Color Atlas and Synopsis of Electrophysiology, 1st Ed.

30. CLASS III ANTIARRHYTHMIC DRUGS

Roi Altit, MD, Agnieszka Mochon, MD, Steven Rothman, MD

CASE PRESENTATION

An 82-year-old man was admitted to the hospital for treatment of recurrent atrial arrhythmias. He had a past medical history of a nonischemic cardiomyopathy and was status postplacement of a biventricular implantable cardioverter-defibrillator (BiV-ICD). His most recent ejection fraction was 45% (20% prior to BiV-ICD implantation). He had complained of malaise, dyspnea on exertion, and lightheadedness for the past couple of weeks, and his ECG on admission showed recurrence of atrial flutter with 2:1 AV conduction (Figure 30-1). The patient was started on dofetilide, and after his second dose he converted spontaneously to an atrial paced rhythm with biventricular pacing. An ECG at that time showed a significantly longer corrected QT interval (Figure 30-2). Soon afterward, the patient developed recurrent episodes of polymorphic ventricular tachycardia resulting in multiple ICD shocks (Figure 30-3). He received intravenous magnesium to suppress his ventricular arrhythmias, and the dofetilide was discontinued. He was eventually placed on amiodarone and was discharged from the hospital in sinus rhythm.

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FIGURE 30-1 Twelve-lead electrocardiogram showing atrial flutter with 2:1 conduction. The corrected QT interval is 490 msec in the presence of a complete left bundle branch block.

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FIGURE 30-2 Twelve-lead electrocardiogram obtained after two doses of dofetilide and spontaneous restoration of an AV sequentially paced rhythm. The corrected QT interval is 650 msec in the presence of biventricular pacing.

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FIGURE 30-3 Telemetry strips showing polymorphic ventricular tachycardia in association with marked QT prolongation (torsade de pointes). Top strips (A) show nonsustained episodes of TdP and the bottom strip (B) shows an episode of TdP degenerating into ventricular fibrillation, terminated by an ICD discharge.

BACKGROUND

Class III Antiarrhythmic Agents

Vaughan-Williams class III drugs are membrane active antiarrhythmic agents that affect the potassium channels located on the surface of myocytes during the plateau and repolarization phases of the action potential (Figure 30-4). The duration of these phases are a direct result of the balance between the inward calcium currents and the outward potassium currents. Blocking of the potassium currents during repolarization causes a prolongation in the action potential duration with a resultant increase in the QT interval on the surface ECG. The most commonly used agents in this class are amiodarone, dronedarone, sotalol, dofetilide, and ibutilide. In addition to their predominant potassium channel effect, some of these drugs exhibit effects on other channels and/or receptors (Table 30-1). A comparison of their pharmacokinetic profiles is shown in Table 30-2.

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FIGURE 30-4 Atrial and ventricular action potentials are shown along with their major ionic currents. Arrows denote direction of current (left = inward current; right = outward current). Class III antiarrhythmic agents block the potassium ion currents I(K).

TABLE 30-1 Class III Antiarrhythmic Channel/Receptor Effects

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TABLE 30-2 Comparison of the Pharmacokinetics of Class III Antiarrhythmic Drugs

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Class III Antiarrhythmic Drugs—General Indications and Usage

• All class III agents can be used for conversion and/or maintenance of sinus rhythm in patients with atrial fibrillation and atrial flutter.

• Amiodarone and sotalol also have indications in the treatment and prevention of ventricular arrhythmias.

• Drugs with predominantly class III effects (dofetilide, sotalol, ibutilide) may decrease defibrillation thresholds and can be used to facilitate direct-current cardioversions.

Proarrhythmic Effects of Class III Antiarrhythmic Agents

• The major side effect of this class of drugs is the risk of torsades de pointes (TdP), a type of polymorphic ventricular tachycardia associated with prolongation of the QT interval.

• Class III agents with predominant potassium channel blocking activity (sotalol, ibutilide, dofetilide) are more likely to cause TdP than those agents with multiple channel blocking activity (amiodarone, dronedarone).

• Patient factors that increase the risk of TdP include hypokalemia, hypomagnesemia, bradycardia, severe left ventricular dysfunction, impaired drug metabolism, and/or elimination and coadministration with other QT prolonging medications.

