Efficacy of low-dose amiodarone in the prevention of paroxysmal atrial fibrillation resistant to type IA antiarrhythmic drugs.

The efficacy and safety of low-dose amiodarone (Cordarone; Wyeth-Ayerst, Philadelphia, PA) was assessed in 62 symptomatic patients with paroxysmal atrial fibrillation who were resistant to at least two types of IA drugs. The beneficial response to this treatment was defined as a reduction in paroxysmal atrial fibrillation of greater than or equal to 50% within 1 month. Of the 42 patients (67.7%) who were responders, 39 (62.9%) were completely free of episodes. Intolerable side effects were seen in 12 patients (19.3%). Tolerable side effects were encountered by 73% of patients. Most of the adverse effects were transient and responded to a reduction in the dose. In conclusion, (1) low-dose amiodarone produces a beneficial response in the prevention of paroxysmal atrial fibrillation, and (2) low-dose amiodarone is well tolerated.

Effect of multiple doses of oral isradipine on atrioventricular conduction in patients with first-degree atrioventricular block.

The purpose of this study was to investigate the effect of multiple doses of orally administered isradipine on atrioventricular nodal conduction in patients with first-degree atrioventricular block. Forty-eight patients with a P-R interval > or =0.22 seconds on a surface electrocardiogram (ECG) (first-degree atrioventricular block) with or without a bundle-branch block were randomized to one of four groups for 6 weeks of treatment with either placebo or 5.0 mg/d, 7.5 mg/d, or 10.0 mg/d isradipine. P-R interval prolongation was assessed at baseline and posttreatment using resting 12-lead ECGs and 24-hour Holter monitoring. The effect of isradipine on the following parameters were assessed: systolic and diastolic blood pressures, heart rate, respiration rate, oral temperature, and weight. Neither isradipine nor placebo treatment had a statistically significant treatment effect on the change from baseline in P-R interval, QRS duration, Q-T interval (uncorrected), or sinus heart rate at week 7 as measured by 12-lead ECG. All treatment groups, however, had small, statistically insignificant decreases from baseline in the mean P-R interval. The largest decrease (from 0.26 seconds at baseline to 0.22 seconds at week 7) was recorded for the 7.5 mg/d isradipine group, which also had the greatest posttreatment decreases in QRS duration, sinus heart rate, and systolic and diastolic blood pressures. The treatment groups did not differ significantly with respect to the change from baseline to study end in P-R interval prolongation or degree of atrioventricular block (as measured by 24-hour Holter monitoring), radial pulse rate, respiration rate, weight, or oral temperature. In this study, isradipine did not have a negative dromotropic effect on the atrioventricular node. The trend toward a posttreatment decrease in P-R interval suggests that isradipine may actually improve atrioventricular nodal conduction in patients with first-degree atrioventricular block and thus may be used safely in this population.

Activity of Procanbid, procainamide twice-daily formulation, to suppress ventricular premature depolarizations. The Study Group Investigators.

Procainamide is a class IA antiarrhythmic drug indicated for the treatment of life-threatening or symptomatic ventricular arrhythmias. The current sustained-release formulation requires 6-hour dosing (qid). To improve patient compliance, a new sustained-release formulation for twice-daily (bid) administration has been developed (Procanbid, Parke-Davis). This study assesses the pharmacologic equivalence of the bid and qid formulations in the suppression of symptomatic ventricular premature depolarizations (VPDs). Fourteen centers enrolled a total of 99 patients with frequent symptomatic VPDs (average > or = 20 VPDs/hr) who previously responded to and tolerated the procainamide qid formulation. During the first week of the double-blind phase, patients were randomized to either placebo or procainamide dosages of 1000, 2000, or 4000 mg/d (bid or qid formulations). In the second week, the patients were crossed over to the alternate formulation. Seventy-seven patients qualified for the primary activity analysis. The bid and qid formulations showed comparable effectiveness in the suppression of mean VPDs with a linear dose-response relationship. The VPD suppression was not attenuated towards the end of the dosing interval for either formulation. Sixty-eight of these patients entered an optional 1-year extension to receive the bid formulation. Thirty-seven (54%) patients had adverse effects. Of those, 15 (22%) had side effects considered treatment related. Most of the adverse events occurred during the first 6 weeks of treatment. Only a few patients (8%) withdrew as a consequence of treatment with the bid formulation. The overall safety profile of the bid formulation was similar to other formulations, and the procainamide bid formulation has a low proarrhythmic rate (< 3%). In conclusion, the effectiveness of the twice-daily formulation of procainamide in the suppression of VPDs is comparable to the currently available qid formulation.

