[When and how to treat ventricular ectopic beats]. / L'extrasistolia ventricolare isolata: quando e come trattarla.

Ventricular ectopic beats are commonly observed in daily clinical practice, either in symptomatic or asymptomatic subjects. In many subjects these arrhythmias are casually detected during a screening visit. Their occurrence is usually associated with no clinical significance. However, in some cases the presence of ventricular ectopic beats indicates susceptibility towards life-threatening arrhythmias or ventricular dysfunction. Appropriate ECG analysis and clinical evaluation are important to detect subjects in whom effective treatment is necessary.

Antifibrillary action of class I-IV antiarrhythmic agents in the model of ventricular fibrillation threshold of anesthetized guinea pigs.

We compared the effects of class I-IV antiarrhythmic agents on the ventricular fibrillation threshold (VFT) induced by electrical stimulation directly on the myocardium in anesthetized, open-chest guinea pigs. VFT was assessed by determining the intensity (mA) of electrical current required to induce ventricular fibrillation (VF) and is expressed as a percentage change of the baseline premedication value. The following antiarrhythmic agents or their solvent were administered intravenously (i.v.) to pentobarbital-anesthetized animals (n = 6-12 per group): class I antiarrhythmic agent encainide (1.5 mg/kg); class II antiarrhythmic agents atenolol (2.5 mg/kg), metoprolol (2.5 mg/kg), and nebivolol (2.5 mg/kg); class III antiarrhythmic agents dofetilide (0.08 mg/kg), terikalant (0.04 mg/kg), and DL-sotalolol (10 mg/kg); and class IV antiarrhythmic agent verapamil (0.16 mg/kg). The antiarrhythmic compounds or their solvents resulted in the following changes in the VFT at 15 min after treatment: saline control, 1 +/- 14% (mean +/- SEM) from its baseline value; 10% hydroxypropyl-beta-cyclodextrine (CD), 4 +/- 13%; encainide, 183 +/- 46% (p < 0.05 vs. saline); atenolol, 66 +/- 23% (p > 0.05 vs. saline); metoprolol, 89 +/- 25% (p > 0.05 vs. saline); nebivolol, 224 +/- 58% (p < 0.05 vs. 10% CD); DL-sotalol, 485 +/- 119% (p < 0.05 vs. saline); dofetilide, 357 +/- 69% (p < 0.05 vs. saline); terikalant, 487 +/- 183% (p < 0.05 vs. saline), and verapamil, -17 +/- 21% (p > 0.05 vs. saline). At the doses used, all compounds significantly reduced heart rate (HR).(ABSTRACT TRUNCATED AT 250 WORDS)

Relations between heart failure, ejection fraction, arrhythmia suppression and mortality: analysis of the Cardiac Arrhythmia Suppression Trial.

OBJECTIVES: We studied the relations between heart failure, ejection fraction, arrhythmia suppression and mortality. BACKGROUND: Both left ventricular ejection fraction and functional class of heart failure are strongly associated with mortality after acute myocardial infarction. Both are also related to the presence of ventricular arrhythmias and have been identified as factors related to the ability to suppress ventricular arrhythmias. Little has been reported about the relations between these two factors and arrhythmia suppression or mortality. METHODS: Baseline data from the Cardiac Arrhythmia Suppression Trial were used to define several categories of heart failure and to relate both the resulting categories and ejection fraction to arrhythmia suppression and mortality using logistic and survival regression analytic methodologies. RESULTS: Regardless of the prospective baseline definition of heart failure used, the data consistently showed that heart failure was a more powerful predictor of subsequent congestive heart failure events and arrhythmia suppression and was equally powerful in predicting death. However, each variable provided incremental information when included in the prediction model. Heart failure and ejection fraction appeared to be independent predictors of death. Interactions were observed: A low ejection fraction was more predictive of failure of arrhythmia suppression in patients with than without evidence of heart failure before or at baseline; a low ejection fraction was more predictive of subsequent congestive heart failure events in patients without than with evidence of heart failure before or at baseline. CONCLUSIONS: Although heart failure as a prognostic feature appears to be somewhat superior to ejection fraction, both are powerful predictors of arrhythmia suppression and cardiac events in patients with ventricular arrhythmia after myocardial infarction. Each provides incremental prediction.

Efficacy and safety of combination therapy with amiodarone and type I agents for treatment of inducible ventricular tachycardia.

