Suppression Of Ventricular Premature Depolarizations Research Articles

Recovery of renal dysfunction after catheter ablation of outflow tract ventricular arrhythmias in patients with ventricular premature depolarization-mediated cardiomyopathy.

Frequent ventricular premature depolarizations (VPDs) may cause cardiomyopathy (VPDCM), which often improves after VPD suppression. This study aimed to evaluate whether ablation of outflow tract ventricular arrhythmias (OT VAs) in patients with VPDCM improves renal in addition to left ventricular (LV) function. We retrospectively evaluated 153 patients with OT VAs and examined VPD burden and LV ejection fraction (LVEF), as well as estimated glomerular filtration rate (eGFR) pre- and post-ablation. LV dysfunction was defined as LVEF <50% and impaired renal function was defined as eGFR of <60mL/min/1.73m2. Fifty-five patients had VPDCM. During mean follow-up of 14months, 140 (92%) were free from arrhythmia. In patients with VPDCM, patients with baseline LVEF 40-50% had greater improvement in the post-ablation LVEF compared to patients with baseline LVEF <40% (p < 0.01). At baseline, 36 (72%) patients had renal dysfunction, 29 (81%) of whom had improvement in eGFR from baseline after successful ablation from eGFR 51 to 57mL/min/1.73m2. There was a significant association between cardiac (ΔLVEF ≥10%) and renal (ΔeGFR ≥10%) improvement (r = 0.54, p = 0.04). Using logistic regression analysis, procedural success was an independent predictor of improvement of cardiac (odds ratio [OR] = 13.7, p = 0.03) and renal function (OR = 21.0, p = 0.047). Successful catheter ablation of OT VA reduces VPD burden and is associated with improved cardiac and renal function in patients with VPDCM.

Use and Misuse of Surrogate Outcomes in Arrhythmia Trials

Rigorous design and careful execution of clinical trials have led to major advances in cardiovascular medicine over the past few decades. A pivotal design feature of any trial is the choice of outcomes. We place great value on reduction of mortality and somewhat less on outcomes, such as myocardial infarction, that lead to major morbidity and death. Changes in quality of life and functional capacity are harder to measure but are clinically meaningful in many situations. On the other hand, surrogate outcomes have very low status in this hierarchy. These are outcomes that “stand in” for more clinically relevant outcomes. The key feature of a surrogate outcome is that unproven assumptions are necessary to connect a change in the surrogate to a change in the accepted clinical outcome. The problem of using surrogate outcomes has been highlighted by situations in which the assumptions have been subsequently discredited. In the early 1980s, on the basis of numerous studies that demonstrated an association between ventricular premature depolarization (VPD) frequency and mortality in post-myocardial infarction (MI) patients, VPD suppression became an accepted method for antiarrhythmic drug selection in clinical practice. Even though VPDs were usually asymptomatic, VPD suppression served as a primary outcome measure in clinical trials that resulted in regulatory approval of antiarrhythmic drugs.1 The underlying assumption that VPD suppression was associated with a reduction in mortality was totally upended when the Cardiac Arrhythmia Suppression Trial (CAST) demonstrated that several drugs, which were highly effective at VPD suppression, actually increased mortality after MI.2 Article p 776 It is not always possible or desirable to perform a full-scale trial with the most highly clinically relevant outcomes. Surrogate outcomes are particularly useful in the early stages of development of a new drug or device when the main goal is to prove a …

