Prevalence and characteristics of proarrhythmia from moricizine (Ethmozine)

Moricizine was studied in 908 patients with ventricular arrhythmia. Proarrhythmia occurred in 29 (3.2%). When the type of proarrhythmia and the type of ventricular arrhythmia were correlated, no proarrhythmic events occurred in patients with benign ventricular arrhythmia. Three of the 4 deaths due to proarrhythmia occurred in patients with lethal ventricular arrhythmia and 14 of the 15 serious proarrhythmic events occurred in patients with potentially lethal ventricular arrhythmia. The overall proarrhythmia incidence in lethal and potentially lethal ventricular arrhythmias was not different (3.2 vs 3.7%, respectively). Proarrhythmia occurred in patients with more significant structural heart disease or conduction defects at baseline, but was not related to the baseline frequency of ventricular premature complexes. There was no relation between dose of moricizine and incidence of proarrhythmia. All 29 proarrhythmic events occurred within 10 days and 26 of 29 (90%) took place within 7 days of therapy start. Thus, moricizine has a low proarrhythmic potential, especially in patients with lethal ventricular arrhythmias, and may have the best risk/benefit ratio among first-line drugs used in these patients.     

Risk factors for the development of proarrhythmic events

Definitions of proarrhythmia, including clinical consequence, were applied to the flecainide and encainide data bases to determine risk factors for serious proarrhythmic events or deaths. Such outcomes with flecainide were far less common for patients with benign or potentially lethal ventricular arrhythmias compared to patients with predominantly lethal ventricular arrhythmias. No deaths from proarrhythmia during flecainide therapy occurred in patients without structural heart disease. Serious proarrhythmic events and deaths were more common in patients in whom therapy was initiated in hospital than in those in whom therapy was initiated out of hospital. When the flecainide dosage for patients with lethal ventricular arrhythmias was chosen using steady-state pharmacologic principles, the occurrence of all proarrhythmic events and deaths dropped from 26% and 13% to 10% and 0%, respectively. Structural heart disease, sustained ventricular tachycardia, inpatient initiation and large-dose escalation of class IC drugs are the primary risk factors for development of proarrhythmic events.     

Proarrhythmic effects of antiarrhythmic drugs during programmed ventricular stimulation in patients without ventricular tachycardia

The proarrhythmic effects of class IA antiarrhythmic drugs were prospectively evaluated during programmed ventricular stimulation in 24 consecutive patients with frequent ventricular premature beats whose baseline study, performed while no antiarrhythmic drugs were being taken, showed no inducible sustained ventricular arrhythmias. No patient had nonsustained (greater than 5 beats) or sustained ventricular tachycardia by history or baseline 24 hour ambulatory electrocardiographic monitoring. Sequential stimulation studies using up to three extra-stimuli were performed after administration of procainamide, quinidine and disopyramide on different days. Proarrhythmic response was defined as induction of one or more of the following: sustained monomorphic ventricular tachycardia; sustained polymorphic ventricular tachycardia; ventricular fibrillation; reproducibly inducible nonsustained monomorphic ventricular tachycardia. During 55 antiarrhythmic drug trials (24 of procainamide, 21 of quinidine, 10 of disopyramide) in the 24 patients, 6 patients had a proarrhythmic response: sustained monomorphic ventricular tachycardia in 3, ventricular fibrillation in 2, nonsustained monomorphic ventricular tachycardia in 1. Thus, 11% of drug trials resulted in a proarrhythmic response and 25% of patients had a proarrhythmic response to one of the drugs tested. A proarrhythmic response to one drug did not predict a similar response to another drug of the same class. The 6 patients with a proarrhythmic response did not differ significantly from the other 18 patients with regard to underlying heart disease, electrocardiographic or baseline 24 hour ambulatory electrocardiographic characteristics; however, they did have a higher incidence of digoxin usage (p less than 0.02), a shorter baseline right ventricular effective refractory period (p less than 0.01) and a smaller increment in effective refractory period during antiarrhythmic drug testing (p = 0.06).(ABSTRACT TRUNCATED AT 250 WORDS)     

Proarrhythmic potential of moricizine: strengths and limitations of a data base analysis.

