CURRENT DRUG THERAPY WALID I. SALIBA, MD Section of Cardiac Electrophysiology and Pacing, CREDIT Department of Cardiology, Cleveland Clinic Dofetilide (Tikosyn): A new drug to control atrial fibrillation ABSTRACT OFETILIDE (Tikosyn), a new antiarrhyth- mic drug, can convert atrial fibrillation Dofetilide, a new class III antiarrhythmic agent, selectively and atrial flutter to sinus rhythm in approxi- blocks a specific cardiac potassium channel, lKr, increasing mately 30% of cases and maintain sinus the effective refractory period of the myocyte and thereby rhythm after electrical or pharmacologic con- terminating reentrant arrhythmias. Given orally, it appears version for up to 1 year in 60% to 70% of to effectively convert atrial fibrillation and atrial flutter to cases, without increasing the risk of sudden sinus rhythm and maintain sinus rhythm after conversion in death in patients at high risk. appropriately selected patients. This paper reviews the Such new drugs are needed, as many of the pharmacology of dofetilide, the evidence of its antiarrhythmic drugs in use up to now have effectiveness, and the appropriate precautions in using it. actually produced higher mortality rates in clinical trials than did placebo, or cause unac- ceptable side effects. KEY POINTS This article reviews the mechanism of action, safety, effectiveness, and clinical use of Dofetilide is generally well tolerated but like other class III dofetilide. drugs can cause torsades de pointes. The risk is dose- dependent and can be minimized by adjusting the dosage • PROBLEMS WITH PREVIOUS DRUGS according to creatinine clearance and QT interval, by excluding patients with known risk factors for long QT A variety of drugs have been used to terminate syndrome and torsades de pointes, and by starting or prevent atrial and ventricular arrhythmias, treatment in an inpatient monitored setting for the first 3 but their safety, efficacy, and tolerability in days. patients at high risk of sudden death have been disappointing. In a meta-analysis of randomized clinical Unlike other antiarrhythmic agents, oral dofetilide did not trials that ran for 3 months to 1 year,1 Coplen increase the mortality rate in clinical studies in et al calculated that patients who received postmyocardial infarction patients or those with congestive quinidine to maintain sinus rhythm after car- heart failure at high risk for sudden cardiac death. dioversion of atrial fibrillation had an unad- justed mortality rate of 2.9%, compared with Concomitant use of drugs that increase the plasma level of 0.8% in control patients. Similarly, survivors dofetilide is contraindicated; these include cimetidine, of myocardial infarction (MI) with left ven- ketoconazole, trimethoprim-sulfamethoxazole, and tricular dysfunction who received the class IC verapamil. agents flecainide, encainide, and moricizine long-term in the CAST study2 and the class III agent sotalol in the SWORD study3 also had higher mortality rates than did those who received placebo. In addition, some of the agents have side effects such as gastrointesti- nal disturbances, arrhythmias, hypotension, 353 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 4 APRIL 2001 Downloaded from www.ccjm.org on October 4, 2021. For personal use only. All other uses require permission. DOFETILIDE SALIBA TABLE 1 in the atria to a greater extent than in the ventricles. Dose for dose, the increase in the Pharmacokinetics of dofetilide atrial effective refractory period is double that Absorption Approximately 100% of the ventricular effective refractory period.7 Bioavailability 92% Perhaps for this reason, dofetilide is more effective in treating atrial arrhythmias than in Volume of distribution 3.3 L/Kg ventricular arrhythmias. Protein binding 65% Time to peak plasma concentration 2.2 hours (range 1-4) • PHARMACODYNAMICS OF DOFETILIDE Half-life 8-10 hours Elimination Renal 80%, hepatic 10% Dofetilide is a cardioselective IKr blocker. At recommended doses, it has no effect on other mmmmmmmmm potassium channels (IKs, IKl), sodium chan- nels, calcium channels, or beta receptors.6 and myocardial depression, which further Therefore, it has a selective effect of prolong- restrict their use in specific patient popula- ing the action potential duration and the tions.4 refractory period in myocardial tissue. On the other hand, amiodarone, which is On the electrocardiogram, dofetilide widely used to treat atrial fibrillation although selectively prolongs the QT interval but has not officially indicated for this purpose, has a no effect on the PR, QRS, AH, or HV inter- proven safety profile in patients with structur- vals.8 It does not significantly affect the func- al heart disease and was not associated with tion of the sinus node (cycle length