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Objectives: To assess the long-term safety and tolerability and to further evaluate the effect of ezetimibe plus simvastatin on LDL-C, HDL-C, and triglyceride levels in subjects with primary hypercholesterolemia. Methods: This was a 12-month, double-blind, placebo-controlled extension study that enrolled patients with primary hypercholesterolemia who had successfully completed the 12-week, double-blind, placebo-controlled trial of ezetimibe coadministered with simvastatin. The initial dose administered to patients in the extension was ezetimibe 10 mg coadministered with simvastatin 10 mg with the option to up-titrate statin dosage if LDL-C goals were not met. Safety and tolerability were assessed through clinical and laboratory adverse experiences (AEs). Changes from baseline in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglyceride levels were measured. Results: Overall, 87 patients were randomized to receive ezetimibe + simvastatin and 22 were randomized to receive simvastatin and placebo. Treatment-emergent AEs were reported for 72/87 (83%) ezetimibe + simvastatin-treated patients and for 17/22 (77%) simvastatin-treated patients. The most commonly reported AEs in the simvastatin treatment group were hypertension, gastroesophageal reflux, and musculoskeletal pain (each reported by 3/22 [14%] patients); and in the ezetimibe + simvastatin group were upper respiratory tract infection (16/87 [18%]), arthralgia and musculoskeletal pain (both reported by 10/87 [11%] patients). Drug-related AEs were reported for 3/22 (14%) simvastatin-treated patients and 21/87 (24%) patients in the coadministration group. AEs considered serious by the investigator were reported by 2/22 (9%) patients taking simvastatin monotherapy and by 20/87 (23%) patients taking ezetimibe + simvastatin. Discontinuations due to AEs occurred in no patients taking simvastatin monotherapy and in 7/87 (8%) patients taking ezetimibe + simvastatin. Percent change±standard deviation from baseline in LDL-C was -29%±15.4 and -44%±14.2 in subjects taking simvastatin monotherapy and ezetimibe + simvastatin, respectively. Conclusions: Ezetimibe coadministered with simvastatin was generally well-tolerated and no new safety concerns were raised. Both treatments effectively maintained improvements in lipid parameters throughout the course of the studies. Interpretation of these results was limited by the small convenience sample included in the trial. [ABSTRACT FROM AUTHOR]

Background: Levels of cholesterol are regulated by its synthesis, absorption, and elimination. Plasma levels of phytosterols (e.g., sitosterol, campesterol) and ratios of these sterols to total cholesterol (TC) are reported to correlate with efficiency of intestinal cholesterol absorption, whereas levels of certain cholesterol precursor sterols (e.g., desmosterol, lathosterol) and their ratios to TC correlate with cholesterol biosynthesis. However, there is a paucity of published data concerning the effects of combined treatment using HMG-CoA reductase inhibitors (statins) and a cholesterol absorption inhibitor (ezetimibe) on these parameters.Objectives: To characterize the effects of ezetimibe co-administered with statins, compared with each treatment alone, on cholesterol precursor sterols and plasma phytosterol levels.Methods: A post-hoc analysis was performed to determine the effects of treatment with ezetimibe 10 mg, simvastatin (10-80 mg), and atorvastatin (10-80 mg), alone or in combination, on these non-cholesterol sterols using plasma samples from two randomized controlled trials involving patients with primary hypercholesterolemia (low-density lipo protein [LDL-C] = 145-250 mg/dL; triglycerides < or = 350 mg/dL; N = 975) but without a recent (< or = 6-month) history of coronary heart disease (CHD) or either uncontrolled or newly diagnosed diabetes mellitus.Results: Ezetimibe monotherapy significantly reduced plasma sitosterol and campesterol concentrations from baseline compared with placebo (both p < 0.001), whereas statins significantly lowered desmo sterol and lathosterol levels (p < 0.001 vs. placebo). Co-administration of ezetimibe and statins significantly decreased plasma levels of all of these sterols (p < 0.001).Conclusions: The observed effects of co-administration of ezetimibe and statins on non-cholesterol sterols are consistent with net inhibition of sterol absorption (driven by ezetimibe) in conjunction with net inhibition of cholesterol synthesis (driven by statins). The potential influence of treatment-induced changes in phytosterols on cardiovascular risk warrants further investigation in long-term, prospective, randomized controlled trials. This post-hoc study was by nature exploratory, and, because data from such analyses are not customarily adjusted for multiple comparisons, some associations may have emerged as statistically significant by chance. Future prospective randomized controlled studies may help to confirm our findings and address other research issues, such as the generalizability of our findings to patients with CHD or diabetes mellitus and possible dose:response relationships between escalating statin (or ezetimibe-statin) doses and circulating non-cholesterol levels. [ABSTRACT FROM AUTHOR]

