THE USE OF AMIODARONE, SOTALOL, AND IBUTILIDE IN CONVERTING ATRIAL FIBRILLATION AND ATRIAL FLUTTER
By: Melissa Borchardt Kelly Keenan Amanda Rhode Jennifer Sanderson
Dr. Straka Phar 5822 February 26, 1997
Amiodarone, sotalol and ibutilide are class III antiarrhythmic agents which have been investigated for their effectiveness in the conversion of atrial fibrillation and atrial flutter to normal sinus rhythm. Class III antiarrhythmics prolong the refractory period of atrial and ventricular myocardium, the AV node, and the His-Purkinje conduction system by increasing the action potential duration. Although the mechanism of action is similar for these three drugs, they each have different efficacies and side effect profiles which may make one agent preferrable in certain situations. This paper reviews the intravenous role of amiodarone, ibutilide and sotalol and then compares them in terms of risk-benefit management. Amiodarone is a unique antiarrhythmic agent due to the fact that it contains some activity in each of the four classes of antiarrhythmic compounds. Although this makes it a very effective antiarrhythmic agent, its pharmacokinetics and side effect profile limit its indication to life-threatening ventricular arrhythmias and supraventricular arrhythmias unresponsive to conventional therapy. Administration of amiodarone in atrial fibrillation and flutter is 5 mg/kg IV over 15 to 30 minutes followed by 15 mg/kg (or up to 1200 mg) over the next 24 hours or until the patient converts (Di Biasi et al. and Galve et al.). In a study published by Galve et al., amiodarone was compared to placebo for conversion of recent-onset atrial fibrillation. This study consisted of 100 patients who were not being treated with other antiarrhythmic drugs. The results showed a small increase in the number of patients who converted with amiodarone over placebo, however, this increase was not statistically significant. The study concluded that because of the high rate of spontaneous conversion, the higher conversion rate for amiodarone cannot necessarily be attributed to the action of the drug. Another study by Di Biasi et al. compared IV amiodarone with IV propafenone in converting acute atrial fibrillaton and flutter after cardiac surgery. The study consisted of 84 patients with atrial tachyarrhythmias lasting more than 30 minutes. These patients were hemodynamically stable and were not being treated with any other antiarrhythmic drugs. The difference in the number of patients on amiodarone (38 out of 46) vs. propafenone (26 out of 38) that converted was not statistically significant. The study concluded that IV amiodarone and IV propafenone were equally effective in converting acute atrial fibrillation and flutter. However, propafenone was found to be more effective during the first hour. This study was not placebo-controlled, so there are no data comparing the pharmacological conversions to spontaneous conversions; the authors stated that a placebo group was unnecessary due to the fact that "amiodarone and propafenone have been shown to be very effective in restoring and maintaining sinus rhythm after cardiac operations." Amiodarone has a wide range of potential side effects. These include cardiac effects such as arrhythmias, CHF, heart block, bradycardia, hypotension (with rapid administration), and QT interval prolongation. Amiodarone also causes mild blockade of the AV and SA nodes. Non-cardiac side effects include nausea, sweating, photosensitivity, headache, pulmonary toxicity, hepatotoxicity, and sleep disturbances (Leatham et al.). In addition, thyroid toxicity has been reported as a result of amiodarone competing with iodide uptake in the thyroid (Georges et al.). Amiodarone was found to have a relatively low incidence of proarrhythmic effects in a 20-year retrospective medline search. The incidence of torsades de pointes was less than 1.0%. This may make amiodarone useful in treating high risk patients. Furthermore, IV amiodarone has demonstrated only small negative inotropic activity (Hohnloser et al.). Ibutilide (Corvert®) is another class III antiarrhythmic which can be used to convert atrial fibrillation and flutter to a normal sinus rhythm. According to the manufacturer, this is done by starting with a 1 mg IV bolus over ten minutes (a 0.01 mg/kg infusion is recommended if the patient weighs less than 60 kg) (Pharmacia & Upjohn). If the arrhythmia has not terminated within ten minutes of completing the initial infusion, a second infusion of the same dose may be administered. The infusion should be discontinued upon the appearance of a ventricular tachycardia, a prolongation of the QT interval, or conversion of the arrhythmia. To decrease the risk of developing polymorphic ventricular tachycardias, the following precautions should be taken. Before administering ibutilide, the patient must have normal fluid electrolytes. The potassium and magnesium levels should be corrected if reported low. If the patient has been in atrial fibrillation for longer than 48-72 hours, he or she must receive anticoagulation therapy for at least two weeks prior to cardioversion. The patient should also be hemodynamically stable with a heart rate of >60 bpm. During ibutilide infusion and for at least four hours post-infusion, the electrocardiogram (ECG) should be monitored and trained personnel should be present in the event that a sustained ventricular tachyarrhythmia should occur. Use of class Ia or other class III antiarrhythmic agents during or four hours post-infusion of ibutilide is not recommended due to additive effects in prolonging the refractory period. According to the efficacy studies submitted to the FDA , ibutilide is safe and effective to use in converting atrial fibrillation and flutter (Pharmacia & Upjohn). In a dose-response trial, recently occurring (<90 days) arrhythmias were terminated in 34% of the 200 patients treated with ibutilide (29% in Afib, 39% in Aflutter). The doses studied ranged from 0.005 mg/kg to 0.025 mg/kg given over a single ten minute infusion. The repeated-dose trial showed similar efficacy of ibutilide. In this trial, 266 patients with