In a prospective study the efficacy of amiodarone in combination with the three Class I drugs mexiletine, flecainide, or encainide was evaluated consecutively in 12 patients with recurrent ventricular tachycardias (VT) by programmed stimulation. None of the tested drug combinations suppressed induction of sustained VT. The combination of amiodarone with Class IC drugs flecainide and encainide prolonged the cycle length of VT significantly, whereas the combination with mexiletine did not have the same degree of slowing on the VT cycle length. Several proarrhythmic effects occurred during the combination therapy with encainide: (1) frequent, spontaneous recurrences of hemodynamically well tolerated VT in four patients; (2) enhanced inducibility of VT in three patients; (3) impaired termination of VT in three patients. Though a marked increase in QRS and QTc intervals was observed by combined treatment with encainide, no significant correlation could be established between aggravation of arrhythmia and plasma levels of encainide, degree of QRS widening, JT or QTc prolongation. The only predictor for the occurrence of proarrhythmic events was found in left ventricular ejection fraction. These findings suggest that in patients refractory to amiodarone alone or a combination with mexiletine, the combined treatment of amiodarone with other Class IC drugs prolongs the VT cycle length but does not suppress induction of VT during programmed stimulation. Combination therapy of amiodarone with encainide was associated with a high incidence of proarrhythmic effects.

Polymorphism of dextromethorphan metabolism: relationships between phenotype, genotype and response to the administration of encainide in humans.

The polymorphism of dextromethorphan and encainide metabolism is genetically determined and is related to the activity of hepatic CYP2D6. In order to examine the relations between CYP2D6 phenotype, genotype and the electrocardiographic response to the oral administration of encainide, 110 healthy subjects were studied. Metabolic ratios were calculated in urine after oral administration of 40 mg of dextromethorphan and in plasma obtained 2.5 h after oral administration of 50 mg of encainide. Encainide-induced electrocardiographic changes were measured 2.5 h after oral administration of the drug. Genotype was determined in 52 subjects. Results showed that phenotype, either extensive or poor metabolizer, for CYP2D6-dependent metabolism could be identified from the dextromethorphan metabolic ratio calculated in urine, from the encainide metabolic ratio calculated in plasma and from the genotype. However, despite the fact that the changes in atrioventricular (PR) and intraventricular (QRS) conduction times produced by encainide were different in extensive and poor metabolizer subjects and correlated with CYP2D6 activity, the electrocardiographic response was never 100% specific and sensitive for the identification of either phenotype. Moreover, genotypic identification of heterozygous and homozygous extensive metabolizer subjects did not predict CYP2D6 activity, as determined by dextromethorphan and encainide metabolic ratios, or encainide response, as determined by intraventricular and atrioventricular changes. Thus, CYP2D6 activity does not fully predict the electrocardiographic effects of encainide, and genotype, as determined in our study, cannot replace the determination of metabolic ratio in predicting CYP2D6 activity and encainide response in extensive metabolizer subjects.

Effects of advancing age on the efficacy and side effects of antiarrhythmic drugs in post-myocardial infarction patients with ventricular arrhythmias. The CAST Investigators.

OBJECTIVE: To determine the effect of age on the response to anti-arrhythmic drugs. DESIGN: Randomized controlled trial comparing particular drugs. SETTING: Multi-institutional (The Cardiac Arrhythmia Suppression Trial, CAST). PARTICIPANTS: 2,371 patients, age less than 80, with ventricular arrhythmias after a recent myocardial infarction. Subjects classified by age as less than or equal to 55, 56-65, and 66-79 years. INTERVENTION: Upwardly titrated doses of encainide, flecainide or moricizine. After identification of a tolerated and effective dose of one of the drugs, participants were randomized to that drug and dose versus its placebo for up to 10 months. MAIN OUTCOME MEASURES: Efficacy of drug (suppression of ventricular premature depolarizations and/or non-sustained ventricular tachycardia), side effects and mortality. RESULTS: Older patients had more previous MIs, congestive heart failure (CHF), hypertension, NSVT, repolarization abnormalities, digitalis use, and diuretic use. They had less pathologic Q-waves or electrocardiographic injury pattern, and their left ventricular ejection fraction (LVEF) was lower. First dose VPD suppression with the first drug averaged 53% and is not associated with age (P = 0.29). Adverse events including death are more frequent in older patients taking study drugs (P less than 0.001). This trend is consistent in all three study drugs and at varying LVEFs. History of prior MI, low LVEF, VPD (in log scale), and digitalis therapy also correlates with adverse events (all P less than 0.05). Following adjustment for these factors, older age is an independent predictor of adverse events (relative risk 1.30 per decade of age, P less than 0.001). CONCLUSIONS: Older age increases the susceptibility to adverse cardiac events from a class of relatively toxic antiarrhythmic agents.