This multicenter, randomized, double-blind, placebo-controlled clinical study assessed the efficacy and safety of ezetimibe administered with lovastatin in primary hypercholesterolemia. After dietary stabilization, a 2- to 12-week washout period, and a 4-week single-blind placebo lead-in period, 548 patients with low-density lipoprotein (LDL) cholesterol > or =145 mg/dl (3.75 mmol/L) and < or =250 mg/dl (6.47 mmol/L) and triglycerides < or =350 mg/dl (3.99 mmol/L) were randomized to one of the following, administered daily for 12 weeks: ezetimibe 10 mg; lovastatin 10, 20, or 40 mg; ezetimibe 10 mg plus lovastatin 10, 20, or 40 mg; or placebo. The primary efficacy variable was percentage decrease in direct LDL cholesterol from baseline to end point for pooled ezetimibe plus lovastatin versus pooled lovastatin alone. Ezetimibe plus lovastatin significantly improved concentrations of LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides compared with lovastatin alone (p <0.01). The coadministration of ezetimibe provided an incremental 14% LDL cholesterol decrease, a 5% HDL cholesterol increase, and a 10% decrease in triglycerides compared with pooled lovastatin alone. Ezetimibe plus lovastatin provided mean LDL cholesterol decreases of 33% to 45%, median triglyceride decreases of 19% to 27%, and mean HDL cholesterol increases of 8% to 9%, depending on the statin dose. The coadministration of ezetimibe 10 mg plus the starting dose of lovastatin (10 mg) provided comparable efficacy to high-dose lovastatin (40 mg) across the lipid profile (LDL cholesterol, HDL cholesterol, and triglycerides). Ezetimibe plus lovastatin was well tolerated, with a safety profile similar to both lovastatin alone and placebo. The coadministration of ezetimibe and lovastatin may offer a new treatment option in lipid management of patients with hypercholesterolemia. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to assess the efficacy and safety of ezetimibe administered with simvastatin in patients with primary hypercholesterolemia.Background: Despite the availability of statins, many patients do not achieve lipid targets. Combination therapy with lipid-lowering agents that act via a complementary pathway may allow additional patients to achieve recommended cholesterol goals.Methods: After dietary stabilization, a 2- to 12-week washout period, and a 4-week, single-blind, placebo lead-in period, patients with baseline low-density lipoprotein cholesterol (LDL-C) > or =145 mg/dl to < or =250 mg/dl and triglycerides (TG) < or =350 mg/dl were randomized to one of the following 10 groups administered daily for 12 consecutive weeks: ezetimibe 10 mg; simvastatin 10, 20, 40, or 80 mg; ezetimibe 10 mg plus simvastatin 10, 20, 40, or 80 mg; or placebo. The primary efficacy variable was percentage reduction from baseline to end point in direct LDL-C for the pooled ezetimibe plus simvastatin groups versus pooled simvastatin groups.Results: Ezetimibe plus simvastatin significantly improved LDL-C (p < 0.01), high-density lipoprotein cholesterol (HDL-C) (p = 0.03), and TG (p < 0.01) compared with simvastatin alone. Ezetimibe plus simvastatin (pooled doses) provided an incremental 13.8% LDL-C reduction, 2.4% HDL-C increase, and 7.5% TG reduction compared with pooled simvastatin alone. Coadministration of ezetimibe and simvastatin provided LDL-C reductions of 44% to 57%, TG reductions of 20% to 28%, and HDL-C increases of 8% to 11%, depending on the simvastatin dose. Ezetimibe 10 mg plus simvastatin 10 mg and simvastatin 80 mg alone each provided a 44% LDL-C reduction. The coadministration of ezetimibe with simvastatin was well tolerated, with a safety profile similar to those of simvastatin and of placebo.Conclusions: When coadministered with simvastatin, ezetimibe provided significant incremental reductions in LDL-C and TG, as well as increases in HDL-C. Coadministration of ezetimibe with simvastatin was well tolerated and comparable to statin alone. [ABSTRACT FROM AUTHOR]

The efficacy and safety of ezetimibe, a new cholesterol absorption inhibitor, was evaluated in this randomized, double-blind, placebo-controlled trial of 892 patients with primary hypercholesterolemia. After > or =2 weeks on the National Cholesterol Education Program (NCEP) Step I or a stricter diet and a 4- to 8-week single-blind placebo lead-in, patients with low-density lipoprotein (LDL) cholesterol 130 to 250 mg/dl and triglycerides < or =350 mg/dl were randomized 3:1 to receive ezetimibe 10 mg or placebo orally each morning for 12 weeks. The primary efficacy end point was the percent reduction in direct plasma LDL cholesterol from baseline to end point. A total of 434 men and 458 women (ages 18 to 85 years) received randomized treatment (666 ezetimibe 10 mg, 226 placebo). Demographics and baseline characteristics were similar between treatment groups. Ezetimibe significantly reduced direct LDL cholesterol by a mean of 16.9%, compared with an increase of 0.4% with placebo (p <0.01). Subgroup analysis indicated that response to ezetimibe was generally consistent across all subgroups, regardless of risk-factor status, gender, age, race, or baseline lipid profile. Ezetimibe effects on LDL cholesterol occurred early (2 weeks) and persisted throughout the 12-week treatment period. Compared with placebo, ezetimibe 10 mg also significantly improved calculated LDL cholesterol, apolipoprotein B, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and HDL(3) cholesterol (p <0.01). Ezetimibe was well tolerated. There were no differences in laboratory or clinical safety parameters, or gastrointestinal, liver, or muscle side effects from that of placebo. Ezetimibe 10 mg/day is well tolerated, reduces LDL cholesterol approximately 17%, and improves other key lipid parameters. [ABSTRACT FROM AUTHOR]

Subjects with increased cholesterol absorption might benefit more from statin therapy combined with a cholesterol absorption inhibitor. We assessed whether baseline cholesterol absorption markers were associated with response to ezetimibe/simvastatin therapy, in terms of LDL-cholesterol (LDL-C) lowering and cholesterol absorption inhibition, in patients with familial hypercholesterolemia (FH). In a posthoc analysis of the two-year ENHANCE trial, we assessed baseline cholesterol-adjusted campesterol (campesterol/TC) and sitosterol/TC ratios in 591 FH patients. Associations with LDL-C changes and changes in cholesterol absorption markers were evaluated by multiple regression analysis. No association was observed between baseline markers of cholesterol absorption and the extent of LDL-C response to ezetimibe/simvastatin therapy (beta = 0.020, P = 0.587 for campesterol/TC and beta<0.001, P = 0.992 for sitosterol/TC). Ezetimibe/simvastatin treatment reduced campesterol levels by 68% and sitosterol levels by 62%; reductions were most pronounced in subjects with the highest cholesterol absorption markers at baseline, the so-called high absorbers (P < 0.001). Baseline cholesterol absorption status does not determine LDL-C lowering response to ezetimibe/simvastatin therapy in FH, despite more pronounced cholesterol absorption inhibition in high absorbers. Hence, these data do not support the use of baseline absorption markers as a tool to determine optimal cholesterol lowering strategy in FH patients. However, due to the exploratory nature of any posthoc analysis, these results warrant further prospective evaluation in different populations.