The efficacy of intravenous amiodarone for the conversion of chronic atrial fibrillation. Amiodarone vs quinidine for conversion of atrial fibrillation.

BACKGROUND: Chronic atrial fibrillation (CAF) is a serious condition with significant morbidity and mortality. The mainstay of drug therapy for the conversion of atrial fibrillation to sinus rhythm continues to be quinidine. The value and safety of intravenously (i.v.) administered amiodarone therapy vs quinidine sulfate therapy was compared in a cohort of patients with CAF of more than 3 weeks' duration. OBJECTIVES: To evaluate the efficacy of i.v. administered amiodarone and oral quinidine sulfate containing 300 mg of quinidine in the conversion of CAF and to assess the effect of oral amiodarone in the conversion of CAF in the patients in whom CAF did not convert with IV amiodarone. METHODS: Thirty-two patients with CAF of more than 3 weeks' duration were randomized to either i.v. amiodarone treatment or oral digoxin/quinidine treatment in a randomized unblinded single crossover study. The converters continued either oral amiodarone therapy or quinidine extended-action tablet (Quinidex) therapy. RESULTS: Seventeen patients were randomized to the quinidine group and 15 patients to the amiodarone group. Nonconverters from the quinidine group crossed over to the amiodarone group. Amiodarone and quinidine were equally effective at 24 hours in converting CAF (eight [47%] of 17 patients in the quinidine group vs 12 [44%] of 27 patients in the amiodarone group; P, not significant). At 2 and 9 months of oral therapy, amiodarone was superior to quinidine in maintaining sinus rhythm. Only two of eight patients in the quinidine group tolerated the medication. All patients in the amiodarone group tolerated the medication. One additional patient converted to sinus rhythm at 2 months (13 [48%] of 27), and five more patients converted at 9 months (18 [67%] of 27). Amiodarone therapy and digoxin/quinidine therapy were equally effective at 48 hours in controlling ventricular response at rest. CONCLUSIONS: During the first 48 hours of treatment, i.v. amiodarone and oral quinidine were equally effective in converting CAF to sinus rhythm. At 2 and 9 months of therapy, treatment with oral amiodarone was superior to that of quinidine in restoring sinus rhythm. Long-term treatment with oral amiodarone is better tolerated than with quinidine.

Proarrhythmia of nonantiarrhythmic drugs.

Proarrhythmic effects of nonantiarrhythmic drugs have not been as extensively studied or reported compared with the effects of antiarrhythmic drugs. The proarrhythmic incidence of many of these agents is not accurately known. In some instances, the facilitation of arrhythmias may be the result of compounding clinical factors. Many agents, however, share structural similarities to antiarrhythmics and manifest the same arrhythmic tendencies. Many reports of proarrhythmia may represent toxic rather than proarrhythmic effects, and in vitro studies to elicit the underlying mechanisms may be warranted for the more common drugs. This report summarizes reported arrhythmic effects of a variety of commonly utilized nonantiarrhythmic drugs. The incidence and mechanism of the proarrhythmia is not always clear. The clinician, however, should be aware of reported events to appropriately diagnose and treat the arrhythmia.

The effectiveness and safety of the simultaneous administration of quinidine and amiodarone in the conversion of chronic atrial fibrillation.

The effectiveness and safety of quinidine in the conversion of chronic atrial fibrillation after administration of amiodarone was assessed in 15 patients. A total quinidine dosage of 1097 +/- 408 mg was administered up the point of conversion or for a total of 48 hours. Nine of 15 patients (60%) converted to sinus rhythm. No clinical variable such as the duration of atrial fibrillation, left atrial size, left ventricular fractional shortening, amiodarone duration, or maintenance dose of amiodarone was able to discriminate between converters and nonconverters when patients were treated with the combination of amiodarone and quinidine. The mean QT interval with amiodarone was 414 +/- 44 msec and slightly increased to 434 +/- 40 msec (p = 0.01) when quinidine was added. The amiodarone-quinidine combination was well tolerated, and no side effects or proarrhythmias were recorded.

Mexiletine. Long-term efficacy and side effects in patients with chronic drug-resistant potentially lethal ventricular arrhythmias.

The antiarrhythmic efficacy of mexiletine hydrochloride (Mexitil) was evaluated in 100 patients with potentially lethal and drug-resistant ventricular arrhythmia. The efficacy of arrhythmia suppression was assessed by Holter monitoring. The overall arrhythmia suppression of ventricular premature contractions of 70% and greater was low and seen in only 22% of patients, with an additional 16% responding to a combination of mexiletine and an additional antiarrhythmic drug. The suppression of high-grade forms, couplets of 90% and greater, and complete abolition of nonsustained runs of ventricular tachycardia was achieved in 22% of patients, with 9% responding to the addition of another antiarrhythmic agent. Ventricular premature contractions, couplets, and nonsustained ventricular tachycardia were suppressed in only 16% of the cohort. The drug was poorly tolerated, with intolerable side effects developing in 49% of patients receiving mexiletine alone and in 57% of patients receiving a combination of antiarrhythmic agents. Tolerable adverse effects were relatively common but transient and dose related.