Effects of ibutilide on spontaneous and induced ventricular arrhythmias in 24-hour canine myocardial infarction: a comparative study with sotalol and encainide.

The electrophysiologic and antiarrhythmic effects of ibutilide, sotalol, and encainide were compared in dogs 24 h after myocardial infarction. Ibutilide (0.03 to 0.3 mg/kg i.v.) prevented the induction of ventricular arrhythmias in 100% of the dogs that had demonstrated inducible ventricular arrhythmias prior to treatment. This antiarrhythmic action was associated with significant increases in ventricular refractoriness and monophasic action potential duration. Sotalol (1.0 to 10.0 mg/kg i.v.) increased the ventricular refractory period and monophasic action potential duration and prevented the induction of ventricular arrhythmias in 75% of the dogs that demonstrated inducible ventricular tachyarrhythmias at baseline. Although 10 mg/kg of sotalol was required to prevent the initiation of ventricular tachycardia, this dose produced marked cardiovascular depression and hypotension in 50% of the dogs tested. Neither ibutilide nor sotalol significantly decreased the incidence of spontaneous ventricular arrhythmias. The class IC agent encainide (0.3 to 3.0 mg/kg i.v.) was successful in preventing the induction of ventricular arrhythmias in only 20% of the dogs tested. However, in contrast to ibutilide and sotalol, encainide significantly reduced spontaneous arrhythmias. Atrial and ventricular refractoriness were significantly increased only after the highest dose of encainide tested (3.0 mg/kg). Over the dose ranges studied, the relative efficacy for prevention of pacing-induced ventricular arrhythmias was ibutilide greater than sotalol much greater than encainide. For suppression of spontaneous ventricular arrhythmias, the relative efficacy was encainide much greater than ibutilide = sotalol.(ABSTRACT TRUNCATED AT 250 WORDS)

Encainide dosing in patients with severe renal dysfunction: report of a case and literature review.

Dosage of encainide for patients with lethal ventricular arrhythmias is based on pharmacodynamic effects and efficacy of arrhythmia suppression, coupled with metabolizer phenotype and extent of renal and hepatic dysfunction. Decreased clearance in patients with renal dysfunction necessitates a reduction in dosage to avoid toxic and dose-related proarrhythmic effects. This case represents a patient with severe renal dysfunction and sustained ventricular tachycardia who achieved electrophysiologically guided suppression of induced ventricular tachycardia at a steady-state encainide dose of only 25 mg daily, significantly lower than package insert or compendial recommendations for initial dosage in patients with renal insufficiency. Documented "therapeutic" metabolite concentrations correlated to electrophysiologic response. Literature review illustrates the complexity of encainide dosage in such individuals and underscores the need for therapeutic drug monitoring to individualize dosage.

Increased risk of death and cardiac arrest from encainide and flecainide in patients after non-Q-wave acute myocardial infarction in the Cardiac Arrhythmia Suppression Trial. CAST Investigators.

This report examines whether in the Cardiac Arrhythmia Suppression Trial death and cardiac arrest from encainide, flecainide and moricizine during the titration phase and from encainide and flecainide during the follow-up phase were related to presence (Q-wave acute myocardial infarction [Q-AMI]) or absence (non-Q-AMI) of pathologic Q waves. In all, 2,371 patients (70% with Q-AMI, 26% with non-Q-AMI, and 4% unknown) entered the titration phase, starting 117 +/- 163 days after index AMI and lasting for an average of 21 days. For the titration phase, no significant differences existed between Q-AMI and non-Q-AMI patients for death and cardiac arrest rate, ventricular premature complex suppression rate, and nonrandomization rate. A total of 1,498 patients entered the follow-up phase of an average of 10 months (starting 129 +/- 158 days after the index AMI), and were randomized to encainide or flecainide, or their matching placebos. In the placebo group, non-Q-AMI patients had a significantly lower rate of death and cardiac arrest than Q-AMI patients (1.0 and 4.6%, respectively; p = 0.04). Encainide and flecainide significantly elevated death and cardiac arrest rate in both non-Q-AMI patients (8.7%, p less than 0.01) and Q-AMI patients (7.8%, p = 0.04). The relative risk for encainide or flecainide over placebo in the non-Q-AMI patients was 8.7, which was significantly higher than 1.7 observed for the Q-AMI patients (p = 0.03). None of the baseline characteristics had any significant interaction with encainide or flecainide.(ABSTRACT TRUNCATED AT 250 WORDS)