Background: Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of low-density lipoprotein (LDL) cholesterol when added to statin treatment. However, the effect of ezetimibe on the progression of atherosclerosis remains unknown., Methods: We conducted a double-blind, randomized, 24-month trial comparing the effects of daily therapy with 80 mg of simvastatin either with placebo or with 10 mg of ezetimibe in 720 patients with familial hypercholesterolemia. Patients underwent B-mode ultrasonography to assess the intima-media thickness of the walls of the carotid and femoral arteries. The primary outcome measure was the change in the mean carotid-artery intima-media thickness, which was defined as the average of the means of the far-wall intima-media thickness of the right and left common carotid arteries, carotid bulbs, and internal carotid arteries., Results: The primary outcome, the mean (+/-SE) change in the carotid-artery intima-media thickness, was 0.0058+/-0.0037 mm in the simvastatin-only group and 0.0111+/-0.0038 mm in the simvastatin-plus-ezetimibe (combined-therapy) group (P=0.29). Secondary outcomes (consisting of other variables regarding the intima-media thickness of the carotid and femoral arteries) did not differ significantly between the two groups. At the end of the study, the mean (+/-SD) LDL cholesterol level was 192.7+/-60.3 mg per deciliter (4.98+/-1.56 mmol per liter) in the simvastatin group and 141.3+/-52.6 mg per deciliter (3.65+/-1.36 mmol per liter) in the combined-therapy group (a between-group difference of 16.5%, P<0.01). The differences between the two groups in reductions in levels of triglycerides and C-reactive protein were 6.6% and 25.7%, respectively, with greater reductions in the combined-therapy group (P<0.01 for both comparisons). Side-effect and safety profiles were similar in the two groups., Conclusions: In patients with familial hypercholesterolemia, combined therapy with ezetimibe and simvastatin did not result in a significant difference in changes in intima-media thickness, as compared with simvastatin alone, despite decreases in levels of LDL cholesterol and C-reactive protein. (ClinicalTrials.gov number, NCT00552097 [ClinicalTrials.gov].)., (Copyright 2008 Massachusetts Medical Society.)

Zetia (ezetimibe) is a selective cholesterol absorption inhibitor, which potently inhibits the absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triglycerides or bile acids. Ezetimibe reduces the small intestinal enterocyte uptake and absorption of cholesterol by binding to Niemann-Pick C1 Like 1 (NPC1L1), which keeps cholesterol in the intestinal lumen for excretion. Ezetimibe undergoes glucuronidation to a single metabolite and localizes at the intestinal wall, where it binds with higher affinity for NPC1L1 than ezetimibe to prevent cholesterol absorption. Enterohepatic recirculation of ezetimibe and/or its glucuronide ensures repeated delivery to the intestinal site of action and limited peripheral exposure. Ezetimibe has no effect on the activity of major drug metabolizing enzymes (CYP450), which reduces any potential drug-drug interactions with other medications. Ezetimibe (10 mg/day) was found to inhibit cholesterol absorption by an average of 54% in hypercholesterolemic individuals and by 58% in vegetarians. Ezetimibe alone reduced plasma total and LDL-Cholesterol (18%) levels in patients with primary hypercholesterolemia. When ezetimibe was added to on-going statin treatment, an additional 25% reduction in LDL-C was found in patients with primary hypercholesterolemia and an additional 21% reduction in LDL-C in homozygous familial hypercholesterolemia. Ezetimibe in combination with statins produces additional reductions in plasma cholesterol levels and allows for more patients to achieve their LDL-C goals.

Low density lipoprotein (LDL) cholesterol and total cholesterol (TC) are the primary clinical parameters of interest for any cholesterol intervention. Clinicians are interested in how the reduction of these lipid parameters as well as increases in high density lipoprotein (HDL) relate to changes in coronary heart disease (CHD) risk. The objective of this analysis was to estimate the additional CHD risk reduction that could potentially be provided by co-administration of ezetimibe with statin therapy. Data from four double-blind placebo controlled clinical trials were used to predict the level of CHD risk reduction that might be achieved by co-administration of ezetimibe with statin therapy when compared to those receiving statin as monotherapy. Patients without a previous history of CHD were included in the analysis. Projected CHD risk reduction was calculated as percent change in projected CHD risk from baseline to 12 weeks based on observed lipid levels at those time points. For all the studies combined greater reductions in percent change in 5-year CHD risk were observed for patients receiving ezetimibe and statin as co-therapy, 53.4%, when compared to those receiving statin alone, 39.7%. Co-administration of ezetimibe with statin therapy provides an additional 13.7% reduction in predicted 5-year CHD risk when compared to statin monotherapy. Reductions in 5-year CHD risk for each of the statin studies ranged from 16.1% for lovastatin to 9.8% for atorvastatin. Co-administration of ezetimibe with statins could significantly reduce CHD events in patients with primary hypercholesterolemia.

Objective: The cholesterol absorption inhibitor, ezetimibe, significantly decreases low-density lipoprotein-cholesterol (LDL-C) levels in patients with primary hypercholesterolemia. The pharmacodynamic, pharmacokinetic, and safety profiles of ezetimibe and fenofibrate were evaluated alone and after co-administration in 32 subjects with primary hypercholesterolemia., Research Design and Methods: This was a randomized, evaluator (single)-blind, placebo-controlled, parallel-group study. Subjects with untreated LDL-C > or = 130 mg/dL (3.37 mmol/L) were randomized to receive one of four oral treatments each morning for 14 days: fenofibrate 200 mg + ezetimibe 10 mg, fenofibrate 200 mg, ezetimibe 10 mg, or placebo. Serum lipids were assessed before drug administration on day 1, day 7, and day 14. Pharmacokinetic parameters were assessed on day 14., Main Outcome Measures: The primary pharmacodynamic parameter was percentage change from baseline in LDL-C concentration following co-administration of ezetimibe and fenofibrate vs either drug alone, or placebo. A secondary outcome was the potential for a pharmacokinetic interaction between ezetimibe and fenofibrate., Results: Ezetimibe and fenofibrate co-administration was well tolerated and produced statistically significant mean percentage reductions from baseline in LDL-C (p < or = 0.05 vs either drug alone or placebo), total cholesterol and triglycerides (p < or = 0.05 vs either fenofibrate or placebo), apolipoprotein C-III (p < or = 0.05 vs placebo), and LDL-III (p < or = 0.05 vs either drug alone or placebo). Ezetimibe did not significantly affect the pharmacokinetics of fenofibrate. Concomitant fenofibrate administration significantly increased the mean C(max) and AUC of total ezetimibe approximately 64% and 48%, respectively. However, based on the established safety profile and flat dose-response of ezetimibe, this effect is not considered to be clinically significant., Conclusion: Co-administration of ezetimibe and fenofibrate produced significantly greater reductions in LDL-C than either drug alone and greater reductions in triglycerides than fenofibrate. These effects were accompanied by improvements in the lipid/lipoprotein profile, suggesting that co-administration therapy with ezetimibe and fenofibrate may be an effective therapeutic option for patients with mixed dyslipidemia.