The Cardiac Arrhythmia Suppression Trial: Implications for nursing practice

Care of patients with ventricular arrhythmia after myocardial infarction requires careful nursing management, including assisting with arrhythmia monitoring and testing. Because ventricular premature depolarization is a known risk factor for sudden cardiac death, it was hypothesized that the suppression of asymptomatic or mildly symptomatic ventricular premature depolarization would improve survival in these patients. To review the Cardiac Arrhythmia Suppression Trial findings and provide implications for nursing practice for patients after myocardial infarction. The Cardiac Arrhythmia Suppression Trial was a multicenter, randomized, placebo-controlled trial designed to determine whether the suppression of ventricular premature depolarizations in postmyocardial infarction patients would improve survival. Three class I antiarrhythmic drugs were used: encainide, flecainide, or moricizine. Patients for whom the drug suppressed their arrhythmia 80% or more were randomly assigned to that drug and dose or its matching placebo and were followed every 4 months (main study). Patients with 1% to 79% suppression were randomly assigned to the drug or its placebo that best treated their arrhythmia and followed every 4 months. Suppression of asymptomatic or mildly symptomatic ventricular premature depolarization in patients using encainide, flecainide, or moricizine failed to improve patient survival and was even harmful in some cases. Our results showed that in the absence of effective antiarrhythmic drug therapy, supportive nursing care and arrhythmia monitoring is important until appropriate therapy for the management of these arrhythmias in patients who have had a myocardial infarction can be found. Clinical trials are essential to provide an evaluation of therapies and direction for further studies, as well as a basis for practicing clinicians.

Mortality Following Ventricular Arrhythmia Suppression by Encainide, Flecainide, and Moricizine After Myocardial Infarction

To test the hypothesis that in survivors of myocardial infarction, the suppression of ventricular premature depolarizations improves survival free of cardiac arrest and arrhythmic death. International, prospective, multicenter, randomized, placebo-controlled trial. University and community hospitals. A total of 3549 patients with myocardial infarction and left ventricular dysfunction. Administration of encainide, flecainide, moricizine, or placebo to suppress ventricular premature depolarizations. Overall survival and survival free of cardiac arrest or arrhythmic death were compared in patients randomized to long-term, active antiarrhythmic drug therapy vs corresponding placebo, using the stratified log rank statistic. At 1 year from the time of randomization to blinded therapy, 95% of placebo-treated patients vs 90% of active drug-treated patients remained alive (P = .0006). Similarly, at 1 year, 96% of placebo-treated patients vs 93% of active drug-treated patients remained free of cardiac arrest or arrhythmic death (P = .003). The suppression of asymptomatic or mildly symptomatic ventricular arrhythmias after myocardial infarction does not improve survival and can increase mortality. Treatment strategies designed solely to suppress these arrhythmias should no longer be followed.

Loss of efficacy during long-term cifenline therapy: development of antiarrhythmic resistance?

To describe the possible development of antiarrhythmic resistance to cifenline, an investigational Class I agent. Forty patients with chronic ventricular premature depolarizations (VPDs) underwent dose-ranging studies with cifenline, an investigational Class I antiarrhythmic agent. Patients had a minimum of 30 VPDs/h detected by ambulatory electrocardiographic (ECG) monitoring over a 48-hour baseline placebo lead-in period. Twenty-two patients (55 percent) who initially responded received long-term cifenline therapy. Ambulatory ECG monitoring over 24 hours was repeated during active cifenline therapy at three-month intervals and during placebo reintroduction at six-month intervals. After an average follow-up of 28 months, VPD frequency during cifenline therapy was similar to that during initial baseline placebo therapy in 8 of the 22 patients (36 percent) who initially responded. Placebo reintroduction following cifenline failure showed a VPD frequency similar to that with active therapy. All patients had further cifenline dosage increases without success. Plasma cifenline concentrations increased in all patients and were in the high therapeutic range. All 8 patients were switched to other Class I antiarrhythmic agents with successful VPD suppression during treatment with the first alternative drug. We conclude that antiarrhythmic resistance occurred with cifenline in these patients as (1) initial efficacy was established for a minimum of two years, (2) VPD frequency was similar during cifenline therapy and placebo reintroduction, (3) cifenline therapy failure continued despite further dosage titration, and (4) alternative Class I antiarrhythmic therapy was successful in all patients. Repeat intermittent ambulatory ECG monitoring is necessary not only to assess the continued need for antiarrhythmic drug therapy, but also to establish continued long-term efficacy.

