impairment Questionnaire, improvements were significant in patient reports of walking speed and specific measures of walking difficulty. Ankle-brachial indexes improved in the cilostazol group (0.64 +/- 0.02 to 0.70 +/- 0.02) compared with the placebo group (0.68 +/- 0.02 to 0.69 +/- 0.02) (p < 0.0125). The most frequent adverse events were headache, abnormal stools (e.g. loose stools), diarrhea, and dizziness. CONCLUSIONS: Cilostazol significantly increased ACD at all measured time points and initial claudication distances at most time points. This agent may represent a new treatment option for patients with intermittent claudication.

Serum lipids and incidence of coronary heart disease. Findings from the Systolic Hypertension in the Elderly Program (SHEP).

BACKGROUND: The association of serum lipids with coronary heart disease has been studied extensively in middle-aged men and, to a lesser extent, in similar women. Less well defined are lipid variables predictive of CHD in individuals of age > or = 60 years. METHODS AND RESULTS: The Systolic Hypertension in the Elderly Program recruited 4736 persons (mean age, 72 years; 14% were black; and 43% were men). Mean systolic and diastolic blood pressures were 170 and 77 mm Hg, respectively. Baseline mean total cholesterol was 6.11 mmol/L (236 mg/dL); HDL cholesterol, 1.39 mmol/L (54 mg/dL); and non-HDL cholesterol, 4.72 mmol/L (182 mg/dL). Triglyceride levels were 1.62 mmol/L (144 mg/dL) for fasting participants and 1.78 mmol/L for the total group. LDL cholesterol, estimated in fasting samples with triglycerides of < 4.52 mmol/L, averaged 3.98 mmol/L (154 mg/dL). Mean follow-up was 4.5 years. In multivariate Cox regression analyses, baseline total, non-HDL, and LDL cholesterol levels and the ratios of total, non-HDL, and LDL to HDL cholesterol were significantly related to CHD incidence. HDL cholesterol and triglycerides were not significant in these analyses. In fasting participants with triglyceride levels of < 4.52 mmol/L, a 1.03 mmol/L (40 mg/dL) higher baseline total, non-HDL, or LDL cholesterol was associated with a 30% to 35% higher CHD event rate. CONCLUSIONS: The results of this study support the concept that serum lipids are CHD risk factors in older Americans.

Coronary heart disease risk factors in men and women aged 60 years and older: findings from the Systolic Hypertension in the Elderly Program.

BACKGROUND: Coronary heart disease (CHD) is the most common cause of death in men and women aged 60 years and older. Although a number of studies support the concept that CHD risk factors that have been defined in younger adults are significantly associated with CHD events in older adults, others do not support this thesis, and further definition of the risk-factor concept in older adults is required. METHODS AND RESULTS: The Systolic Hypertension in the Elderly Program recruited 4736 persons (mean age, 72 years); 14% were black, and 43% were men. Mean systolic and diastolic blood pressures were 170 and 77 mm Hg, respectively. About 13% of participants were current smokers; 10% had a history of diabetes; 5%, a prior myocardial infarction; 5% angina pectoris; 2.3%, intermittent claudication; and 7%, a carotid bruit. Mean total cholesterol value was 6.11 mmol/L. Mean follow-up was 4.5 years. In multivariate Cox regression analyses for CHD, variables that were significant were baseline total cholesterol value, smoking, history of diabetes, presence of carotid bruit, and treatment group in the trial. Active treatment yielded a 27% reduction in CHD risk. For each 1.03 mmol/L increase in total cholesterol value, there was an increase in risk of about 20%. Current smokers had a 73% increase, diabetics a 121% increase, and those with carotid bruit a 113% increase in CHD risk. CONCLUSIONS: The results of this study support the concept that CHD risk factors are important in older men and women with isolated systolic hypertension.

Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia.

