Jonathan L. Isaacsohn

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.

Eicosapentaenoic Acid Ethyl Ester (AMR101) Therapy in Patients With Very High Triglyceride Levels (from the Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension (MARINE) Trial)

AMR101 is an omega-3 fatty acid agent containing ≥96% eicosapentaenoic acid ethyl ester and no docosahexaenoic acid. Previous smaller studies suggested that highly purified eicosapentaenoic acid lowered triglyceride (TG) levels without increasing low-density lipoprotein (LDL) cholesterol levels. TG-lowering therapies such as fibrates, and fish oils containing both eicosapentaenoic acid and docosahexaenoic acid, can substantially increase LDL cholesterol levels when administered to patients with very high TG levels (≥500 mg/dl). The present double-blind study randomized 229 diet-stable patients with fasting TG ≥500 mg/dl and ≤2,000 mg/dl (with or without background statin therapy) to AMR101 4 g/day, AMR101 2 g/day, or placebo. The primary end point was the placebo-corrected median percentage of change in TG from baseline to week 12. The baseline TG level was 680, 657, and 703 mg/dl for AMR101 4 g/day, AMR101 2 g/day, and placebo. AMR101 4 g/day reduced the placebo-corrected TG levels by 33.1% (n = 76, p <0.0001) and AMR101 2 g/day by 19.7% (n = 73, p = 0.0051). For a baseline TG level >750 mg/dl, AMR101 4 g/day reduced the placebo-corrected TG levels by 45.4% (n = 28, p = 0.0001) and AMR101 2 g/day by 32.9% (n = 28, p = 0.0016). AMR101 did not significantly increase the placebo-corrected median LDL cholesterol levels at 4 g/day (-2.3%) or 2 g/day (+5.2%; both p = NS). AMR101 significantly reduced non-high-density lipoprotein cholesterol, apolipoprotein B, lipoprotein-associated phospholipase A(2), very low-density lipoprotein cholesterol, and total cholesterol. AMR101 was generally well tolerated, with a safety profile similar to that of the placebo. In conclusion, the present randomized, double-blind trial of patients with very high TG levels demonstrated that AMR101 significantly reduced the TG levels and improved other lipid parameters without significantly increasing the LDL cholesterol levels.

Efficacy and Safety of Eicosapentaenoic Acid Ethyl Ester (AMR101) Therapy in Statin-Treated Patients With Persistent High Triglycerides (from the ANCHOR Study)

AMR101 is an ω-3 fatty acid agent containing ≥96% pure icosapent-ethyl, the ethyl ester of eicosapentaenoic acid. The efficacy and safety of AMR101 were evaluated in this phase 3, multicenter, placebo-controlled, randomized, double-blinded, 12-week clinical trial (ANCHOR) in high-risk statin-treated patients with residually high triglyceride (TG) levels (≥200 and <500 mg/dl) despite low-density lipoprotein (LDL) cholesterol control (≥40 and <100 mg/dl). Patients (n = 702) on a stable diet were randomized to AMR101 4 or 2 g/day or placebo. The primary end point was median percent change in TG levels from baseline versus placebo at 12 weeks. AMR101 4 and 2 g/day significantly decreased TG levels by 21.5% (p <0.0001) and 10.1% (p = 0.0005), respectively, and non-high-density lipoprotein (non-HDL) cholesterol by 13.6% (p <0.0001) and 5.5% (p = 0.0054), respectively. AMR101 4 g/day produced greater TG and non-HDL cholesterol decreases in patients with higher-efficacy statin regimens and greater TG decreases in patients with higher baseline TG levels. AMR101 4 g/day decreased LDL cholesterol by 6.2% (p = 0.0067) and decreased apolipoprotein B (9.3%), total cholesterol (12.0%), very-low-density lipoprotein cholesterol (24.4%), lipoprotein-associated phospholipase A(2) (19.0%), and high-sensitivity C-reactive protein (22.0%) versus placebo (p <0.001 for all comparisons). AMR101 was generally well tolerated, with safety profiles similar to placebo. In conclusion, AMR101 4 g/day significantly decreased median placebo-adjusted TG, non-HDL cholesterol, LDL cholesterol, apolipoprotein B, total cholesterol, very-low-density lipoprotein cholesterol, lipoprotein-associated phospholipase A(2), and high-sensitivity C-reactive protein in statin-treated patients with residual TG elevations.

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.

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

Abstract 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.

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 Tolerability of Low-dose Simvastatin and Niacin, Alone and in Combination, in Patients With Combined Hyperlipidemia: A Prospective Trial.