sustained atrial fibrillation or flutter were randomized to one of two ibutilide treatment arms or a placebo group. Nearly half (47%) of the ibutilide treated patients were converted within 20 minutes. Another repeated-dose trial published by Stambler et al. provided similar results. This study showed that there was no statistically significant difference between the two dose levels of ibutilide (1.0 mg short infusion followed by a 0.5 mg infusion vs. 1.0 mg followed by 1.0 mg). However, the study did show that conversion of atrial flutter was greater than in atrial fibrillation (63% vs. 31%). One of the most common side effects shown in FDA clinical trials was ventricular extrasystole (5.1%). Adverse effects which were less frequent included: non-sustained monomorphic ventricular tachycardia, headache, tachycardia, PVT, hypotension, bundle branch block, nausea, AV block. Overall, ibutilide is well tolerated and has minimal side effects. As with most cardiovascular drugs, however, adverse effects in the cardiovascular system were more common than with placebo (24.9% vs. 7.1% in phase II/III clinical trials). The biggest concern with ibutilide is proarrhythmic events. Ibutilide is not recommended in patients with a history of torsades de pointes, a very serious ventricular tachyarrhythmia that can result from the prolongation of the QT interval typical of class III antiarrhythmic activity. Sotalol, a racemic mixture of d- and l-sotalol, possesses both nonselective b-adrenergic antagonist activity (conferred by the l-enantiomer) and class III antiarrhythmic activity (conferred by the d-enantiomer). Although sotalol is FDA-approved only for use in life-threatening ventricular tachyarrhythmias, it also has been shown to be effective in the treatment and prevention of atrial fibrillation in a variety of clinical settings (Pill, et al.). In a review of studies of sotalol in supraventricular arrhythmias, Daubert et al. cite early studies that were neither blinded nor placebo-controlled that showed limited success (mean success rates were 35 and 23% in atrial fibrillation and atrial flutter, respectively) of low-dose (0.2-0.6 mg/kg) intravenous sotalol in converting to normal sinus rhythm. Increased success was seen with more commonly used dosages of 1.0-1.5 mg/kg. Low-dose intravenous sotalol was found to slow ventricular rate. More recently, Sung et al. performed a multicenter, randomized, double-blind, placebo-controlled study designed to assess the safety and efficacy of intravenous sotalol in terminating supraventricular tachycardia, atrial fibrillation, and atrial flutter. The study included 48 patients with atrial fibrillation and atrial flutter of >5 minute and >7 day duration and a ventricular rate >120 bpm. Intravenous sotalol given as a ten minute infusion of either 1.0 mg/kg or 1.5 mg/kg was not effective in converting to normal sinus rhythm (within 30 minutes of starting the infusion) compared to placebo. Sotalol was, however, effective in decreasing ventricular rate by >20% at both doses (p<0.05 vs. placebo for both doses). The two most commonly reported adverse effects during the study, hypotension and dyspnea, occurred at the same rate as with placebo. Sotalol is generally well-tolerated compared to other antiarrhythmics, although the major risk associated with its use is torsades de pointes (Daubert et al.). This risk is greatest at higher doses of sotalol, and was not reported at the intravenous doses used in the studies reviewed here. Life-threatening arrhythmias have been reported in cases of renal failure, as the elimination half-life of sotalol is prolonged in patients with renal insufficiency (Patrick et al.). Other adverse effects resulting from the b-blocking activity of sotalol include fatigue, bradycardia, and dyspnea. Sotalol should not be used in patients with bronchial asthma, sinus bradycardia, 2nd or 3rd degree AV block, or in patients with a history of drug-induced torsades de pointes. Caution should be used in patients with congestive heart failure and renal insufficiency. Although no studies comparing amiodarone, sotalol and ibutilide were reviewed for this paper, it appears that ibutilide is the most efficacious for rapidly converting acute atrial fibrillation and flutter. Ibutilide showed a substantial benefit in converting atrial fibrillation and flutter in the manufacturer's Sotalol Comparator Study (approximately 30% increase over sotalol). In addition, both sotalol and amiodarone showed limited success in converting these arrhythmias vs. placebo in the trials reviewed in this paper. When choosing a drug for conversion of atrial fibrillation or flutter, side effect profiles, in addition to efficacy, need to be taken into consideration. Of the three drugs reviewed here, amiodarone has the highest incidence of troublesome side effects, many of which make the drug intolerable to patients. However, amiodarone has the lowest incidence of provoking torsades de pointes (<1%, 1.7%, and 2-4% for amiodarone, ibutilide, and sotalol, respectively). The adverse effect profile of sotalol is not as broad as amiodarone; contraindications mainly stem from sotalol's b-blocking activity. Ibutilide seems to be the most well-tolerated of the three drugs. The majority of its adverse efects, as with any antiarrhythmic, are cardiovascular. For an initial infusion of any of these drugs, the price is approximately the same (AWP=$150). When comparing these drugs in terms of speed in conversion, ibutilide appears to be the most cost-effective. Two infusions of sotalol would cost around $300, and amiodarone may need to be used as an infsion for 24 hours, in which case the cost would be greater than $600. Many patients convert with a single infusion of ibutilide. After comparing amiodarone, ibutilide and sotalol in terms of efficacy, side effect profiles, and cost, it seems apparent that ibutilide should be the intravenous drug of choice for pharmacological conversion of atrial fibrillation or flutter. As always, however, specific patient characteristics should be considered in choosing an agent.
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