• Sotalol, dofetilide, and ibutilide demonstrate reverse-use dependence, resulting in a more potent potassium channel blocking effect at slower heart rates. This results in a longer QT interval with bradycardia and a higher risk of TdP.1

SPECIFIC AGENTS

Dofetilide

Dofetilide is a highly specific blocker of the rapid component of the delayed rectifier potassium current (Ikr), causing prolongation of the atrial and ventricular effective refractory periods. The drug is cleared predominantly through renal excretion and is contraindicated in patients with a creatinine clearance (CrCl) less than 20 mL/min. There are several drugs that significantly increase the plasma level of dofetilide and are contraindicated in its use. These include verapamil and trimethoprim, which increase the peak plasma concentrations of dofetilide, cimetidine, which inhibits renal tubular secretion of dofetilide, and ketoconazole, which is a significant inhibitor of the cytochrome p450 CYP3A4 isoenzyme, used in the hepatic metabolism of dofetilide. Hydrochlorothiazide is also contraindicated with the use of dofetilide due to both an increase in dofetilide’s serum plasma concentration and a reduction in serum potassium, the combination of which can result in a marked increase in the QT interval.

Indications

Dofetilide is currently indicated for the treatment of atrial fibrillation. In the SAFIRE-D trial,2 up to 29% of patients with persistent atrial fibrillation converted to sinus rhythm, most within the first 36 hours, and up to 58% of patients were able to maintain sinus rhythm for 1 year. In another study assessing the acute efficacy of dofetilide, Cotiga et al reported cardioversion rates ranging from 20% to 85% depending on the CrCl-based dosage.3 The risk of proarrhythmia, including TdP, in this same trial was 1.2%.

Current guidelines recommend dofetilide as a second line agent in patients with atrial fibrillation and no structural heart disease.4 In patients with depressed left ventricular function and congestive heart failure, however, dofetilide is a first-line agent as it has been shown to have a neutral effect on mortality in this patient population.5,6 Like other predominant potassium channel blockers, however, the use of dofetilide should be avoided in patients with significant hypertrophic cardiomyopathy due to an increased risk of proarrhythmia. While dofetilide is not indicated for use in patients with ventricular arrhythmias, there have been studies demonstrating a decreased incidence of ventricular tachycardia in patients with previously implanted cardioverter defibrillators.7

Dosing

• Dosing algorithm for dofetilide is shown in Table 30-3.

TABLE 30-3 Initial Dosing Schedule for Dofetilide

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• Dofetilide should be discontinued if any QTc interval after the second or subsequent doses exceed 500 msec (550 msec in the presence of a bundle branch block).

• Requires in-hospital initiation.

• Correction of serum potassium and magnesium levels prior to drug initiation.

• Restricted to providers who have completed specialized training.

Side Effects

• No significant hemodynamic effects.

• Major cardiovascular adverse events are related to QT prolongation and risk of TdP (about 1%-3%).

• Risk factors for TdP include high dose, female gender, baseline QT >450 msec, and history of sustained VT.

• Excessive QTc increase during loading calls for immediate discontinuation of the drug.

• Avoid in combination with other QT prolonging agents (antifungals, macrolide antibiotics, and protease inhibitors).

Sotalol

Sotalol is a water-soluble, racemic mixture of L- and D-isomers. While both isomers have class III antiarrhythmic properties, the L-isomer also has mild β-blocker properties. Sotalol prolongs atrial and ventricular repolarization by blocking the rapid component of the Ikr current. ECG changes associated with the use of sotalol result from its β-blocking properties (slowing of the sinus rate and PR prolongation), as well as its class III potassium blocking activity (QT prolongation) in a dose-dependent fashion.

Indications

Sotalol is predominantly used for the treatment of atrial fibrillation and is considered a first-line antiarrhythmic agent in patients without structural heart disease or those with coronary artery disease and normal left ventricular function.4 It should be avoided in patients with severe left ventricular hypertrophy and also in those with left ventricular dysfunction. While not particularly effective in pharmacologic cardioversion, it is useful in the prevention of recurrent atrial fibrillation, especially at doses of 120 mg or 160 mg BID.8 Sotalol has also been shown to decrease the recurrence of ventricular arrhythmias in patients with inducible VT and also to decrease the incidence of ICD shock therapy in patients with a previously implanted cardioverter-defibrillator.9

Dosing

• Initiation should occur in the hospital with ECG monitoring and close monitoring of renal function.

• Initial dose 80 to 160 mg/d with therapeutic effect usually at the dose of 160 to 320 mg/d.

• Patients with refractory ventricular arrhythmias may require doses of up to 480 to 640 mg/d (only if benefit outweighs potential proarrhythmic drug effects).

