Steven Lampert

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.

Clinical predictors of arrhythmia worsening by antiarrhythmic drugs

Aggravation of ventricular arrhythmia is a serious, potentially lethal, side effect that can occur with all antiarrhythmic agents. The purpose of this retrospective case-controlled study was to identify clinically useful parameters that would predict aggravation of arrhythmia. Patients in whom arrhythmia worsened while taking either quinidine, mexiletine or encainide were selected and matched to 2 similar patients who never developed this drug complication with any antiarrhythmic tested. A number of hemodynamic, electrophysiologic and pharmacologic parameters were compared. Only the presenting arrhythmia and a left ventricular ejection fraction less than 35% identified patients at risk for drug-induced aggravation of arrhythmia. Patients who presented with either sustained ventricular tachycardia or ventricular fibrillation were 3.4 times more likely to have arrhythmia aggravation compared with patients presenting with nonsustained ventricular tachycardia or ventricular premature beats. Patients with a left ventricular ejection fraction less than 35% were 2.2 times more likely to develop this drug complication compared with patients with an ejection fraction greater than 35%. There was no association between other clinical parameters, electrocardiographic intervals, ventricular arrhythmia density, drug dose or drug levels and aggravation of arrhythmia. In addition, drug aggravation to 1 drug did not predict its occurrence with another drug of the same class. Patients with a history of a sustained ventricular arrhythmia, especially when left ventricular dysfunction is present, are at high risk for the development of aggravation of arrhythmia.

Safety of maximal exercise testing in patients at high risk for ventricular arrhythmia.

While maximal exercise testing is useful for detection of arrhythmias and assessment of antiarrhythmic drug efficacy, few reports have documented the safety of this procedure in patients with malignant ventricular arrhythmias. We reviewed the complications of symptom-limited exercise in 263 patients with such arrhythmias who underwent a total of 1377 maximal treadmill tests. Seventy-four percent of the population studied had a history of ventricular fibrillation or hemodynamically compromising ventricular tachycardia and the remainder had experienced ventricular tachycardia in the setting of either recent myocardial infarction or poor left ventricular function. A complication was defined as the occurrence of arrhythmia during exercise testing--ventricular fibrillation, ventricular tachycardia, or bradycardia--that mandated immediate medical treatment (cardioversion, use of intravenous drugs, or closed-chest compression). Complications were noted in 24 patients (9.1%) during 32 tests (2.3%), whereas 239 patients (90.9%) were free of complication during 1345 tests (97.7%). There were no deaths, myocardial infarctions, or lasting morbid events. Clinical descriptors associated with complications included male sex, presence of coronary artery disease, and a history of exertional arrhythmia (p less than .05). Clinical variables previously considered to confer increased risk during exercise, such as poor left ventricular function, high-grade ventricular arrhythmias (Lown grade 4A or 4B) before or during exercise, exertional hypotension, and ST depression, were not predictive of complications (p greater than .05). Occurrence of a complication was also unaffected by the use of antiarrhythmic drugs at the time of exercise (chi square = 0.19, p greater than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Use of nonsustained ventricular tachycardia as a guide to antiarrhythmic drug therapy in patients with malignant ventricular arrhythmia

From a population of 260 patients with malignant ventricular arrhythmia (ventricular fibrillation or ventricular tachycardia with syncope) we identified 52 (20%) who had infrequent ventricular premature beats during exercise testing and 48 hours of ambulatory monitoring. These patients underwent invasive electrophysiologic study utilizing programmed premature stimulation with up to three extrastimuli at currents of twice and three times middiastolic threshold. The end point for testing was nonsustained ventricular tachycardia (NSVT), defined as 3 to 20 propagated responses resulting from the last premature stimulus. A multiple response was obtained in 45 patients consisting of reproducible NSVT in 36 and sustained ventricular tachycardia in nine. The 36 patients with NSVT underwent 540 electrophysiologic tests with 18 antiarrhythmic agents. Suppression of the repetitive response was achieved in 31 of the 36 patients (86.1%). After an average follow-up of 21 months, one of 31 patients in whom the repetitive response had been abolished had recurrent arrhythmia. This contrasted with recurrence in two of the five patients in whom NSVT was still provoked. During the extensive testing, ventricular fibrillation was not induced. Sustained ventricular tachycardia occurred in 27 of the 540 tests (5.0%), but cardioversion was required in only 12 (2.2%). We conclude that NSVT constitutes a safe electrophysiologic end point for selecting an effective antiarrhythmic program in patients who have experienced malignant ventricular arrhythmia but in whom monitoring and exercise testing are inadequate to guide therapy.