Background: Combination lipid-lowering therapy may be desirable in patients with elevated low-density lipoprotein cholesterol, high triglycerides, and low high-density lipoprotein cholesterol. This study was conducted to determine the lipid-lowering efficacy of the combination of low-dose simvastatin and niacin in patients with combined hyperlipidemia and low high-density lipoprotein cholesterol. Methods and Results: In this multicenter, prospective, randomized trial, 180 patients with hyper cholesterolemia and hypertriglyceridernia and/or low high-density lipoprotein cholesterol were randomized to combination simvastatin (10 mg/day) and niacin (0.75 g/day) or to either drug alone for 9 weeks. The dose of niacin was doubled (from 0.75 g/day to 1.5 g/day) in both the combination and niacin arms for the remaining 8 weeks. The combination of simvastatin, 10 mg/day, and niacin, 1.5 g/day, reduced total. low-density lipoprotein, and very low-density lipoprotein cholesterol and triglycerides by 248, 29%, 45%, and 31%, respectively, while increasing high-density lipoprotein cholesterol by 31%. The addition of niacin to simvastatin did not enhance the low-density lipoprotein cholesterol-lowering effect of simvastatin; however, the combination was more effective than either monotherapy at raising high-density lipoprotein cholesterol and lowering very low-density lipoprotein cholesterol (P <.05). More patients discontinued treatment because of an adverse event in the niacin (P <.03) and combination groups (P =.06) than the simvastatin group. Conclusions: Treatment of patients with combined hyperlipidemia and/or low high-density lipoprotein with combination low-dose simvastatin and niacin resulted in large reductions in total, low-density lipoprotein, and very low-density lipoprotein cholesterol and increases in HDL cholesterol. Although the combination was well tolerated in the current trial, its safety needs to be evaluated in larger trials of longer duration.

Effects of baseline level of triglycerides on changes in lipid levels from combined fluvastatin + fibrate (bezafibrate, fenofibrate, or gemfibrozil).

This analysis was conducted to evaluate the effect of baseline triglyceride levels on lipid and lipoprotein changes after treatment with the combination of fluvastatin and fibrates. The analysis involved pooling data from 10 studies that included 1,018 patients with either mixed hyperlipidemia or primary hypercholesterolemia. Patients received a combination of fluvastatin and a fibrate (bezafibrate, fenofibrate, or gemfibrozil) from 16 to 108 weeks. The combination of fluvastatin and a fibrate improved lipid profiles, with reductions in triglycerides, low-density lipoprotein (LDL) cholesterol, and non-high-density lipoprotein (non-HDL) cholesterol that were dependent on baseline triglyceride levels. The greatest triglyceride reductions were observed in patients with high baseline triglyceride levels (> or =400 mg/dl) (41%, p <0.0001). The greatest LDL cholesterol and non-HDL cholesterol reductions occurred in patients with normal baseline triglyceride levels (<150 mg/dl) (35% and 33%, respectively; p <0.0001). The combined fluvastatin-fibrate therapy was well tolerated. Two patients (0.2%) (1 patient on fluvastatin 80 mg + gemfibrozil 1,200 mg and 1 patient on fluvastatin 20 mg + fenofibrate 200 mg) had creatine kinase levels > or =10 times the upper limit of normal, 11 patients (1.1%) had an elevation in alanine transaminase >3 times the upper limit of normal, and 7 patients (0.7%) had elevations in aspartate transaminase >3 times the upper limit of normal. Combined fluvastatin-fibrate therapy takes advantage of the complementary effects of the 2 agents, with the extent of triglyceride, LDL cholesterol, and non-HDL cholesterol lowering dependent on baseline triglyceride levels. The combination of fluvastatin and fibrates was well tolerated with no major safety concerns.

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.

A Randomized Multicenter Trial Comparing the Efficacy of Simvastatin and Fluvastatin

Background: Inhibitors of hydroxymethylglutaryl co-enzyme A reductase are widely used for the treatment of hypercholesterolemia. Physicians and third-party payers need an accurate measure of their relative potency and hypolipidemic efficacy. We have therefore compared simvastatin against fluvastatin, the newest member of this class. Methods and Results: One hundred fifty-eight hypercholesterolemic patients in seven United States lipid clinics participated in this balanced double-blind incomplete block study. After a placebo-diet run-in period, patients received treatment with active drug for three con secutive 5-week periods, with measurement of lipids in a NHLBI-CDC standardized central laboratory at the end of each period. Each patient was randomly assigned to three of the fol lowing five treatments: simvastatin 5 mg, 10 mg, and 20 mg and fluvastatin 20 mg and 40 mg. The mean percent reductions in low density lipoprotein cholesterol from baaeline were 21, 27, 32, 16, and 23 respectively. The simvastatin/fluvastatin milligram potency ratio was 6.8 (95% CI, 5.3-9.3). At the same 20 mg dosage, simvastatin produced an effect on LDL cholesterol approximately double that of fluvastatin and resulted in 46% of patients achieving their National Cholesterol Education Program low density lipoprotein cholesterol target levels, compared to 12% for fluvastatin. Conclusions. Fluvastatin at its maximal dose of 40 mg daily is approximately equivalent to simvastatin 5 mg daily. Higher doses of simvastatin are considerably more effective in the treatment of primary hypercholesterolemia.