Moricizine was studied in 908 patients with ventricular arrhythmias. A proarrhythmia occurred in 29 (3.2%). When the severity of the proarrhythmia and the type of presenting ventricular arrhythmia were correlated, no proarrhythmic events occurred in patients who presented with benign ventricular arrhythmias. Four deaths were attributed to the proarrhythmic effects of moricizine. Of these, 3 occurred in patients presenting with lethal ventricular arrhythmias. A total of 15 serious proarrhythmic events occurred, all of which resolved without lethal consequence. The overall proarrhythmia incidence in the lethal and potentially lethal ventricular arrhythmia categories was not different (3.2 vs 3.7%, respectively). Thus, a proarrhythmia occurred in patients with more advanced structural heart disease, and occurred almost exclusively in patients who presented with potentially lethal or lethal ventricular arrhythmia. There was no relation between the dose of moricizine and the incidence of proarrhythmic events. Of the 29 proarrhythmic events, 26 occurred within 7 days (90%) of the initiation of moricizine therapy. Thus, moricizine appears to have a low proarrhythmic potential in the populations tested, including patients presenting with lethal ventricular arrhythmias. The implications of the Cardiac Arrhythmia Suppression Trial on such a data base analysis are discussed.     

Inpatient versus outpatient initiation of antiarrhythmic drug therapy for patients with supraventricular tachycardia

In-hospital initiation of antiarrhythmic drug therapy is often recommended to observe the effects of the drug and monitor for possible adverse reactions, especially proarrhythmia. However, the actual risk of proarrhythmia in patients undergoing treatment for supraventricular tachyarrhythmias is not well defined. While patients with ventricular tachycardia or ventricular fibrillation most often have underlying structural heart disease, this is not true for many patients with supraventricular tachycardia. It is therefore necessary to define more precisely which patients with supraventricular tachycardia are at risk for ventricular proarrhythmia and sudden cardiac death. An indepth analysis was conducted of 162 patients from 51 published reports of ventricular proarrhythmic events in patients treated for supraventricular tachycardia. Heart disease of various etiologies was present in 96% of patients. Proarrhythmia occurred most commonly with quinidine (72% of cases), and torsade de pointes was the most frequent proarrhythmic event (54%). More than half of all proarrhythmic events occurred within the first 3 days of initiating therapy or soon after increasing the dose of chronic drug therapy. Information was scant regarding the time to occurrence of ventricular proarrhythmia with flecainide and propafenone. With flecainide, nine cases were reported at varying times after initiation of therapy, from in-hospital to 8 months. Two cases of proarrhythmia with propafenone occurred at Day 10 and at 2 years. Because of the low frequency of proarrhythmia, in-hospital initiation of antiarrhythmic drug therapy may not be cost-effective. It is recommended when the effects of the drug on the arrhythmia must be monitored, or when initiating treatment or increasing the drug dose in patients with structural heart disease. These include patients with structural heart disease in whom quinidine, disopyramide, procainamide, amiodarone, or sotalol are being used. Observation should extend at least 2 to 3 days after sinus rhythm is restored.     

Proarrhythmic responses during electrophysiologic testing

Antiarrhythmic drugs may worsen ventricular arrhythmias in certain patients. This effect, termed proarrhythmia, aggravation or provocation of arrhythmia, can be investigated with either noninvasive or invasive techniques. Using electrophysiologic study, 160 patients with ventricular tachycardia or ventricular fibrillation were evaluated during treatment with 432 different antiarrhythmic regimens. Proarrhythmic responses were noted in 68 drug trials (16%), and at least 1 event was observed in 51 patients (32%). Nonsustained ventricular tachycardia was converted to sustained ventricular tachycardia in 17% of these studies. Hemodynamically stable ventricular tachycardia was converted to an arrhythmia that required cardioversion for termination in 5% of the studies. Ventricular tachyrhythmia was more easily induced in 12% of trials. These proarrhythmic responses were not related to changes in QRS duration, QT interval or JT interval measured at baseline or to changes produced by antiarrhythmic drugs.     