Long-term safety and tolerability of ezetimibe plus atorvastatin (EZE + ATV) coadministration therapy were compared to those of ATV monotherapy in patients with primary hypercholesterolaemia. Upon completion of a 12 week randomised, double-blind, placebo-controlled study comparing EZE 10 mg; ATV 10, 20, 40 or 80 mg; EZE + ATV 10, 20, 40 or 80 mg or placebo, 246 patients were enrolled in a 12-month extension, with reassignment to double-blind EZE 10 mg (n = 201) or matching placebo (n = 45) coadministered daily with open-label ATV 10 mg. At intervals of 6 weeks, patients not at National Cholesterol Education Program Adult Treatment Panel II LDL-C goals were titrated to the next higher ATV dose. Safety evaluations included adverse event (AE) reports and laboratory test results. EZE + ATV and ATV monotherapy groups were similar with regard to incidence of all AEs (71 vs. 67%), treatment-related AEs (22 vs. 27%) and discontinuations due to AEs (9 vs. 7%) or treatment-related AEs (6 vs. 7%), respectively. Neither clinically significant elevations in hepatic transaminases or creatine kinase nor any cases of myopathy or rhabdomyolysis were observed in either group during the extension study. After 6 weeks, EZE + ATV 10mg produced greater reductions in low-density lipoprotein cholesterol (LDL-C; -53 vs. -37%), total cholesterol (TC; -38.8 vs. -26.0%) and triglycerides (TG; -28 vs. -12%) and similar increases in high-density lipoprotein cholesterol (4.6 vs. 4.5%) compared to ATV 10 mg, respectively, and these changes were maintained and significant at 1 year (p < 0.01 for LDL-C, TC and TG). More EZE + ATV patients achieved LDL-C goal than ATV patients at study endpoint (91 vs. 78%, respectively; p = 0.02). Thus, the coadministration of EZE + ATV for 12 months was well tolerated and more efficacious than ATV monotherapy.

Background: Ezetimibe is a cholesterol absorption inhibitor which decreases low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia. This study investigated the potential for pharmacodynamic and/or pharmacokinetic interactions between ezetimibe and lovastatin., Methods: In a randomized, evaluator (single)-blind, placebo-controlled, parallel-group study, 48 healthy men with hypercholesterolemia (screening LDL-C >or= 130 mg/dL) who were stabilized and maintained on a National Cholesterol Education Program (NCEP) Step I diet were randomized to one of the following six oral treatments once daily for 14 days: lovastatin 20 mg; lovastatin 20 mg plus ezetimibe 5, 10, or 20 mg; lovastatin 40 mg plus ezetimibe 10mg; or placebo., Results: Reported adverse events were generally mild, nonspecific, and similar among treatments. There were no significant changes in safety laboratory test results, including those for enzymes indicative of muscle or liver injury. Coadministration of ezetimibe and lovastatin did not increase the plasma concentrations of lovastatin or beta-hydroxylovastatin. In this parallel comparison study there was an apparent decrease in lovastatin exposure, however, the reduction in lovastatin or beta-hydroxylovastatin concentrations was not related to the ezetimibe dose and is not considered to be clinically important. Ezetimibe 5, 10, or 20 mg combined with lovastatin 20 mg caused a significantly (p < 0.01) greater reduction in LDL-C than lovastatin 20 mg alone, with no apparent effect on HDL-C or triglycerides. LDL-C was reduced by 51.0% with ezetimibe 10 mg plus lovastatin 20 mg, 56.0% with ezetimibe 10 mg plus lovastatin 40 mg, 33.2% with lovastatin alone, and 17.3% with placebo., Conclusions: The co-administration of ezetimibe and lovastatin was well tolerated and resulted in a significantly greater percentage reduction in serum LDL-C concentrations than with lovastatin alone, with an average incremental reduction of 16-18%. Ezetimibe 10mg appears to be the optimal dose when co-administered with lovastatin 20mg once daily. Further incremental reductions in LDL-C from the co-administration of ezetimibe and lovastatin are expected only when the dose of lovastatin is increased. The co-administration of ezetimibe and lovastatin has the potential to produce clinically significant reductions in LDL-C compared to either drug alone, with favorable safety and tolerability.

Aims: This randomized, double-blind, placebo-controlled, parallel-group study evaluated the safety and efficacy of ezetimibe 10 mg/day in patients with primary hypercholesterolemia., Methods and Results: Following dietary stabilization, a 2-12-week washout period, and a 4-week, single-blind, placebo lead-in period, 827 patients with baseline low-density lipoprotein cholesterol (LDL-C) > or =3.36 mmol/l (130 mg/dl) to < or =6.47 mmol/l (250 mg/dl) and triglycerides < or =3.95 mmol/l (350 mg/dl) were randomized 3:1 to receive ezetimibe 10 mg or placebo orally once daily in the morning for 12 weeks. The primary efficacy endpoint was percentage reduction in direct plasma LDL-C. Ezetimibe reduced direct LDL-C by a mean of 17.7% from baseline to endpoint, compared with an increase of 0.8% with placebo (P<0.01). Response to ezetimibe was generally consistent across all subgroups analyzed. Ezetimibe also significantly improved levels of plasma total cholesterol, apolipoprotein B, high-density lipoprotein(2)-cholesterol and lipoprotein(a), and elicited a trend toward lower triglyceride levels. Ezetimibe did not alter the serum concentrations of lipid-soluble vitamins or significantly affect baseline or stimulated cortisol production. Ezetimibe was well tolerated, with a safety profile similar to that of placebo., Conclusions: Ezetimibe, which significantly reduces LDL-C and favorably affects other lipid variables, may provide a well tolerated and effective new option for lipid management in the future.