Events in the cardiac arrhythmia suppression trial: Baseline predictors of mortality in placebo-treated patients

Patients randomized to placebo in the encainide and flecainide arms of the Cardiac Arrhythmia Suppression Trial (CAST) have been found to have a relatively low 1-year mortality rate of 3.9% in comparison with previous studies of patients in the postmyocardial infarction period. To determine the comparability of CAST with previous studies, baseline variables were examined in the 743 patients randomized to placebo in the flecainide and encainide arms of CAST. Twenty-three baseline characteristics were correlated with major outcome events: arrhythmic death (16 events), total mortality (26 events) and congestive heart failure (51 events).On multivariate analysis the risk of new or worsening congestive heart failure was significantly associated with diuretic use, diabetes, high New York Heart Association functional class, age, prolonged QRS duration and low ejection fraction. The risk of arrhythmic death or resuscitated cardiac arrest was significantly associated with an index Q wave myocardial infarction, history of heart failure, use of digitalis, diabetes and prolonged QRS duration. Total mortality or resuscitated cardiac arrest was significantly associated with an index Q wave myocardial infarction, diabetes, ST segment depression, high functional class, prolonged QRS duration and low ejection fraction.The variables at baseline associated with mortality from all causes or arrhythmic death or resuscitated cardiac arrest and heart failure in the CAST placebo-treated patients are similar to those identified in previous postmyocardial infarction studies. Thus, the observation of increased mortality in CAST associated with the administration of encainide and flecainide for suppression of ventricular premature depolarizations is probably applicable to any comparably defined group of patients in the postmyocardial infarction period.

Post-myocardial infarction mortality in patients with ventricular premature depolarizations. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Pilot Study.

Among survivors of acute myocardial infarction, frequent and repetitive ventricular premature depolarizations (VPDs) detected on ambulatory monitoring contribute independently to the risk of all-cause mortality and sudden death. Apart from the beta-blockers, no antiarrhythmic drug has been reliably demonstrated to reduce mortality among patients with VPDs. A pilot study was undertaken to gather data to aid in the design of a multicenter trial of amiodarone for the reduction of mortality from cardiac arrhythmias in such patients. Seventy-seven patients with acute myocardial infarction within the previous 6-30 days and 10 or more VPDs/hr or one or more runs of ventricular tachycardia on 24-hour electrocardiographic recording were randomized in a double-blind fashion in a 2:1 amiodarone-to-placebo ratio. The loading dose was 10 mg/kg/day for 3 weeks. The maintenance dose was 300-400 mg/day with reductions at 4-month intervals in response to VPD suppression, excessive plasma levels, or toxicity. VPD suppression at 1 week and 2 weeks was 63% and 85%, respectively, on amiodarone and 17% and 27%, respectively, on placebo. Apart from thyroid-stimulating hormone elevation and skin reactions, no side effects occurred more frequently with amiodarone. The study drug was stopped for side effects or noncompliance in 35% of amiodarone patients and 34% of placebo patients. Patients were followed for a maximum of 2 years (mean, 20 months). Arrhythmic death or resuscitated ventricular fibrillation occurred in two of 48 amiodarone patients (6%) and four of 29 placebo patients (14%), whereas the rates of all-cause mortality were five of 48 (10%) and six of 29 (21%), respectively. Amiodarone, in moderate loading and maintenance dosages with adjustments in response to plasma levels, VPD suppression, and side effects, results in effective VPD suppression and acceptable levels of toxicity.