Proarrhythmic events

Virtually all antiarrhythmic agents can, under certain circumstances, be arrhythmogenic. The expected therapeutic and potentially arrhythmogenic effects of these agents may be altered if there is (1) an increase or decrease in the serum concentration of the antiarrhythmic agent due to interaction with other drugs, renal or hepatic disease or altered pharmacokinetics; (2) an idiosyncratic reaction to the antiarrhythmic agent; (3) an alteration in serum potassium or magnesium concentration; (4) interaction between the antiarrhythmic agent and the autonomic nervous system or between the autonomic nervous system and the heart, or (5) alteration of myocardial performance and the peripheral vascular system by the antiarrhythmic agent. Because of the lack of uniform reporting of data, guidelines have been suggested to evaluate proarrhythmic events. Of 412 patients receiving 1,080 drug trials for treatment of ventricular tachycardia or ventricular fibrillation, proarrhythmic events occurred in 33 patients (8%) and 43 drug trials (4%). The proarrhythmic event occurred more often during treatment for sustained ventricular tachycardia than for ventricular fibrillation or nonsustained ventricular tachycardia. The initial step in treating a proarrhythmic event is to discontinue the offending drug. Further recommendations are based on the nature of the particular arrhythmia.     

Evaluation of cardiac arrhythmias by exercise testing.

Exercise testing is an important noninvasive method for the exposure of arrhythmias. It provides complementary information to that obtained from ambulatory monitoring or electrophysiologic testing. By producing a number of important physiologic changes, especially activation of the sympathetic nervous system and an increase in circulating catecholamines, exercise testing provides a more complete assessment. On continuous monitoring, exercise-induced ventricular premature beats may be found in up to 34% of healthy subjects, in 60 to 70% of those with heart disease and in all patients who have experienced sustained ventricular tachycardia. Couplets or nonsustained ventricular tachycardia can be found during exercise in 0 to 6% of healthy subjects, in 15 to 31% of patients with heart disease and in 75% of those with sustained ventricular tachycardia. Even in patients with heart disease, there is only a small risk of inducing sustained ventricular tachycardia or ventricular fibrillation during exercise. The prognostic relevance of exercise-induced ventricular arrhythmias in patients with coronary artery disease or cardiomyopathy has not been clearly established. There appears to be an increased risk, however, in patients with ventricular premature beats as well as ST-segment depression or in patients with repetitive forms of ventricular arrhythmias during exercise which cannot be medically controlled. In healthy subjects, exercise-induced ventricular premature beats are of no prognostic relevance. In particular, for patients in whom arrhythmias are induced by exercise, exercise testing should be used to assess the effectiveness of antiarrhythmic drug treatment. Importantly, serious cardiac toxicity, often not observed at rest or during routine activities, may become apparent during exercise testing. It should be a standard part of arrhythmia assessment and management.     

Efficacy and safety of sotalol in patients with complex ventricular arrhythmias.

Sotalol is a unique beta-blocker that prolongs repolarization. Its use in 626 patients with complex ventricular ectopic activity, as reported in the literature, resulted in suppression of arrhythmia in 50 to 60% of treatment attempts. Detailed analysis of data on arrhythmias in 356 patients that were entered prospectively into a database revealed a median reduction in ventricular premature beats of 76%, compared to a median suppression of repetitive ventricular ectopic activity of 91% and of episodes of nonsustained ventricular tachycardia of 97% (p = 0.002 vs reduction of ventricular premature beats). This marked antiarrhythmic potency of sotalol in repetitive ventricular arrhythmias is thought to be due to its class III activity. Drug efficacy was independent of age, sex, the presence or absence of organic heart disease and the degree of sotalol-induced prolongation of corrected QT interval. Evaluation of left ventricular function in 215 patients treated with the drug demonstrated that depression of left ventricular ejection fraction occurred far less frequently than expected with conventional beta-blockers. Even patients with severely depressed pump function tolerated sotalol surprisingly well. There is a propensity of the drug to aggravate arrhythmia, which resulted in serious proarrhythmic events in 30 (3.5%) of 853 patients. These often consisted of torsades de pointes (9 of 30 patients). Proarrhythmia occurred primarily within the first 3 days of dosing, and exhibited a dose-dependence. In conclusion, sotalol is an effective and well-tolerated antiarrhythmic drug in patients with complex ventricular ectopic activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Aggravation of arrhythmia by antiarrhythmic drugs--incidence and predictors