Classification of antiarrhythmic drugs.

Although many classification schemes for antiarrhythmic drugs have been proposed, the system introduced by Vaughan Williams and later modified by Harrison has been widely accepted. This classification system is comprised of four categories. Class I agents block sodium channels. Class II agents are Beta blockers. Class III agents prolong the cardiac action potential. Class IV agents are calcium channel blockers. This classification scheme, based largely on clinical observation continues to be useful almost two decades after its introduction. The electrophysiologic bases, strengths and weaknesses of this system are discussed.

Long-term efficacy and toxicity of high- and low-dose amiodarone regimens.

Amiodarone is an effective antiarrhythmic drug for the control of potentially lethal and lethal ventricular arrhythmias (VA). In the United States, a high-dose regimen has been used at the expense of a high toxicity profile for the control of lethal VAs. Significant antiarrhythmic efficacy has also been established with low-dose regimens, which carry a low rate of intolerable side effects (5.4%) when compared with the high-dose regimen (16.7%). The high incidence of tolerable and intolerable adverse side effects is probably related to high amiodarone loading (31.92 g) and maintenance doses (520 mg/d). In contrast, the low-dose regimen uses much lower loading (7.2 g) and maintenance (280 mg/d) doses.

Potentially lethal ventricular arrhythmias: from mundane to esoteric.

Patients with potentially lethal ventricular arrhythmias (VAs) represent a heterogenous group with frequent and high grade ventricular arrhythmias (including couplets and runs of nonsustained ventricular tachycardia), structural heart disease and decreased left ventricular function. This is a group at intermediate risk of sudden death, with risks varying from 10% to 38%. The electrical and mechanical risks of patients with potentially lethal VA is discussed in relation to their ability of promoting sudden death. The studies reviewing the impact of antiarrhythmic treatment on survival of patients with potentially lethal VA is discussed.

The incidence, magnitude, and time course of the amiodarone-warfarin interaction.

Eight patients concurrently treated with amiodarone and warfarin sodium were studied to characterize the interaction between these drugs. All fulfilled the following criteria: (1) stable and therapeutic prothrombin time (PT) at baseline, defined as at least two consecutive PTs obtained within two weeks before beginning amiodarone therapy that varied by less than or equal to 15%; (2) no warfarin dosage adjustment in the two weeks prior to amiodarone therapy; (3) no other drugs given that alter coagulation study results; and (4) follow-up PTs obtained 1, 2, 4, and 8 weeks after initiation of amiodarone treatment. A clinically significant change in PT was defined as greater than 15%. Mean baseline PT was 19.8 s for patients receiving 5.99 mg/d of warfarin sodium. Patients had a mean maximum increase in PT of 44% (range, 22% to 108%), which occurred during the first two weeks. In six patients, the PT returned to within 15% of baseline by week 4 or 8, and the daily warfarin requirement had decreased by 35% (range, 25% to 50%). Two patients had PTs varying by greater than 15% from baseline at week 8 despite a 33% reduction in warfarin dosage in each case. No patient in this series encountered complications of anticoagulant therapy, perhaps due to early recognition and dosage reduction. Although the mechanism remains unclear, our study indicates that amiodarone potentiation of warfarin effects occurs in all patients, occurs in the first two weeks of amiodarone therapy, variably increases PT by 22% to 108%, and lowers the warfarin requirement by 25% to 50%. We recommend a 25% prophylactic reduction of warfarin dosage and weekly measurements of PT for one month when amiodarone therapy is initiated.

Long-term efficacy, safety and survival of patients with potentially lethal ventricular arrhythmias treated with low-dose amiodarone.