Events in the cardiac arrhythmia suppression trial (CAST): Mortality in patients surviving open label titration but not randomized to double-blind therapy

The patient characteristics and outcomes were studied in the 318 patients who survived open label drug titration in the Cardiac Arrhythmia Suppression Trial (CAST) and who were not randomized to double-blind therapy and in 942 patients, who were randomized to double-blind placebo therapy. The patients randomized to placebo therapy had a lower total mortality or resuscitated cardiac arrest rate (4% vs. 8.5%). However, at baseline, nonrandomized patients were dissimilar from patients randomized to placebo in the following ways: older; lower left ventricular ejection fraction; greater use of digitalis, diuretic drugs and antihypertensive agents; lesser use of beta-adrenoceptor blocking agents and more frequent prior cardiac problems, including runs of ventricular tachycardia and left bundle branch block. A matched comparison that took these inequities into account showed no significant differences in mortality or rate of resuscitation from cardiac arrest between nonrandomized patients and clinically equivalent patients randomized to placebo. Cox regression analysis indicated that two factors significantly increased the hazard ratio for arrhythmic death or resuscitated cardiac arrest in the nonrandomized patients: female gender (4.7, p less than 0.05) and electrocardiographic events (ventricular tachycardia, proarrhythmia, widened QRS complex, heart block, bradycardia) during open label titration (7.0, p less than 0.005). However, some potentially important differences between men and women were not included in the Cox regression model. Of the nonrandomized patients, approximately 70% were not randomized because of lack of suppression of ventricular premature depolarizations or adverse events, or both, and the remaining 30% because of patient or private physician request with no indication of another reason.(ABSTRACT TRUNCATED AT 250 WORDS)

The Diurnal Variability of Ventricular Premature Depolarizations: Influence of Heart Rate, Sleep, and Wakefulness

The relationships between ventricular premature depolarizations (VPDs) and heart rate (HR) were determined in 14 patients with ventricular arrhythmias and the influence of these relationships on the diurnal variability of ventricular arrhythmias was evaluated. The influence of sleep state, wakefulness, and level of activity on the frequency of VPDs was also studied. Subjects completed 48-72 h of ambulatory electrocardiographic monitoring and nocturnal sleep recordings. Plots of VPD frequency vs. HR were examined and subjects were categorized as HR-dependent if they manifested log-linear increase in VPDs with increasing HR and as HR-independent if no relation between VPD frequency and HR was detected. Sleep suppression of VPDs was observed in the HR-dependent group (p less than 0.05). The reduction in VPD frequency correlated with the reduction in HR and was independent of sleep state or wakefulness. No change in VPD frequency was observed during wakefulness, rapid eye movement sleep, or non-rapid-eye-movement sleep in the HR-independent group. The influence of level of activity on ventricular arrhythmia frequency was also assessed in seven subjects. Any decreases in VPD frequency observed during inactivity were associated with a decrease in HR. These observations suggest that HR is a major determinant of the diurnal variation of VPD frequency in a subset of patients with frequent VPDs.

Long-term efficacy of oral pirmenol in suppressing ventricular premature depolarizations

Pirmenol is an investigational type 1A antiarrhythmic drug the long-term efficacy of which has not been fully determined. Therefore the long-term efficacy of oral pirmenol in supprossing ventricular premature depolarizations (VPDs) was assessed in an open-label, dose-titration study. Twelve patients (eight men and four women; mean age 57 ± 12 years) were treated for 24 to 36 months (mean 33 ± 4). Seven had structural heart disease (three valvular heart disease, two ischemic heart disease, and two hypertensive heart disease) and five did not. The mean left ventricular ejection fraction was 0.63 ± 0.13. Exclusion criteria included <30 VPDs/hr, >15 beats of ventricular tachycardia (VT), or prior failure of more than two antiarrhythmic drugs. Drug efficacy was assessed by 24-hour ambulatory ECG monitoring performed every 3 months during the first year, every 4 months during the second year, and at 6-month intervals during the third year. The mean hourly frequency of VPDs during the placebo phase was 732 ± 608. Seven patients (58%) were treated successfully with effective (>75%) long-term suppression of VPDs. Two patients (17%) had a partial response with effective suppression of VPDs for the first 16 months and 5 months of treatment, respectively. Three patients falled to show consistent suppression of VPDs while receiving pirmenol. The daily dose of pirmenol ranged from 200 to 500 mg (mean 317 ± 94 mg at the beginning of the study and 375 ± 97 mg at the end). No proarrhythmic effects were identified during long-term treatment, and none of the patients withdrew from the study prematurely. Mild side effects included dry mouth, bad taste, and urinary hesitancy. We conclude that oral pirmenol maintains effective long-term suppression of VPDs in approximately 60% of patients and is well tolerated during chronic administration. No proarrhythmic effects occurred during long-term treatment.