Aggravation of arrhythmia by antiarrhythmic drugs is a potentially serious complication. In over 1,287 noninvasive drug studies involving 11 antiarrhythmic drugs, arrhythmia aggravation occurred in 117 tests (9%). During 248 electrophysiologic tests, 45 cases (18%) of aggravation occurred. In an attempt to define predictors of this complication, 51 patients with aggravated arrhythmia were compared with 102 patients without this complication. Arrhythmia aggravation was not associated with age, sex, type or extent of heart disease, baseline electrocardiogram, drug-induced changes on electrocardiogram or density of baseline arrhythmia on monitoring or exercise testing. Aggravation with 1 drug did not predict occurrence with another drug of the same class. The only statistically important relation was the type of presenting arrhythmia. Patients with a history of a sustained tachyarrhythmia (ventricular tachycardia or ventricular fibrillation) had a risk of this complication that was 2.5 times greater than that of patients presenting with only nonsustained ventricular tachycardia or ventricular premature beats (p = 0.01). There was also a relation to the presence of left ventricular dysfunction (p = 0.04). For the most part, however, aggravation of arrhythmia is not predictable, and cautious use of antiarrhythmic drugs is essential.     

Efficacy and risks of moricizine in inducible sustained ventricular tachycardia.

OBJECTIVE: To assess the efficacy and toxicity of moricizine in treating patients with serious ventricular arrhythmias and inducible sustained ventricular tachycardia. DESIGN: Uncontrolled clinical trial. SETTING: The intensive care and telemetry units of Northwestern Memorial Hospital, St. Francis Hospital and Medical Center, and Lenox Hill Hospital. PATIENTS: Twenty-six patients with sustained ventricular arrhythmias or hemodynamically significant nonsustained ventricular tachycardia, most of whom failed therapy with at least one class I antiarrhythmic agent. INTERVENTION: Patients were treated with moricizine, 400 to 1000 mg/d. MEASUREMENT: Efficacy was assessed by the results of programmed ventricular stimulation done during moricizine therapy. MAIN RESULTS: Seven of the 26 patients (27%) developed life-threatening ventricular proarrhythmia during moricizine loading. Three patients had incessant sustained ventricular tachycardia, two had incessant nonsustained ventricular tachycardia, one had new sustained ventricular tachycardia, and one had new cardiac arrest. One of these patients died of intractable ventricular fibrillation. No clinical or electrophysiologic variables clearly identified those at risk for proarrhythmia. Only 3 of 26 patients (12%) became noninducible on moricizine. CONCLUSION: Moricizine has a low rate of efficacy and carries a considerable risk for life-threatening proarrhythmia in patients with serious ventricular arrhythmias and inducible ventricular tachycardia who have failed therapy with other class I antiarrhythmic agents.     

Short- and long-term experience with flecainide acetate in the management of refractory life-threatening ventricular arrhythmias

Thirty-eight patients with organic heart disease and history of sudden cardiac arrest or recurrent sustained ventricular tachycardia were treated with flecainide. Coronary artery disease was present in 33 patients. Previous antiarrhythmic therapy consisted of two to eight drugs (mean four). Fourteen patients were resuscitated from sudden cardiac death and 24 patients had chronic recurrent sustained ventricular tachycardia. Twenty-eight patients had electrophysiologic testing before and during flecainide treatment. Sustained ventricular tachycardia became noninducible in 5 patients, nonsustained in 5 patients and slowed in 13 patients (cycle length increased from 278 +/- 64 to 395 +/- 91 ms; p = 0.002). Three of the 14 patients with sudden cardiac death and 15 of the 24 patients with recurrent sustained ventricular tachycardia remained on long-term flecainide treatment. The mean left ventricular ejection fraction in 16 of these 18 patients was 37%. Nonlimiting side effects occurred in seven patients (18%). Proarrhythmic effects were seen in four patients (10%). At a mean follow-up time of 11 +/- 3 months, 15 patients (39%) had had no recurrence, including 5 who had inducible sustained ventricular tachycardia and 5 who did not on retesting during treatment. In the 18 patients who received long-term therapy, 3 late deaths occurred, 1 of which was of arrhythmic origin. These data suggest that flecainide is effective in about 40% of patients with severe refractory ventricular arrhythmias. Its value as a single drug in the treatment of sudden cardiac death remains to be defined.     