The effect of low-dose amiodarone was prospectively evaluated in 110 patients with potentially lethal ventricular arrhythmias and structural heart disease. The patient population had frequent and high-grade ventricular premature complexes (VPCs) (greater than or equal to 39/h) (multifocal, couplets, nonsustained ventricular tachycardia) refractory to conventional antiarrhythmic drugs. All patients had structural heart disease (coronary artery disease in 61%) and also a decreased left ventricular ejection fraction (LVEF) (43 +/- 16%). Patients were treated with low-dose amiodarone (maintenance dose of 275 +/- 102 mg/day.) During follow-up over a period of 15 +/- 11.5 months, 24 patients died of cardiac cause and, of these, 13 died of sudden death. Ventricular arrhythmia suppression at 1, 2, 3, and 4 years was 69%, 80%, 78%, 92% for VPCs, respectively; 96%, 90%, 92%, and 98% for couplets, respectively, and 57%, 57%, 97%, and 91% for nonsustained VTs (NVTs), respectively. Intolerable, reversible side effects requiring withdrawal were encountered in 24 patients (22%) (neurologic 10%, gastrointestinal 6.5%, skin 3.7%, proarrhythmic 0.9%, and cardiac 0.9%). Except for keratopathy (less than or equal to grade II) seen in all patients, the tolerable side effects were transient with dose adjustment. The study population was divided into two groups according to LVEF: Group A (LVEF greater than or equal to 40%, mean 54.4 +/- 9.7) and Group B (LVEF less than 40% mean, 27.7 +/- 7.2). The patients were further classified into responders (suppression of at least 70% of VPCs, 90% of couplets, and 100% of NVTs) and nonresponders. The difference in survival between responders and nonresponders in groups A and B was not statistically significant. Cumulative survival at 1, 2, 3, and 4 years was 90%, 85%, 85%, and 85%, respectively. In conclusion, low-dose amiodarone treatment: 1) Is effective in controlling VPCs and its complex forms and maintains long-term arrhythmia suppression. 2) The side effect profile compares favorably with conventional antiarrhythmics; severe side effects associated with high dosages (pulmonary, hepatic, neurologic, etc.) were rare or absent. 3) Amiodarone improves survival of patients with potentially lethal ventricular arrhythmias.

The efficacy, electrophysiologic and electrocardiographic effects of intravenous pirmenol, a new class I antiarrhythmic agent, in patients with ventricular tachycardia: comparison with procainamide.

UNLABELLED: The electrophysiologic and electrocardiographic effects of intravenous pirmenol were compared with intravenous procainamide in 17 patients with symptomatic ventricular tachycardia. Pirmenol was found to prolong the PR interval, the QRS duration, the QTc interval, the HV interval, the atrial effective refractory period, and the ventricular effective refractory period. The sinus cycle length decreased following pirmenol administration. The sinus node recovery time, the PA interval, the AH interval, the Wenckebach cycle length, and the AV nodal ERP were unchanged. In patients whose ventricular tachycardias remained inducible on pirmenol, the cycle length was significantly prolonged compared to baseline. These changes were similar to those seen following the administration of procainamide. All 17 patients had sustained ventricular tachycardia inducible during programmed ventricular stimulation in the baseline state. In four patients the ventricular tachycardia was suppressed with both primenol and procainamide. In the remaining 13 patients ventricular tachycardia remained inducible on procainamide. Of these 13 patients, an additional two patients had their ventricular tachycardias rendered noninducible on pirmenol. IN CONCLUSION: (1) the electrophysiologic and electrocardiographic effects of pirmenol are similar to those of procainamide; (2) although ventricular tachycardia inducibility following procainamide was similar to that of pirmenol, an occasional patient with ventricular tachycardia inducible on procainamide had ventricular tachycardias suppressed on pirmenol.

Amiodarone in the management of refractory atrial fibrillation.

Thirty-eight patients were studied to evaluate amiodarone hydrochloride in the treatment of refractory atrial fibrillation. Among them were 25 with sustained atrial fibrillation and 13 with paroxysmal atrial fibrillation. All patients were symptomatic and refractory to therapeutic doses of at least two conventional drug trials, and patients with atrial fibrillation had relapsed from electroversion. Amiodarone hydrochloride was administered in doses of 5 mg/kg intravenously, then 600 to 800 mg/d for seven to ten days, followed by 200 to 400 mg/d. Holter recordings were obtained every one to three months. The effect of amiodarone on the ventricular rate during sustained atrial fibrillation was evaluated in 18 patients and decreased from 99/min (range, 72/min to 143/min) at baseline to 75/min (range, 60/min to 102/min) at follow-up before conversion. Conversion to normal sinus rhythm occurred in 19 patients (76%), including 11 with and eight without direct-current cardioversion. During long-term treatment, sinus rhythm was sustained on an average of 16 months (range, three to 27 months) in 20 patients (53%). This included 11 of 25 patients with sustained atrial fibrillation and nine of 13 patients with paroxysmal atrial fibrillation, with only four of these patients relapsing. Four patients (11%) developed intolerable side effects, but no serious toxic effects were encountered, perhaps because of the relatively low doses of amiodarone hydrochloride that were used (average, 232 +/- 80 mg/d). Amiodarone is a safe and effective alternative to standard therapy in patients with refractory sustained or paroxysmal atrial fibrillation.