Congestive heart failure induced by six of the newer antiarrhythmic drugs

The incidence of drug-induced congestive heart failure with several newer antiarrhythmic agents including encainide, ethmozine, lorcainide, mexiletine, propafenone and tocainide was determined in a group of 407 patients who underwent 1,133 drug tests. The incidence rate ranged from 0.7% with lorcainide to 4.7% with propafenone. Congestive heart failure was present in 167 patients (41%) who underwent 491 drug trials. Congestive failure was induced in 15 (9%) of these 167 patients and involved 19 (3.9%) of the 491 tests. Left ventricular ejection fraction was 20 +/- 8% in patients who developed congestive failure, in contrast to 39 +/- 19% in those who did not (p less than 0.001). It is concluded that each of the six antiarrhythmic drugs examined has the potential to aggravate congestive heart failure in patients with reduced left ventricular ejection fraction or a history of congestive heart failure, but the incidence rate is low and its occurrence unpredictable.

Determinants of survival in patients with malignant ventricular arrhythmia associated with coronary artery disease

The long-term survival data in patients with coronary artery disease and a history of malignant ventricular arrhythmia, defined as noninfarction ventricular fibrillation (VF) or hemodynamically compromising ventricular tachycardia (VT) followed for up to 9 years, were analyzed. In this group of 161 patients there was a total of 57 deaths, of which 35 (63%) were sudden. Life-table analysis demonstrated a 10% sudden death rate for all patients in the first year and a 7% annual rate in the subsequent 4 years. In patients managed noninvasively, the overall mortality rate was 27% over 9 years, or 3% per year. Suppression of ventricular tachycardia on both ambulatory monitoring and exercise testing was associated with improved survival. In patients evaluated by electrophysiologic testing the sudden death rate was 1.4% per year over an average of 5 years. This survival rate was not different compared with the noninvasive group (p = 0.09). Measures of left ventricular dysfunction and the frequency of ventricular arrhythmia before and after drug therapy were associated with a risk of sudden cardiac death by univariate analysis. Multivariate regression analysis identified 4 variables as independent predictors of sudden cardiac death: rales (p = 0.009), the number of runs of VT during exercise testing while receiving antiarrhythmic drug therapy (p = 0.0003), a history of congestive heart failure (p = 0.0009) and the number of premature beats on Holter monitoring (p = 0.01). These findings support the concept that suppression of repetitive arrhythmia on Holter monitor and exercise testing is a marker for improved survival among patients with malignant ventricular arrhythmia.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of beta blocking agents as adjunct therapy to membrane stabilizing drugs in malignant ventricular arrhythmia

Antiarrhythmic drugs are often either partially or totally ineffective for the suppression of ventricular arrhythmias in a given patient. Drug combinations afford an additional therapeutic option. We report the role of beta-blocking agents as adjunct therapy to membrane stabilizing drugs in the management of patients with malignant ventricular arrhythmias. The study group included 54 patients who were evaluated by 24-hour ambulatory monitoring and symptom-limited exercise testing. Patients underwent control studies without antiarrhythmic drugs, were evaluated on membrane stabilizing drugs and beta blocking agents separately, and were then tested on combination therapy. The combination of a beta-blocking agent and a membrane stabilizing drug abolished ventricular tachycardia and couplets in 83% and 86% of exercise tests in patients with this arrhythmia present during therapy with membrane drugs alone (p less than 0.01). The addition of a beta blocker to a membrane drug, as evaluated by ambulatory monitoring, resulted in an abolition of ventricular tachycardia and couplets in 43% and 20% of studies (p less than 0.05). Ventricular premature beat frequency was reduced by more than 50% in 65% of exercise tests and in 52% of monitoring studies (p less than 0.05). In this population, beta-blocking agents failed to reduce ventricular arrhythmias when used alone. Thus the addition of a beta blocker to a membrane stabilizing drug significantly enhances the suppression of ventricular arrhythmia, especially when assessed by exercise testing. This results from synergistic drug effects of the combination rather than from the effect of the individual drugs.