Aims: The primary aims of these two single-centre, randomized, evaluator-blind, placebo/positive-controlled, parallel-group studies were to evaluate the potential for pharmacodynamic and pharmacokinetic interaction between ezetimibe 0.25, 1, or 10 mg and simvastatin 10 mg (Study 1), and a pharmacodynamic interaction between ezetimibe 10 mg and simvastatin 20 mg (Study 2). Evaluation of the tolerance of the coadministration of ezetimibe and simvastatin was a secondary objective., Methods: Eighty-two healthy men with low-density lipoprotein cholesterol (LDL-C) >or=130 mg dl-1 received study drug once daily in the morning for 14 days. In Study 1 (n=58), five groups of 11-12 subjects received simvastatin 10 mg alone, or with ezetimibe 0.25, 1, or 10 mg or placebo. In Study 2 (n=24), three groups of eight subjects received simvastatin 20 mg alone, ezetimibe 10 mg alone, or the combination. Blood samples were collected to measure serum lipids in both studies. Steady-state pharmacokinetics of simvastatin and its beta-hydroxy metabolite were evaluated in Study 1 only., Results: In both studies, reported side-effects were generally mild, nonspecific, and similar among treatment groups. In Study 1, there were no indications of pharmacokinetic interactions between simvastatin and ezetimibe. All active treatments caused statistically significant (P<0.01) decreases in LDL-C concentration vs placebo from baseline to day 14. The coadministration of ezetimibe and simvastatin caused a dose-dependent reduction in LDL-C and total cholesterol, with no apparent effect on high-density lipoprotein cholesterol (HDL-C) or triglycerides. The coadministration of ezetimibe 10 mg and simvastatin 10 mg or 20 mg caused a statistically (P<0.01) greater percentage reduction (mean -17%, 95% CI -27.7, -6.2, and -18%, -28.4, -7.4, respectively) in LDL-C than simvastatin alone., Conclusions: The coadministration of ezetimibe at doses up to 10 mg with simvastatin 10 or 20 mg daily was well tolerated and caused a significant additive reduction in LDL-C compared with simvastatin alone. Additional clinical studies to assess the efficacy and safety of coadministration of ezetimibe and simvastatin are warranted.

Background: Ezetimibe (SCH 58235) is a novel cholesterol absorption inhibitor that selectively and potently blocks intestinal absorption of dietary and biliary cholesterol., Objective: Data from 2 multicenter, placebo-controlled, double-blind, randomized, parallel-group, 12-week studies of ezetimibe were pooled to evaluate the drug's effect on lipid parameters in patients with primary hypercholesterolemia., Methods: After dietary stabilization (National Cholesterol Education Program Step I diet or a stricter diet), washout of lipid-altering drugs, and a 6-week placebo lead-in period, patients with baseline plasma low-density lipoprotein cholesterol (LDL-C) levels > or = 130 and < or = 250 mg/dL and plasma triglyceride (TG) levels < or = 300 mg/dL were randomized to receive either ezetimibe 0.25, 1, 5, or 10 mg, or placebo administered once daily before the morning meal in study A (dose-response study) or ezetimibe 5 or 10 mg or placebo administered once daily before the morning meal or at bedtime in study B (dose-regimen study)., Results: A total of 432 patients were included in this pooled analysis, 243 in study A and 189 in study B. The 5- and 10-mg doses of ezetimibe significantly reduced LDL-C levels by 15.7% and 18.5%, respectively (P < 0.01 vs placebo) and significantly increased high-density lipoprotein cholesterol (hDL-C) levels by 2.9% and 3.5%, respectively (P < 0.05 vs placebo). A reduction in plasma TG levels was observed (P = NS). With the 10-mg dose of ezetimibe, 67.8% of patients achieved > or = 15% reduction in plasma LDL-C levels, and 22.0% achieved > or = 25% reduction. With the 5-mg dose, 54.0% of patients achieved > or = 15% reduction in plasma LDL-C levels, and 15.3% achieved > or = 25% reduction. The decrease in plasma LDL-C levels was significantly greater with ezetimibe 10 mg compared with ezetimibe 5 mg (P < 0.05). Ezetimibe was well tolerated, with an adverse event profile similar to that of placebo., Conclusions: In these two 12-week studies, ezetimibe significantly decreased plasma LDL-C levels and increased plasma HDL-C levels, with a tolerability profile similar to that of placebo.

The Survival With ORal D-sotalol (SWORD) trial tested the hypothesis that the prophylactic administration of oral d-sotalol would reduce total mortality in patients surviving myocardial infarction (MI) with a left ventricular ejection fraction (LVEF) of < or = 40%. Two index MI groups were included: recent (6 to 42 days) and remote (> 42 days) with clinical heart failure (n = 915 and 2,206, respectively). The trial was discontinued when the statistical boundary for harm was crossed (RR = 1.65; p = 0.006). All baseline variables known to be associated with mortality risk (e.g., LVEF, heart failure class, age) as well as variables related to torsades de pointes (e.g., time from beginning of therapy, QTc, gender, potassium, renal function, dose of d-sotalol) were assessed for interaction of each variable with treatment assignment, computing RR and 95% confidence interval (CI) from Cox regression models. The d-sotalol-associated mortality was greatest in the group with remote MI and LVEFs of 31% to 40% (RR = 7.9; 95% CI 2.4 to 26.2). Most variables known to be associated with torsades de pointes were not differentially predictive of d-sotalol-associated risk, except female gender (RR = 4.7; 95% CI 1.4 to 16.5). These findings suggest that (1) most of the d-sotalol-associated risk was in patients remote from MI with a LVEF of 31% to 40%; comparable placebo patients had a very low mortality (0.5%); and (2) very little objective data supports torsades de pointes or any specific proarrhythmic mechanism as an explanation for d-sotalol-associated mortality risk.