Concentration response relationships of amiodarone and desethylamiodarone

Twelve patients with frequent ventricular premature depolarizations (VPDs) received amiodarone, 600 mg/day, for up to 8 weeks. On days 0, 1, 4, 8, 15, 22, 36, and 57 of treatment, 24-hour ambulatory ECGs were obtained, and multiple blood samples were taken for determination of amiodarone and desethylamiodarone plasma concentrations. All patients had at least 75% suppression of VPDs. The mean duration of therapy before the onset of antiarrhythmic effect was 13.2 days (range 1 to 36 days). Trough amiodarone and desethylamiodarone plasma concentrations at the time of onset of antiarrhythmic effect were 0.86 ± 0.48 mg/L and 0.23 ± 0.15 mg/L, respectively. Sixty-seven percent of patients responded at amiodarone concentrations below 1.0 mg/L. For each patient there was a progressive decrease in frequency of VPDs as both amiodarone and desethylamiodarone concentrations increased. Regression modelling indicated that both amiodarone and desthylamiodarone plasma concentrations explained significant variability in the frequency of VPDs, and amiodarone and desethylamiodarone plasma concentrations were highly correlated with each other. There was a trend for desethylamiodarone to explain more variability in frequency of VPDs than amiodarone.

Cardiovascular effects of doxepin in cardiac patients with ventricular arrhythmias.

The effect of doxepin on ventricular arrhythmias, the ECG, and left ventricular function was evaluated in 10 cardiac patients with symptoms with frequent ventricular premature depolarizations in a dose-ranging protocol. Four patients (40%) had greater than or equal to 80% ventricular premature depolarization suppression; four of eight with pairs and four of six with ventricular tachycardia had greater than or equal to 90% suppression. The mean maximal doxepin dose was 115 +/- 41 mg/day; mean nadir total doxepin concentration was 61 +/- 48 ng/ml and mean nadir total desmethyldoxepin concentration was 51 +/- 42 ng/ml. Doxepin increased the heart rate and the PR, QRS, and QTc intervals of the surface ECG (P not significant). There was no significant change in resting mean left ventricular ejection fraction with doxepin: 41% +/- 15% vs. 43% +/- 19% (P not significant). Complaints of sedation (eight patients) limited dose ranging and tolerance to the drug. Although doxepin suppressed ventricular premature depolarizations in four patients, marked sedation limits its usefulness for primary treatment of arrhythmias in this population.

Comparison of intravenous mexiletine and lidocaine for the treatment of ventricular arrhythmias

