Baseline cholesterol absorption and the response to ezetimibe/simvastatin therapy: a post-hoc analysis of the ENHANCE trial.

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.

Long-term safety and tolerability profile of ezetimibe and atorvastatin coadministration therapy in patients with primary hypercholesterolaemia.

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.

Evaluation of the efficacy, safety, and tolerability of ezetimibe in primary hypercholesterolaemia: a pooled analysis from two controlled phase III clinical studies.

Ezetimibe is a novel cholesterol absorption inhibitor that blocks intestinal absorption of dietary and biliary cholesterol. Data from 1719 patients who participated in two multicentre, double-blind studies of ezetimibe were pooled to evaluate the drug's efficacy and safety in patients with primary hypercholesterolaemia. Following dietary stabilisation, a two- to 12-week washout period, and a four-week, single-blind, placebo lead-in period, patients were randomised to ezetimibe 10 mg or placebo once daily in the morning for 12 consecutive weeks. The primary efficacy endpoint was percent reduction in plasma low-density lipoprotein (LDL)-cholesterol from baseline at endpoint. Ezetimibe reduced LDL-cholesterol by a mean of 18.2% compared with an increase of 0.9% with placebo (p<0.01) and resulted in favourable, statistically significant changes in HDL-cholesterol, triglycerides and apo B. The response to ezetimibe was consistent across all subgroups analysed. Ezetimibe was well tolerated, with a safety profile similar to placebo.

Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia.

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.

Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies.

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.

Mortality in the Survival With ORal D-sotalol (SWORD) trial: why did patients die?

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.

Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol.

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 (

A comparison of ventricular arrhythmias induced with programmed stimulation versus alternating current.

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.

The automatic implantable cardioverter-defibrillator. Long-term clinical experience and outcome at a hospital without an open-heart surgery program.

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.

Long-term follow-up of patients with nonischemic dilated cardiomyopathy and ventricular tachyarrhythmias treated with implantable cardioverter defibrillators.

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.

Predictors of first discharge and subsequent survival in patients with automatic implantable cardioverter-defibrillators.

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.

The efficacy of amiodarone in the treatment of refractory nonsustained ventricular tachycardia.

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.

Mexiletine-associated left ventricular dysfunction: a case study.

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.

Ventricular pacing threshold and time to capture postdefibrillation in patients undergoing implantable cardioverter-defibrillator implantation.

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.

Implantable cardioverter-defibrillators: the second decade.

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.

Anxiety and depression in patients with life-threatening ventricular arrhythmias: impact of the implantable cardioverter-defibrillator.

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.