Background: Left ventricular dysfunction after myocardial infarction is associated with an increased risk of death. Other studies have suggested that a potassium-channel blocker might reduce this risk with minimal adverse effects. We investigated whether d-sotalol, a pure potassium-channel blocker with no clinically significant beta-blocking activity, could reduce all-cause mortality in these high-risk patients., Methods: Patients with a left ventricular ejection fraction of 40% or less and either a recent (6-42 days) myocardial infarction or symptomatic heart failure with a remote (> 42 days) myocardial infarction were randomly assigned d-sotalol (100 mg increased to 200 mg twice daily, if tolerated) or matching placebo twice daily., Findings: After 3121 of the planned 6400 patients had been recruited, the trial was stopped. Among 1549 patients assigned d-sotalol, there were 78 deaths (5.0%) compared with 48 deaths (3.1%) among the 1572 patients assigned placebo (relative risk 1.65 [95% CI 1.15-2.36], p = 0.006). Presumed arrhythmic deaths (relative risk 1.77 [1.15-2.74], p = 0.008) accounted for the increased mortality. The effect was greater in patients with a left ventricular ejection fraction of 31-40% than in those with lower (

In patients undergoing implantation and testing of the implantable cardioverter defibrillator (ICD), alternating current (AC) may be used to induce ventricular tachyarrhythmias in a prompt, safe, and efficient manner. These arrhythmias have been previously reported to be similar to those induced during programmed electrical stimulation (PES). We compared the ventricular tachyarrhythmias induced by both methods in 14 patients: 8 male, 6 female; mean age 61 years; coronary disease in 10, cardiomyopathy in 4; mean ejection fraction 31%. The presenting arrhythmia was nonsustained ventricular tachycardia (VT) in four, sustained monomorphic ventricular tachycardia (SMVT) in five, ventricular fibrillation (VF) in four, and unknown in one patient with syncope. PES (single, double, triple extrastimuli; burst pacing) and AC (1-2 sec application) stimulation via right ventricular endocardial electrode catheter was performed off antiarrhythmic drugs in the nonsedated state. PES induced SMVT in nine, polymorphic VT in two, and VF in three. AC induced VF in all patients. Although AC can reliably induce ventricular tachyarrhythmias during defibrillation threshold and ICD testing, there is poor correlation to PES induced tachyarrhythmias.

From November 1982 through April 1989, 111 patients with refractory sustained ventricular tachycardia/fibrillation had the automatic cardioverter-defibrillator implanted at our institution, the first community hospital involved in implantation of such a device. We have reviewed our long-term clinical experience to assess the feasibility, learning curve, and efficacy of device implantation in a facility with cardiac electrophysiology expertise but without open-heart surgery facilities. All patients were considered inoperable or at high risk for other concomitant surgery. Eighty-six patients (77%) underwent uneventful implantation. Nine patients (8%) died prior to hospital discharge. Operative mortality declined from 10.9% to 5.4% during the first half (55 patients; November 1982 through September 1986) and second half (56 patients; October 1986 through April 1989) of the experience. Other postoperative complications occurred in 16 patients (14%), 12 of whom experienced complications during the first half of the experience. At 22 +/- 20 (mean +/- SD) months' follow-up, 78 (76%) of 102 patients discharged were alive, and 24 patients (24%) had died. Fifty patients (49%) had experienced at least one automatic cardioverter-defibrillator discharge associated with hypotensive symptoms. The actuarial incidence of sudden death at 1, 2, and 3 years was 1.2%, 5.5%, and 6.2%, respectively. We concluded that the automatic implantable cardioverter-defibrillator is an effective therapy for refractory ventricular tachycardia/fibrillation and that device implantation at community hospitals with an experienced cardiac electrophysiology team is both feasible and practical.

We analyzed our 10-year cumulative experience of 40 consecutive patients with idiopathic dilated cardiomyopathy and associated ventricular tachyarrhythmias, treated with implantable cardioverter defibrillators. Dilated cardiomyopathy was defined as left ventricular ejection fraction (EF) less than or equal to 50% with no defineable etiology. Patient characteristics included: 24 male, mean age 52 years, mean EF = 33%, New York Heart Association Class I-III, presenting syndrome--cardiac arrest (n = 28), syncope/near syncope (n = 12). At 2.5 years mean follow-up, there were 16 deaths: one operative, three sudden, two incessant ventricular tachycardia/ventricular fibrillation (VT/VF), six heart failure, and four noncardiac. The actuarial mortality at 1 and 4 years was 0% and 14% for sudden death, 11% and 34% for cardiac death. The projected mortality was 52% and 78% for same time intervals (P less than 0.01). No useful baseline variable predicted who would or would not receive an ICD shock in follow-up. ICD therapy appears effective in reducing sudden death mortality in this high risk population.

Background: Two hundred eighteen patients were evaluated in a two-phase approach (time to first appropriate discharge, survival after discharge) to identify factors that may be related to maximal benefit derived from use of an automatic implantable cardioverter-defibrillator (AICD)., Methods and Results: One hundred ninety-seven patients survived implantation of AICD, with or without concomitant cardiac surgery. One hundred five patients had an AICD discharge associated with syncope, presyncope, documented sustained ventricular tachycardia or fibrillation, or sleep at 9.1 +/- 11.1 months after implantation. Patients survived 23.8 +/- 18.0 months after AICD discharge. Left ventricular dysfunction (p = 0.008 for ejection fraction less than 25%) was associated with earlier AICD discharge and shortened survival after AICD discharge (p = 0.008 for ejection fraction less than 25%; p = 0.01 for New York Heart Association functional class III and IV). beta-Blocker administration (p = 0.006) and coronary bypass surgery (p = 0.06) were associated with later AICD discharge. Coronary bypass surgery (p = 0.035) but not beta-blockers was associated with more prolonged survival after AICD discharge., Conclusions: These data suggest that a relatively easy algorithm can be applied to predict which patient will benefit most from AICD implantation.

Mexiletine is a lidocaine analogue used in the treatment of symptomatic ventricular arrhythmias. However, in selected individuals with baseline diminished left ventricular function, it may possess clinically significant negative inotropic effects.

Amiodarone is very effective in suppressing refractory nonsustained ventricular tachycardia. Efficacy can be assessed after one week of therapy with continued long-term response in the vast majority of patients.