Clinical safety profile of sotalol in patients with arrhythmias

Key safety parameters of sotalol were examined in 1,288 patients entered into recent controlled trials of ventricular (85% of patients) or supraventricular arrhythmias (15%). Most patients were middle-aged male Caucasians with significant heart disease. The most serious adverse event was proarrhythmia, occurring in 56 patients (4.3%). Of these, 27 had hemodynamic compromise due to malignant ventricular arrhythmias. Most had a history of sustained ventricular tachycardia, myocardial infarction, congestive heart failure (CHF) or cardiomyopathy, or a combination of these. The other 29 had nonsevere events; 38% continued taking sotalol. Proarrhythmia was manifested by torsades de pointes in 24 of the 56 patients. No universal causal relation was found with commonly associated factors such as bradycardia, hypokalemia and long QT interval. The mean QT and QTc at baseline within 1 week of a severe proarrhythmic event were greater than those of patients not having proarrhythmia. Nineteen patients (1%) discontinued therapy with sotalol because of drug-related CHF. Predisposing conditions included low initial baseline ejection fraction, history of CHF, cardiomyopathy or cardiomegaly, or both, male gender and age greater than 65 years. Heart failure usually occurred within 7 to 30 days of initiating therapy. The most common reason for premature discontinuation of the drug in patients treated for sustained ventricular tachycardia was ineffectiveness (39%), whereas adverse effects were the most common reasons among patients treated for complex ventricular ectopy (21%). Dyspnea and bradycardia were the most common cardiovascular effects, and fatigue, dizziness and asthenia the most common noncardiac, adverse effects. Although frequently reported, these adverse effects resulted in discontinuation of only 1 to 4% of the patients at risk.(ABSTRACT TRUNCATED AT 250 WORDS)     

Flecainide in the treatment of nonsustained ventricular tachycardia

Thirty-two patients received flecainide acetate for nonsustained ventricular tachycardia after having had unsuccessful treatment with a mean of four antiarrhythmic drugs. The mean left ventricular ejection fraction was 41% in 27. Thirty-one patients had organic heart disease, and 22 patients had arrhythmia-related symptoms. Total suppression of ventricular tachycardia occurred in 22 patients. Thirty patients were discharged from the hospital receiving flecainide at a mean (+/- SD) dosage of 315 +/- 76 mg/d and 26 of these patients attained a mean trough plasma drug level of 567 +/- 254 ng/mL. One patient had proarrhythmia and 3 had worsening of heart failure. Twenty-two patients remained in the trial for a mean follow-up of 13 +/- 7 months. Five patients died (1 suddenly) during the follow-up period. Our data indicate that flecainide suppresses refractory nonsustained ventricular tachycardia in 69% of patients who have organic heart disease. Serious adverse effects were minimized by initiation of treatment in the hospital and careful surveillance of electrocardiograms and plasma drug levels.     

Significance of ventricular arrhythmias initiated by programmed ventricular stimulation: the importance of the type of ventricular arrhythmia induced and the number of premature stimuli required