• Dosing intervals should be adjusted depending on CrCl, with 2 times a day dosing for CrCl >60 mL/min and once a day dosing for CrCl 40 to 60 mL/min.

• Two to three days should be allowed between dose adjustments.

• Discontinuation of this medication occurs over a 1 to 2 week taper.

• Avoid the concomitant use of other QT prolonging agents.

Side effects

• Torsades de pointes has been observed in up to 2.3% of patients being treated for the prevention of atrial fibrillation with sotalol.

• Symptoms mostly related to the β-blocker effect: fatigue, dyspnea, bradycardia, and heart failure.

Contraindications

• CrCl <40 mL/min (dose should be adjusted for renal function).

• QTc >500 ms.

• Significant LVH (>1.4 cm).

• Decompensated heart failure.

• Sick sinus syndrome and advanced AV block.

• Severe asthma.

Ibutilide

Ibutilide is a class III agent with potassium channel blocking activity of the rapid Ikr current and also delays the inactivation of the slow inward sodium current. It is metabolized in the liver and has a half-life of approximately 6 hours. There are no significant drug–drug interactions when administered with calcium channel blockers, β-blockers, or digoxin. Proarrhythmic effects include sustained and nonsustained polymorphic VT in up to 4% to 5% of patients.

Indications

Ibutilide is indicated for the pharmacologic cardioversion of atrial fibrillation and atrial flutter. It is effective in terminating atrial fibrillation in approximately 50% of patients and atrial flutter in 65% to 76% of patients.10 It has been used to facilitate cardioversion in patients already on a sodium channel blocker, such as procainamide, flecainide, or propafenone, and also those on amiodarone. Ibutilide decreases the defibrillation threshold and can be used to enhance the effectiveness of electrical cardioversion in patients with atrial fibrillation.11

Dosing

• Dosing algorithm shown in Table 30-4.

TABLE 30-4 Dosing of Ibutilide

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• Administer with continuous ECG monitoring due to proarrhythmic effects.

• No dose adjustment in patients with hepatic or renal dysfunction, but drug clearance may be prolonged in patients with hepatic dysfunction.

• Arrhythmia termination occurs within 1 hour of infusion.

• ECG monitoring for 4 hours after drug administration or until QTc returns to baseline is required. Patients with hepatic dysfunction or nonsustained ventricular tachycardia during drug administration should be monitored longer.

Side effects

• ECG effects include QT prolongation and mild slowing of the heart rate.

• May cause transient hypotension and bradycardia.

• Like other class III agents it can trigger TdP.

• Risk of ventricular tachycardia is approximately 4%.

Contraindications

• Avoid in patients with high risk of ventricular arrhythmias (baseline QTc >440 ms, hypokalemia, hypomagnesemia, sinus node dysfunction, low ejection fraction).

• Should not be coadministered with other QT-prolonging medications.

Amiodarone

While classified as a class III antiarrhythmic agent, amiodarone has properties than span across all of the Von Williams classifications.12 In addition to blocking multiple potassium channels, including IKr, IKs, Ito, IK1, IKACh, and IKNa, amiodarone also has significant sodium channel, calcium channel, and β-receptor blocking activity. As a result, the electrocardiogram may show a slowing of the heart rate, increase in the PR interval, and widening of the QRS and QT prolongation. Amiodarone is primarily metabolized in the liver, and due to its significant lipophilic nature, accumulation in fatty tissue, and large volume of distribution, it has a long and variable half-life of typically 35 to 40 days, though it can be as long as 100 days.

Although amiodarone is a class III antiarrhythmic and can cause significant QT prolongation, it has a relatively low risk of TdP.13 The exact mechanism for the low risk of TdP is not definitively known, but several theories have been postulated:

• Some evidence suggests that TdP is initiated and/or propagated by calcium-dependant early afterdepolarizations. Amiodarone’s ability to block the slow inward calcium current via the L-calcium channels, leads to lower influx calcium availability and therefore a decreased risk of TdP.

• Another theory involves the differential prolongation of the repolarization period between Purkinje fibers and ventricular myocardium amongst different class III agents. Nearly all class III agents other than amiodarone prolong the repolarization of Purkinje fibers, where early afterdepolarizations resulting in TdP appear to be generated, more so than ventricular myocardium. The reverse is true of amiodarone.