To assess the effect of defibrillation and amiodarone on ventricular pacing threshold and time to capture in patients undergoing automatic implantable cardioverter-defibrillator (AICD) implantation, 28 patients were prospectively evaluated. The patients were entered into one of two protocols: Ia--epicardial ventricular pacing threshold measured at baseline (preventricular fibrillation induction) and 10 and 60 seconds postdefibrillation with 20 J, or Ib--two fibrillation-defibrillation sequences were performed 3 minutes apart and ventricular pacing thresholds were measured for each sequence at baseline and at 10 and 60 seconds postdefibrillation with 20 J. Ten patients also underwent asynchronous pacing at 1.1 times baseline threshold during ventricular fibrillation with measurement of time to capture postdefibrillation. All patients were randomly assigned to receive either amiodarone or no antiarrhythmic drug therapy. Ventricular fibrillation was induced with AC (applied for 1-2 seconds), and standard epicardial bipolar and epicardial patch electrodes of the AICD were used for pacing and defibrillation, respectively. Ventricular pacing threshold at baseline, 10 seconds, 60 seconds, and 3 minutes postdefibrillation did not differ significantly. There were no significant differences in patients with or without amiodarone therapy. Furthermore, there was no transient loss of ventricular capture postdefibrillation or significant difference in time to capture with amiodarone (less than or equal to 2 seconds). We conclude that following internal defibrillation with 20 J: (1) ventricular pacing threshold at 10 seconds, 60 seconds, and 3 minutes were not significantly different from baseline with one or two fibrillation-defibrillation sequences, (2) time to capture was short, and (3) there was no significant difference in no drug versus amiodarone. These findings have direct clinical importance in considering device therapy with both pacing and defibrillating capabilities.

In order to assess the psychological responses to the automatic implantable cardioverter-defibrillator (AICD), 18 patients with a history of life-threatening ventricular arrhythmias were requested to complete the Spielberger State-Trait Anxiety Inventory and the Beck Depression Inventory. The patients were divided into three groups of six and matched for age, sex, underlying cardiac disease, ejection fraction, and NYHA Functional Classification. Group I had experienced conscious discharges from the AICD, group II had the AICD but without discharges, and group III without the AICD were treated with antiarrhythmic medications alone based on electrophysiological guided testing. Patients with the AICD were also requested to complete a questionnaire directed specifically at their experiences with the AICD. All of the 18 patients completed the study responses and results were analyzed by blinded review. There were no significant differences in anxiety and depression scores in the three groups studied, nor any significant differences in responses to the questionnaire in group I versus group II. One patient in group I reported experiencing adverse psychological responses to the AICD. Although there appears to be no significant differences in psychological responses as a result of the AICD implantation in patients with life-threatening ventricular arrhythmias, further study with larger patient groups is needed to identify and support patients who may develop adverse responses to the AICD.

Implantable cardioverter-defibrillators (ICD) have advanced from a hypothetical device (1970s), to the first human trials (1980s), to the current and future models capable of differentiating ventricular tachyarrhythmias and bradyarrhythmias and of applying selective electrical therapy. The device is successful in decreasing the expected high risk of sudden cardiac death in implantees from approximately 30% to approximately 2% at 1 year. However, because of the major surgical procedure required for implantation and cost of therapy, controversy remains regarding the specific selection of patients to whom the device should be offered. Technologic advances have expanded the potential applicability of this therapy but may simultaneously diminish the survival benefit because of the complexity and sophistication of programming. In this review, we discuss the current status of ICD use, controversies that have yet to be settled, and the direction of future devices based on recently available information.

Concomitant use of a pacemaker and an automatic implantable cardioverter-defibrillator (AICD) is common. Seventeen percent of patients receiving an AICD at The Johns Hopkins Hospital also had a permanent pacemaker implanted before (16 patients), at the same time as (2 patients) or after (12 patients) AICD implantation. Four types of interactions were noted: 1) transient failure to sense or capture immediately after AICD discharge (seven patients); 2) oversensing of the pacemaker stimulus by the AICD, leading to double counting (one patient); 3) AICD failure to sense ventricular fibrillation resulting from pacemaker stimulus oversensing (three patients, one only at high asynchronous output); and 4) pacemaker reprogramming caused by AICD discharge (three patients). No clinical sequelae of these interactions were noted during follow-up study. Thus, potentially adverse clinical interactions are common and routine screening is recommended. With proper attention to lead placements and programming of the devices, clinical consequences of these interactions can be avoided.

We analyzed the results of exercise testing performed in the absence of all antiarrhythmic drugs in 11 case patients with newly documented polymorphic ventricular tachycardia in response to type Ia antiarrhythmic agents. These results were compared with those found in 11 control patients matched for age, sex, and heart disease to determine whether the response of the QT interval to exercise testing was abnormal in patients who developed worsening of arrhythmia while taking antiarrhythmic drugs. QT, RR, and QTc intervals (by Bazett's method) were evaluated at rest and at 3 minutes of exercise in both groups. At rest, there was no significant difference in the QT interval (410 +/- 13 vs. 386 +/- 11 msec), RR interval (890 +/- 56 vs. 781 +/- 43 msec), or corrected QT interval (438 +/- 10 vs. 438 +/- 4 msec) in the case patients and the control patients. Both groups demonstrated a similar chronotropic response to exercise. The QT interval shortened in both groups with exercise (p less than 0.001), but the degree of shortening tended to be greater in the control patients (to 310 +/- 9 msec) than in the case patients (to 357 +/- 11 msec) (p = 0.06). Thus, there was a paradoxical increase in the QTc interval in the patients who experienced a proarrhythmic effect of type Ia drugs but not in the control patients (to 482 +/- 8 vs. 431 +/- 5 msec; p less than 0.001). Ten of 11 case patients but only one of 11 control patients had an increase in QTc interval of more than 10 msec with exercise (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

The hemodynamic responses to rapid atrial and ventricular pacing were examined in 10 closed-chest anesthetized dogs in an attempt to distinguish hemodynamically stable from unstable tachycardias. Pressure monitoring catheters were placed in the femoral artery, right atrium, and right ventricle to measure mean arterial pressure, mean right atrial pressure, and mean right ventricular pressure at baseline heart rate and after rapid high right atrial and right ventricular apex pacing. Pressures recorded during rapid pacing (average of the pressures at 30 and 60 seconds of pacing) at pacing rates of 180, 250, and 280/minute were compared to those recorded initially at baseline heart rates. Rapid right ventricular apex pacing resulted in significant increases in mean right atrial pressure (from 6 +/- 1 mmHg (mean +/- standard error) to 12 +/- 1 mmHg, a 100% increase, P less than 0.001) and mean right ventricular pressure (from 11 +/- 1 mmHg to 16 +/- 1 mmHg, a 45% increase, p less than 0.02) with marked hemodynamic compromise (mean arterial pressure decreased from 85 +/- 6 mmHg to 50 +/- 6 mmHg, a 41% decrease, P less than 0.01). These parameters remained stable (no statistically significant difference from baseline) during high right atrial pacing. In half of the dogs high right atrial pacing at rates greater than or equal to 250 resulted in atrioventricular Wenckebach. Thus, it is concluded that mean right atrial pressure and mean right ventricular pressure may be useful in distinguishing hemodynamically significant tachycardias, and in the future design of antitachycardia devices.