An increasing number of premature ventricular stimuli are being used during programmed stimulation of the heart in the investigation of patients with documented or suspected ventricular arrhythmias. To analyze the significance of the different types of ventricular arrhythmias that are initiated, we evaluated in a prospective study the effect of from one to four ventricular premature stimuli in 52 patients without (non-VT group) and 50 patients with (prior-VT group) documented ventricular tachycardia or ventricular fibrillation. More than half of the patients in the prior-VT group had coronary heart disease. In the majority of patients of the non-VT group the heart was normal. In 44 of the 50 patients in the prior-VT group the clinically documented ventricular arrhythmia was initiated by programmed ventricular stimulation of the heart. In 88% of these 44 patients, one or two ventricular premature beats were required to initiate the clinical arrhythmia. A ventricular arrhythmia could be initiated in 31 of the 52 patients in the non-VT group. The ventricular arrhythmias included nonsustained monomorphic ventricular tachycardia (two patients), six to 25 complexes of sustained polymorphic ventricular tachycardia (24 patients), and ventricular fibrillation (five patients). In 70% of patients in the non-VT group three or four ventricular premature beats were required to initiate the ventricular arrhythmia. Our results indicate that not only the number of extrastimuli required to initiate ventricular arrhythmias but also the type of ventricular arrhythmia initiated differed between the two groups of patients. Nonsustained polymorphic ventricular tachycardia and ventricular fibrillation are nonspecific responses to aggressive stimulation protocols.     

A proposal for the clinical use of flecainide

Effective antiarrhythmic therapy requires a carefully considered approach, including an understanding of the arrhythmia, the underlying cardiac disease and the drug's pharmacokinetics. Flecainide is a new antiarrhythmic drug that may soon be released for general use. Flecainide demonstrates unsurpassed efficacy in chronic ventricular arrhythmias in stable patients and may become a first-choice drug because of its ease of administration, efficacy and favorable tolerance. Twice-daily dosing with 100 to 200 mg usually provides effective therapy. Clinical experience suggests flecainide to be indicated in the treatment of uniform and multiform ventricular premature complexes, coupled ventricular premature complexes, and episodes of nonsustained ventricular tachycardia. A lower response rate is observed in preventing induction of sustained ventricular tachycardia, and these patients should be carefully selected. Flecainide is promising in the treatment of supraventricular tachycardias using atrioventricular nodal or extranodal reentrant pathways, although this use is still investigational in the United States. The drug's use for arrhythmias during acute myocardial infarction requires further study. Flecainide possesses modest negative inotropic potential. Proarrhythmic or other adverse reactions have occurred primarily in settings of high drug level, poor ventricular function or refractory, malignant arrhythmias, suggesting caution in these groups.     

Use of electrophysiologic testing in patients with nonsustained ventricular tachycardia: prognostic and therapeutic implications

Forty patients with coronary artery disease and nonsustained ventricular tachycardia on ambulatory electrocardiographic monitoring underwent programmed electrical stimulation. In 22 patients, monomorphic ventricular tachycardia was induced at baseline drug-free electrophysiologic testing; 9 of these patients subsequently developed a clinical sustained ventricular tachyarrhythmia. In 18 patients, no tachycardia could be induced, and none of these 18 had subsequent tachycardia. In 25 of the 40 patients, arrhythmia management was guided by the results of electrophysiologic testing; this group included 11 patients who received antiarrhythmic therapy for induced ventricular tachycardia and 14 patients without inducible ventricular tachycardia who did not receive antiarrhythmic therapy. In the remaining 15 patients, arrhythmia management was not based on the results of electrophysiologic testing. Only two episodes of clinical sustained tachyarrhythmia occurred in the group receiving electrophysiologically guided therapy compared with seven episodes in the group treated without electrophysiologic guidance (p less than 0.01). Thus, in patients with coronary artery disease with nonsustained ventricular tachycardia on ambulatory electrocardiography, electrophysiologic testing can identify those at high and low risk for subsequent clinical tachycardia events. Furthermore, results of such testing can be used to optimize arrhythmia management in these patients.     

Value of Holter monitoring in predicting long-term efficacy and inefficacy of amiodarone used alone and in combination with class 1A antiarrhythmic agents in patients with ventricular tachycardia