OBJECTIVE: To assess the lipid-lowering effect of atorvastatin (a new 3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitor) on levels of serum triglycerides and other lipoprotein fractions in patients with primary hypertriglyceridemia, determine if atorvastatin causes a redistribution of triglycerides in various lipoprotein fractions, and assess its safety by reporting adverse events and clinical laboratory measurements. DESIGN: Randomized double-blind, placebo-controlled, parallel-group, multicenter trial. SETTING: Community- and university-based research centers. PATIENTS: A total of 56 patients (aged 26 to 74 years) with a mean baseline triglyceride level of 6.80 mmol/L (603.3 mg/dL) and a mean baseline low-density lipoprotein cholesterol (LDL-C) level of 3.07 mmol/L (118.7 mg/dL). INTERVENTIONS: Cholesterol-lowering diet (National Institutes of Health National Cholesterol Education Program Step I Diet) and either 5 mg, 20 mg, or 80 mg of atorvastatin, or placebo. MAIN OUTCOME MEASURES: Percent change from baseline in total triglycerides for three dose levels of atorvastatin compared with placebo. RESULTS: Mean reductions in total triglycerides between 5 mg, 20 mg, and 80 mg of atorvastatin and placebo after 4 weeks of treatment were -26.5%, -32.4%, -45.8%, and -8.9%, respectively. Mean reductions in LDL-C were -16.7%, -33.2%, -41.4%, and -1.4%, respectively, and very low-density lipoprotein cholesterol (VLDL-C) were -34.3%, -45.9%, -57.7%, and -5.5%, respectively. Similar mean changes in total apolipoprotein B (apo B) (-16.9%, -32.8%, -41.7%, and +1.0%), apo B in LDL (-14.8%, -29.8%, -42.0%, and -3.1%), and apo B in VLDL (-23.8%, -35.8%, -34.4%, and +11.7%) were observed. In addition, comparable mean changes in LDL triglycerides (-22.5%, -30.7%, -39.9%, and +3.9%) and VLDL triglycerides (-28.1%, -34.0%, -47.3%, and -10.8%) were seen. CONCLUSIONS: In atorvastatin treatment groups, total serum triglyceride levels decreased in a dose-dependent manner, reductions in the 20-mg and 80-mg groups were statistically significant (P < .05) compared with placebo. Atorvastatin did not cause a redistribution of triglycerides but consistently lowered triglycerides in all lipoprotein fractions. Atorvastatin was well tolerated.

A comparison of the safety of therapeutically equivalent doses of isradipine and diltiazem for treatment of essential hypertension.

We compared the safety of a new dihydropyridine calcium entry blocker, isradipine, with an equipotent dose of diltiazem in 174 mild hypertensives (diastolic blood pressure [DBP] 95 to 105 mm Hg). After appropriate washout and placebo periods, patients were randomly assigned to receive either 1.25 mg isradipine twice daily (Group I) or 40 mg diltiazem thrice daily (Group D). If DBP remained above 90 mm Hg, doses were increased to a maximum of 5 mg isradipine twice daily or 120 mg diltiazem thrice daily. Active therapy was given for a total of 12 weeks. Only 18 patients (nine from each group) did not complete the protocol. The patients were well-matched at baseline with a mean BP of 149/100 mm Hg for those who were randomized to isradipine and completed the protocol and 153/99 mm Hg for the diltiazem group. The responses to each drug were excellent with 72% of the isradipine patients and 73% of the diltiazem group having DBP less than 90 mm Hg at the completion of the study. Of the 156 patients who completed the protocol, only 18 patients (ten in Group I and eight in Group D) failed to respond. Both drugs were well-tolerated. No adverse reactions were reported by 68 percent of the patients in Group I and 65% of those in Group D. The most common side effect was headache (9.0% in Group I and 7.8% in Group D) followed by fatigue (5.2% in Group I and 3.9% in Group D). Age and race did not predict response to either agent but men responded slightly better to diltiazem than women. We conclude that isradipine and diltiazem are equally well tolerated and can be used successfully as a monotherapy to treat hypertension in a wide variety of patients.

A study of twins and stroke.

BACKGROUND AND PURPOSE: Although there are strong genetic contributions to coronary artery disease, only a few studies have considered heritable influences on stroke. METHODS: We investigated the role of genetic factors in stroke using the Twin Registry maintained by the National Academy of Sciences-National Research Council. The registry includes 15,948 male twin pairs born between 1917 and 1927. In 1985, 9,475 twins responded to a mailed questionnaire, which covered vascular risk factors, cardiac events, and stroke. RESULTS: Analysis of twin pairs in which both responded to the questionnaire, and a question on stroke, indicated proband concordance rates of 17.7% for monozygotic pairs and 3.6% for dizygotic pairs (relative risk = 4.3; chi 2 = 4.94, df = 1; p less than 0.05). CONCLUSIONS: This nearly fivefold increase in the prevalence of stroke among the monozygotic compared with the dizygotic twin pairs suggests that genetic factors are involved in the etiology of stroke. The twin study paradigm holds considerable promise for identifying both genetic and environmental influences on stroke.

Intraoperative angioscopy: principles of irrigation and description of a new dedicated irrigation pump.

The value of intraoperative angioscopy in the detection and immediate correction of technical errors and deficiencies during vascular surgery has been previously documented. The inability to see through blood remains the most significant limitation to the general application of angioscopy. Local irrigation with a balanced salt solution is the most commonly used method to clear the blood from a restricted field in a particular vessel. We have developed a new catheter irrigation pump system (maximum flow rate 340 ml/min) to establish and maintain visibility of the field during intraoperative angioscopy. Furthermore, we have demonstrated the safety of irrigating with high volume flows in the peripheral arteries and defined the basic principles of irrigation for angioscopy. The prototype pump tested in this study provides a wide range of flow rates and permits precise measurements of the fluid delivered. The instrument's display and its control with a single foot pedal makes its use relatively simple, obviating the need for additional support personnel while increasing the efficacy and safety of the angioscopic examination and increasing the number of situations where angioscopy may be very useful.