or recov- increased mortality when compared with ery time). placebo in the treatment of various arrhyth- mias.5 It maintains sinus rhythm in nearly two • HEMODYNAMIC EFFECTS OF DOFETILIDE thirds erf patients in up to 1 year of follow-up. However, in clinical trials, 41% of patients By virtue of its pure class III antiarrhythmic Dofetilide does stopped taking amiodarone compared with action, dofetilide does not depress myocardial not affect 27% taking placebo. The difference was pri- function, unlike nonspecific class III agents marily due to adverse effects. Amiodarone has such as amiodarone or sotalol.9 When it was cardiac output toxic effects on the liver, thyroid, and lungs, given to patients with congestive heart failure and its pulmonary toxicity can be life-threat- and compromised ventricular function (in ening 5 New York Heart Association class II or III and with left ventricular ejection fractions < • DOFETILIDE'S MECHANISM OF ACTION 35%), their mean cardiac output was main- tained despite a small reduction in mean heart Dofetilide is a Vaughn Williams class III rate.10 antiarrhythmic drug, meaning that it is a potassium channel blocker. (Other drugs in • PHARMACOKINETICS OF DOFETILIDE this class include sotalol and amiodarone.) Specifically, it blocks the rapid component of Absorption and distribution. After an the major repolarizing current, the delayed oral dose, dofetilide is almost 100% absorbed rectifier (IK,-)-6 (TABLE 1) and reaches a peak plasma concentra- By blocking the IKr channel, dofetilide tion in approximately 2 hours (range 1-4 delays myocardial repolarization and increases hours), irrespective of dose.11 However, food the refractory period (FIGURE 1). This consti- nearly doubles the time to peak plasma con- tutes the basis of its antiarrhythmic action: if centration.12 Dofetilide is widely distributed the myocytes have a longer refractory period, in the body. a reentrant arrhythmic wavefront has a greater Elimination is mainly through renal chance of encountering refractory tissue and excretion via passive glomerular filtration and would therefore be suppressed or terminated. cationic tubular secretion. Approximately Dofetilide prolongs the refractory period 80% of a dose is excreted in the urine.13 The 354 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 4 APRIL 2001 Downloaded from www.ccjm.org on October 4, 2021. For personal use only. All other uses require permission. How class III antiarrhythmic drugs work The action potential of a heart cell (electrical activity required for contraction) depends on Ions moving in and out of the cell through specific ion channels that open and close in a specific sequence. +20 - 0 - -20 - 1. Sodium floods into the cell via sodium channels as it rapidly depolarizes. -40 - 2. Calcium slowly enters -60 - the cell via calcium channels. -80 3. Potassium is allowed to leave the cell via potassium channels as it repolarizes. Class III drugs such as amiodarone, sotalol, and dofetilide block potassium efflux Na-K and extend the refractory ATPase period of the cell, making pump it less likely to depolarize in response to electrical stimuli. Myocyte 4. Sodium and calcium are exchanged for potassium via the sodium-potassium ATPase pump. Direction of conduction In the atria, class III antiarrhythmic drugs decrease the refractory gap Re-entrant Re-entrant circuit, encountering circuit excitable cells (left), can stimulate them to depolarize and perpetuate the arrythmia; Refractory with a class III drug (right), the gap re-entrant circuit is more likely to encounter a gap of refractory cells and be terminated. 6ccitatAe CCF ©2001 FIGURE 1 355 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 4 APRIL 2001 Downloaded from www.ccjm.org on October 4, 2021. For personal use only. All other uses require permission. DOFETILIDE SALIBA TABLE 2 centrations than men even after correcting for body weight and creatinine clearance. Dofetilide drug interactions Smoking or coronary artery disease do not These drugs increase affect the disposition of dofetilide.16 the plasma level of dofetilide: Cimetidine* • DRUG INTERACTIONS Ketoconazole* Megestrol Dofetilide has significant interactions with cer- Prochlorperazine tain drugs that interfere with either its hepatic Trimethoprim-sulfamethoxazole* metabolism or renal excretion (TABLE 2). It has Verapamil* no known effects on any laboratory tests. These drugs have no effect on dofetilide: Antacids • EFFECTIVENESS IN ATRIAL FIBRILLATION Amlodipine Glyburide Atrial fibrillation, one of the most common Hormone replacement therapy arrhythmias, occurs in 5.9% of patients older Omeprazole than 65 years17 and is an independent risk fac- Phenytoin tor for thromboembolism and stroke.18 Ranitidine In three randomized, double-blind,