The purpose of the present study was to examine at autopsy the effect of multiple defibrillations on the myocardium and the pathologic consequences of short- and long-term placement of the intravascular and interpericardial leads of the automatic implantable cardioverter-defibrillator. Twenty-five patients were examined at autopsy; 8 of them underwent lead implantation only and 17 received both leads and the automatic implantable cardioverter-defibrillator. Twelve patients (48%) died of ventricular tachycardia or ventricular fibrillation; seven (28%) died of other causes. Acute pericarditis occurred in all patients, resulting in a localized, progressive fibrosis around the apical patch lead without giving rise to pericardial restriction. Thrombus formation was associated with the superior vena cava spring electrode in four patients (17%) and the right ventricular rate-sensing electrode in one patient (4%). Asymptomatic pulmonary emboli occurred in two patients (8%). In one patient who underwent defibrillation 59 times, superior vena cava changes consisted of vein wall destruction, fibrosis and thrombus formation. Pathologic changes under the apical patch related to defibrillation were observed in seven patients; two of these had fewer than 5 defibrillations, one had 8 defibrillations and four had 21 to 74 defibrillations. These changes consisted of contraction band necrosis in four patients, vacuolar cytoplasmic clearing and loss of myocytes confined to the myocardium under the patch electrode in five patients who had multiple defibrillations. The observed pathologic changes were estimated to affect less than 2% of the total myocardial mass. Thus, the automatic implantable cardioverter-defibrillator lead system and multiple defibrillations result in localized myocardial injury confined to the tissue under the patch electrode.(ABSTRACT TRUNCATED AT 250 WORDS)

Because the automatic internal cardioverter defibrillator's long-term ability to reduce arrhythmic mortality in patients with ventricular tachycardia/fibrillation is unknown, it is important to determine whether the threshold for defibrillation changes over time. Serial defibrillation thresholds were measured in 23 patients over a mean replacement time of 24.8 +/- 7.5 months. In all cases the lead system was a superior vena cava coil to a left ventricular epicardial patch. The defibrillation threshold for the entire group increased from 12.3 +/- 4.7 J to 16.9 +/- 5.9 J (p less than 0.05). Striking increases in the defibrillation threshold were seen in the subgroup of patients taking amiodarone (from 10.9 +/- 4.3 J at implantation to 20.0 +/- 4.7 J at replacement, p less than 0.05). Defibrillation threshold decreased in patients taking no antiarrhythmic drugs or taking class I agents. Thus, the increase in mean defibrillation threshold was the result of an increase in the patients taking amiodarone. These data suggest that at initial implantation lead systems associated with the lowest defibrillation threshold should be used and the defibrillation threshold should be measured at generator change to guarantee an adequate margin of safety.

The automatic implantable cardioverter-defibrillator is an electronic device designed to monitor the heart continuously, identify ventricular tachycardias and ventricular fibrillation, and terminate the life-threatening arrhythmias with an internal countershock. This device has been proved to be safe and effective, and its use has led to a significant decrease of arrhythmic mortality in the implantees.

Thirteen patients with refractory, recurrent, life-threatening ventricular tachycardia (VT) underwent electrophysiologic testing before and after long-term amiodarone therapy. Nine patients (69%) had coronary artery disease, 3 (23%) had nonischemic cardiomyopathy and 1 patient (8%) had mitral valve prolapse. At control electrophysiologic study, programmed electrical stimulation (PES) induced VT in all patients: sustained VT in 11 and nonsustained VT in 2 (9 beats and 31 beats). After oral loading with amiodarone, 1200 mg/day for 14 days, followed by maintenance therapy with 408 +/- 20 mg/day (mean +/- standard error of the mean), repeat PES at 6 +/- 1.6 months revealed inducible VT in 12 of 13 patients: sustained VT in 11 and nonsustained VT (32 beats) in 1 patient. Inducible VT was suppressed in only 1 patient. Amiodarone significantly increased sinus cycle length, PR interval, QRS duration and right ventricular effective refractory period. Insignificant increases in AH, HV and QTc intervals were noted. At 24 +/- 2 months, 8 patients (62%) (all with inducible VT at late PES) were free of clinical arrhythmic events (syncope or sudden death), compared with 5 patients (38%) (4 with inducible VT at late PES) with events. There were no significant differences in the induced VT cycle length, VT cycle length change, ease of inducibility or hemodynamic response to induced VT at late PES in patients with and without arrhythmic events.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone is an investigational antiarrhythmic agent known to cause pulmonary toxicity. This report describes two patients with previous amiodarone pulmonary toxicity and complete resolution who at rechallenge 5 to 6 months later developed within 2 weeks of therapy a significant reduction in lung diffusion capacity before overt clinical toxicity occurred. This suggests that toxicity may present early with reduction in diffusion capacity and that such changes may warrant the need to alter treatment.

The AICD uses an automatic gain control amplifier for detecting the small electrograms during ventricular fibrillation. The latest generation of the AICD appears to have a more sensitive lock on gain amplifier, as 6 of 76 patients implanted with the new AICD had double counting of the QRS-T wave complex resulting in asymptomatic discharges. Solutions to the problem of limiting these asymptomatic discharges are difficult and include slowing of the heart rate with beta blockers, changing the lead system, or replacement of the device. One of the six patients was treated with beta blockers. Three patients had their device changed, two patients requested the inactivation of their device until a rate programmable unit was available. The potential for T wave sensing in a lock on gain amplifier represents the unique dilemma between detecting small electrograms of ventricular fibrillation, and detecting diastolic events which occur shortly after the QRS complex.