The value of two reported and two new ambulatory electrocardiographic (Holter) criteria was studied in 80 patients taking amiodarone for refractory recurrent sustained ventricular tachycardia. In the 80 patients, the four Holter criteria were as follows: I-85% or greater reduction of ventricular premature complexes and abolition of couplets and nonsustained ventricular tachycardia in 74 patients who had 10 or more ventricular premature complexes/h, or any couplets or nonsustained ventricular tachycardia/24 hours at baseline; II-abolition of nonsustained ventricular tachycardia in 51 patients who had nonsustained ventricular tachycardia at baseline; III-85% or greater reduction of ventricular premature complexes and abolition of nonsustained ventricular tachycardia in 64 patients who had 30 or more ventricular premature complexes/h at baseline; and IV-85% or greater reduction of ventricular premature complexes and abolition of nonsustained ventricular tachycardia in 73 patients who had 10 or more ventricular premature complexes/h at baseline. Amiodarone was judged effective in, respectively, 51 of 74, 44 of 51, 51 of 64 and 61 of 73 patients by criterion I, II, III or IV. During the follow-up period (19 +/- 20 months), there were 19 instances of recurrence of ventricular arrhythmia or sudden death. Actuarial arrhythmia-free survival rate at 24 months was 84, 74, 86 and 85%, respectively, in patients with efficacy by criterion I, II, III or IV and 61, 43, 48 and 39%, respectively, in patients with inefficacy (p less than 0.015 for all). Many patients with efficacy by Holter criteria, however, had a recurrence of arrhythmia, suggesting insensitivity of these Holter criteria.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reversal of proarrhythmic effects of flecainide acetate and encainide hydrochloride by propranolol

The use of membrane-active antiarrhythmic agents may be complicated by aggravation of existing arrhythmias or development of new drug-induced arrhythmias. Four patients, referred because of out-of-hospital cardiac arrest or symptomatic sustained ventricular tachycardia, were receiving class IC antiarrhythmic agents in an attempt to prevent inducibility of sustained ventricular tachycardia. New or worsening spontaneous arrhythmias developed while they were on flecainide acetate (n = 3) or encainide hydrochloride (n = 1) therapy. Spontaneous runs of rapid nonsustained and sustained ventricular tachycardia developed in two. Increased frequency of premature ventricular contractions and repetitive forms of ventricular ectopic activity developed in one, despite the fact that inducibility of sustained ventricular tachycardia had been prevented. Salvos and nonsustained ventricular tachycardia developed in the fourth patient. Propranolol had failed to prevent inducibility of sustained ventricular tachycardia during previous programmed stimulation studies in three of the four patients, but it reproducibly suppressed drug-induced arrhythmias that appeared only after administration of the IC agents in each patient. Suppression of the proarrhythmic effects by beta-adrenergic blockade suggests a possible interaction of these drugs with autonomic function in the genesis of the observed proarrhythmic effects. Direct pharmacologic control of proarrhythmic drug effects has not previously been reported.     

Evaluation of antiarrhythmic therapy using Holter monitoring

Premature ventricular complexes and nonsustained ventricular tachycardia mark a person with structural cardiac disease as a high--risk candidate for sudden cardiac death. Such ventricular arrhythmias are considered potentially lethal and should be distinguished from both those that are benign and those that cause hemodynamic consequences (i.e., lethal or malignant arrhythmias). Noninvasive Holter monitoring is the principal technique for detecting and evaluating the presence of potentially lethal ventricular arrhythmias. These arrhythmias undergo a high degree of spontaneous variability. Thus, to define a therapeutic drug effect, a reduction in the frequency of premature ventricular complexes of at least 75% and a reduction in the frequency of nonsustained ventricular tachycardia by at least 90% are required to eliminate the likelihood of spontaneous variability as the cause of this change in the frequency of arrhythmia. To define proarrhythmia, a different algorithm must be applied. When using antiarrhythmic drugs, a quantitative ventricular arrhythmia baseline for both frequency and type of arrhythmia must be established so that after therapeutic intervention repeat Holter monitoring can determine whether efficacy, inefficacy or proarrhythmia had occurred. Holter monitoring clearly reveals differential antiarrhythmic response rates among classes of antiarrhythmic drugs in patients with benign or potentially lethal arrhythmias. However, preliminary data have not clearly defined the relation between antiarrhythmic pharmacotherapy and a reduction in sudden cardiac death. The results of large-scale clinical trials that have only recently been undertaken must be assessed to determine whether sudden cardiac death can be prevented by adequately suppressing potentially lethal ventricular arrhythmias.