The efficacy and safety of intravenous loading of mexiletine was compared to lidocaine in patients with ventricular premature depolarizations (VPDs). Seventeen men and five women, average age 63 years, completed this randomized parallel study. Twelve patients recelved mexiletine intravenously at (5 to 10 mg/min) until ≥95% VPD suppression was achieved or a total of 450 mg of drug was given. The average loading dose of mexiletine was 4.4 mg/kg, at an infusion rate of 0.1 mg/kg/min. Ten patients received lidocaine (1 mg/kg) given over 3 minutes, with a second similar bolus given if after 10 minutes ≥95% VPD suppression was not achieved. Total VPDs were determined for the 60 minutes before drug administration, during drug infusion, and 60 minutes thereafter. Eleven of 12 (92%) patients receiving mexiletine were full responders (≥95% suppression) and one was a partial responder (≥75% ≤95% suppression). Five of 10 lidocaine patients (50%) were full responders, three (30%) were partial responders, and two failed to respond. At peak suppression, mexiletine reduced mean VPD from 37 ± 33 5 minutes (mean ± S.D.) to 0.8 ± 0.9 5 minutes ( p < 0.01) and lidocaine decreased mean VPDs from 28 ± 47 5 minutes to 4.7 ± 2.2 5 minutes ( p < 0.01). Mexiletine resulted in greater suppression of VPDs than lidocaine in terma of mean percent reduction (96% vs 68%, p < 0.01). All lidocaine patients had therapeutic plasma levels (range 1.6 to 3.5 μg/ml). In the mexiletine patients, there was one subtherapeutic and one toxic level observed (mean 1.4 μg/ml, range 0.4 to 3.2 μg/ml). No significant changes in blood pressure, heart rate, or ECG intervals were noted for either drug. Three mexiletine and one lidocaine patient experienced transient adverse effects. Intravenous mexiletine was found safe and effective and may be a useful alternative drug in the management of ventricular arrhythmias.

Comparative efficacy and safety of oral cibenzoline and quinidine in ventricular arrhythmias: A randomized crossover study

We compared the clinical efficacy and safety of oral cibenzoline and quinidine in 13 patients with complex ventricular arrhythmias using a randomized, open-label, crossover study. Employing an quinidine (300 mg every 6 hours and 400 mg every 6 hours) were administered for 7 days at each dose level, with preceding washout periods. ECG intervals, total number of ventricular premature depolarizations (VPDs), ventricularpairs (VP), and ventricular tachycardia (VT) events were analyzed at control on cibenzoline and on quinidine. Suppression of VPDs was comparable on both drugs (cibenzoline—six patients; quinidine—five patients). Mean serum quinidine concentration was 2.6 ± 1.2 μg/ml, and plasma cibenzoline concentration was 0.48 ± 0.27 μg/ml. Significant clinical and laboratory toxicity was more frequent with quinidine than with cibenzoline (p < 0.05). Chronic cibenzoline therapy maintained long-term arrhythmia suppression in five of six responders (mean follow-up, 23 ± 12 weeks). We conclude that cibenzoline and quinidine are equally effective for control of ventricular arrhythmias. Cibenzoline has a more desirable dosing regimen, superior safety profile, and better patient tolerance than quinidine.

Effect of imipramine and nortriptyline on left ventricular function and blood pressure in patients treated for arrhythmias

The effect of imipramine or nortriptyline on left ventricular function and orthostatic blood pressure was evaluated in 20 nondepressed cardiac patients treated for ventricular premature depolarizations (VPDs). Drug was administered by mouth and dose ranging used, 1 mg/kg/day (imipramine) or 0.5 mg/kg/day (nortriptyline), was increased after four doses (imipramine) or six doses (nortriptyline) until >80% suppression of VPDs or adverse effects occurred or until a maximum dose of 5 mg/kg/day (imipramine) or 3.5 mg/kg/day (nortriptyline) was given. Fourteen (70%) had >80% VPD suppression, five had <80% improvement (range 25% to 77%), and one had a VPD frequency increase of 6%. Mean daily imipramine dose was 210 ± 103 mg and mean nortriptyline dose was 100 ± 29 mg. Neither drug significantly changed mean ejection fraction or peak systolic pressure end-systolic volume ratio by radionuclide angiogram. Both reduced standing systolic blood pressure: mean change after imipramine was 26 mm Hg (NS), and after nortriptyline, 14 mm Hg ( p < 0.05). Drug was discontinued in two patients because of symptomatic orthostatic blood pressure change > 30 mm Hg. There was not a significant relationship between dose, drug concentration, or functional class and orthostatic change in systolic blood pressure but there was for age ( p < 0.05). These observations suggest that even cardiac patients with impaired systolic function may take imipramine or nortriptyline for VPDs; however, frequent blood pressure measurement is advised, particularly in older patients.