Long-term mexiletine for ventricular arrhythmia

Use of mexiletine was evaluated in 313 patients with ventricular tachyarrhythmias refractory to conventional antiarrhythmic drugs. Therapy with mexiletine was continued long term in 107 patients who responded to the drug and were free of side effects during a short-term evaluation in hospital. During an average follow-up of 22.8 months (0.1 to 70 months), 19 patients died (17.8%). Eleven patients had sudden death (3.6% per year), while six patients died of progressive congestive heart failure and two of noncardiac causes. Nonfatal ventricular arrhythmia recurred in 14 patients (4.9% per year). Overall, 25 patients had recurrent arrhythmia (incidence of 5.5% per year). Side effects occurred in 13 patients after an average of 5.1 months and were primarily gastrointestinal and neurologic. Sixty-one patients (57%) have continued on mexiletine therapy for an average of 32.2 months (1 to 70 months). Outcome during long-term therapy was not related to drug dose, blood level, or presenting arrhythmia. We conclude that if therapy with mexiletine is carefully evaluated and individualized, the drug is effective and well tolerated during long-term use.

Lorcainide in patients with refractory ventricular tachyarrhythmia

Lorcainide, a new antiarrhythmic agent with local anesthetic or membrane-stabilizing properties similar to those of quinidine, was tested in 76 patients with diverse types of heart disease and recurrent ventricular tachycardia or ventricular fibrillation. Lorcainide was administered for 72 to 96 hours in a dose ranging from 200 to 400 mg daily. Evaluation of drug efficacy involved ambulatory monitoring and exercise stress testing in 60 patients who had high grade ventricular arrhythmia. Invasive electrophysiologic testing was carried out in the remaining 16 patients who exhibited infrequent ventricular ectopic activity during control studies. Lorcainide was effective in 21 (38%) of 56 patients evaluated for suppression of ventricular ectopic activity and in 6 (40%) of 15 who had invasive testing. In five patients, the drug was discontinued because of toxic reactions. Thus, 27 (38%) of the 71 patients who completed the drug study responded to lorcainide. Side effects, reported by 42 patients (55.3%), consisted primarily of insomnia and gastrointestinal symptoms; 7 experienced aggravation of arrhythmia. Fifteen patients were discharged while receiving lorcainide therapy, but in four the treatment was discontinued after 2 months because of side effects. Three patients died, one suddenly. It is concluded that lorcainide is of value in a small subset of patients with life-threatening ventricular arrhythmias who have proven refractory to conventional drugs. Its usefulness is limited by the high frequency of insomnia.

Ethmozine® (moricizine HCl) therapy for complex ventricular arrhythmias

Moricizine HCl (Ethmozine), a new antiarrhythmic agent, was administered to 102 patients with refractory ventricular fibrillation (n = 31), sustained ventricular tachycardia (VT) (n = 46) or symptomatic nonsustained VT (n = 25). A noninvasive approach utilizing monitoring and exercise testing was used in 82 patients who had a high density of reproducible spontaneous arrhythmia, whereas 20 patients without such arrhythmia required invasive electrophysiologic testing. The dosage of moricizine HCl was 200 mg 3 times daily, and during 5 to 6 days was titrated up to a maximum of 400 mg 3 times daily or 15 mg/kg daily, based on arrhythmia suppression and occurrence of side effects. Criteria for efficacy were a greater than 90% reduction in repetitive ventricular premature beats (couplets and runs of VT) and a greater than 50% reduction in ventricular premature beats when noninvasive methods were used. When electrophysiologic testing was used, the drug was judged effective if it prevented the induction of greater than 2 repetitive responses. Of 75 patients completing noninvasive study, 30 (40%) responded to moricizine HCl therapy, whereas only 1 of 20 patients undergoing electrophysiologic testing responded. There was no difference in moricizine HCl blood levels between responders and nonresponders (0.41 microgram/ml vs 0.43 microgram/ml, difference not significant). Side effects occurred in 28 patients (27%). Most frequent were aggravation of arrhythmia (n = 12), nausea and vomiting (n = 5), central nervous system toxicity (n = 3) and anticholinergic side effects (n = 3). The response rate to moricizine HCl therapy was higher in patients with nonsustained VT (62%) compared with those with sustained VT (19%) or ventricular fibrillation (33%).(ABSTRACT TRUNCATED AT 250 WORDS)