• Finally, amiodarone may selectively block the action of triiodothyronine at the myocardial nuclear receptor. This leads to increased homogeneity of repolarization in contiguous myocardial cells and to a significant reduction in QT dispersion on the surface electrocardiogram as opposed to a drug like quinidine, which increases QT dispersion.

Indications

Amiodarone has been used extensively in the treatment of both ventricular and supraventricular arrhythmias, including atrial fibrillation and atrial flutter. Its favorable hemodynamic profile and low risk of proarrhythmia make it the drug of choice in patients with severe cardiomyopathy, heart failure, and recurrent cardiac arrhythmias. Prior to the use of ICDs, amiodarone was shown to decrease sudden cardiac death by up to 30% in high-risk patients.14Amiodarone and also been shown to be useful in preventing ICD therapy/shocks in patients with cardiac arrhythmias and prior ICD implantation. It may, however, increase the defibrillation threshold in these patients and can also result in significant slowly of the VT rate.

In patients with atrial fibrillation, it is the most commonly used and most effective antiarrhythmic agent, with over 60% of patients maintaining sinus rhythm in one year.15 Similar to dofetilide, amiodarone has not been shown to cause an increased mortality in a high-risk patient population with severe LV dysfunction and heart failure.16 Unfortunately, the drug does have significant long-term side effects and should be limited in its use for patients with non–life-threatening arrhythmias. Therefore, current guidelines recommend the use of amiodarone to maintain sinus rhythm in patients with coronary artery disease who are not candidates for dofetilide or sotalol; patients with heart failure who are not candidates for dofetilide; patients with severe concentric left ventricular hypertrophy; and in patients refractory to other antiarrhythmic drugs as an alternative to ablation.4 Preventive loading with amiodarone can be considered in high-risk patients (previous AF, valvular surgery) who are undergoing cardiac surgery. Amiodarone is contraindicated in patients with severe lung or liver disease, advanced sinus node dysfunction, and AV conduction disease greater than first-degree AV block.

Dosing

• Amiodarone typically requires a significant loading dose secondary to its large volume of distribution.

• For ventricular arrhythmias, a total loading dose of 8 to 10 grams is usually required while smaller loading doses are used for atrial arrhythmias.

• An algorithm for the initiation of amiodarone (po and IV) is shown in Table 30-5 for both supraventricular and ventricular indications.

TABLE 30-5 Amiodarone Dosing

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Side effects

• Amiodarone can have significant effects on multiple organ systems, many of which are listed in Table 30-6.

TABLE 30-6 Side Effects of Amiodarone

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• Bradycardia can occur due to both sinus node suppression and AV conduction effects.

• Hypotension may occur during IV administration.

Drug–Drug Interactions

• Increased concentration and effect of warfarin and digoxin.

• Increased risk of bradycardia and AV block with concomitant AV nodal blocking agents.

• Potential proarrhythmic effect in combination with other drugs that prolong the QT interval.

• Increased risk of liver function abnormalities and myopathy with simvastatin and atorvastatin.

Dronedarone

Dronedarone is a noniodinated derivative of amiodarone with an added methane sulfonyl group, resulting in a shorter half-life and lower tissue accumulation due to decreased lipophilicity. Similar to amiodarone, dronedarone blocks several multiple potassium currents, the inward sodium currents, L-type calcium currents, and β-adrenergic receptors. The electrocardiographic effects caused by dronedarone are similar to those of amiodarone and include a decrease in the heart rate, an increase in the PR interval, QRS duration, and QT interval.

Indications

Dronedarone is clinically indicated for the maintenance of sinus rhythm in a patient with recurrent paroxysmal or persistent AF and is effective in prolonging the time to recurrence of atrial fibrillation.17 The ATHENA trial also demonstrated dronedarone to be effective in decreasing cardiovascular hospitalizations in patients with atrial arrhythmias.18 It is not as effective in maintaining sinus rhythm; however, when compared to amiodarone dronedarone has a low risk of TdP, but unlike amiodarone, the use of dronedarone should be limited to patients without a history of congestive heart failure or significant left ventricular dysfunction, as an increased mortality has been noted in this high-risk population.19 Although effective in slowing the ventricular response rate during atrial fibrillation, dronedarone should not be used as a rate control agent in patients with permanent atrial fibrillation.20

Dosing

• Dronedarone is available in only one dosage form of 400 mg every 12 hours.

• Absorption is increased 2- to 3-fold when taken with food and should therefore be taken with meals.

Side Effects

• Causes dose-dependant QT prolongation, but TdP not reported.

• Much less extra cardiac toxicities than amiodarone.

• GI side effects including abdominal pain, nausea, and diarrhea.

• Transient increase in serum creatinine without reduction in renal function.

Contraindications

• Congestive heart failure

• Permanent atrial fibrillation

• Severe liver impairment

• Bradycardia (HR <50 bpm)

• Sick sinus syndrome

• First degree AV block with PR interval >280 ms or higher AV block

• Prolonged QT (QTc >500 msec) or coadministration with QT prolonging agents (antifungals, macrolide antibiotics, and protease inhibitors)

Drug–Drug Interactions

• Use with verapamil, diltiazem, digoxin, warfarin, and/or statin medications requires caution and dose adjustment due to risk of QT prolongation.

SUMMARY

The Vaughan-Williams class III antiarrhythmic agents provide an important option in the treatment of atrial and ventricular arrhythmias. Those drugs with predominant class III effects, however, are at a higher risk of causing proarrhythmia (TdP) and should be initiated in a monitored setting. While amiodarone and dronedarone appear to have a significantly lower risk of TdP, their use is limited by either noncardiac side effects (amiodarone) or an increased mortality in patients with structural heart disease and heart failure (dronedarone). With careful patient selection and appropriate follow-up, however, all of the class III antiarrhythmics can be used successfully in the treatment of cardiac arrhythmias.

REFERENCES

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  2. Singh S, Zoble RG, Yellen L, et al. Efficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter: the symptomatic atrial fibrillation investigative research on dofetilide (SAFIRE-D) study. Circulation. 2000;102(19):2385-2390.

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  7. Boriana G, Lubinski A, Capucci A, et al; Ventricular Arrhythmias Dofetide Investigators. A multicentre, double-blind randomized crossover comparative study on the efficacy and safety of dofetilide vs sotalol in patients with inducible sustained ventricular tachycardia and ischaemic heart disease. Eur Heart J. 2001:22(23):2180-2191.

  8. Benditt DG, Williams JH, Jin J, et al. Maintenance of sinus rhythm with oral d,l-sotalol therapy in patients with symptomatic atrial fibrillation and/or atrial flutter. d,l-Sotalol Atrial Fibrillation/Flutter Study Group. Am J Cardiol. 1999;84(3):270-277.

  9. Pacifico A, Hohnloser SH, Williams JH, et al. Prevention of implantable-defibrillator shocks by treatment with sotalol. d,l-Sotalol Implantable Cardioverter-Defibrillator Study Group. N Eng J Med. 1999;340(24):1855-1862.

 10. Volgman AS, Carberry PA, Stambler B, et al. Conversion efficacy and safety of intravenous ibutilide compared with intravenous procainamide in patients with atrial flutter or fibrillation. J Am Coll Cardiol. 1998;31(6):1414-1419.

 11. Oral H, Souza JJ, Michaud GF, et al. Facilitating transthoracic cardioversion of atrial fibrillation with ibutilide pretreatment. N Eng J Med. 1999;340(24):1849-1854.

 12. Goldschlager N, Epstein AE, Naccarelli GV, et al. A practical guide for clinicians who treat patients with amiodarone: 2007. Heart Rhythm. 2007;4(9):1250-1259.

 13. Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Lancet. 1997;350:1417-1424.

 14. Sim I, McDonald KM, Lavori PW, Norbutas CM, Hlatky MA. Quantitative overview of randomized trials of amiodarone to prevent sudden cardiac death. Circulation. 1997;96(9):2823-2829.

 15. AFFIRM First Antiarrhythmic Drug Substudy Investigators. Maintenance of sinus rhythm in patients with atrial fibrillation: an AFFIRM substudy of the first antiarrhythmic drug. J Am Coll Cardiol. 2003;42(1):20-29.

 16. Singh SN, Fletcher RD, Fisher SG, et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N Eng J Med. 1995;333(2):77-82.

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 18. Hohnloser SH, Crijns HJ, van Eickels M, et al; ATHENA Investgators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Eng J Med. 2009;360(7):668-678.

 19. Kober L, Torp-Pedersen C, McMurray JJ, et al; Dronedarone Study Group. Increased mortality after dronedarone therapy for severe heart failure. N Eng J Med. 2008;358(25):2678-2687.

 20. Connolly SJ, Camm AJ, Halpern JL, et al. Dronedarone in high-risk permanent atrial fibrillation. N Eng J Med. 2011;365(24):2268-2276.