JACC Vol. 9. NO.2 459 February 1987:459-63 EDITORIAL REVIEWS Second Generation Antiarrhythmic Agents: Have We Reached Antiarrhythmic Nirvana? LEONARD N. HOROWITZ, MD, FACC, JOEL MORGANROTH, MD, FACC Philadelphia, Pennsylvania During the first half of the 20th century, antiarrhythmic some cases novel, but because their preapproval evaluations therapy was principally directed toward supraventricular ar­ followed a more rigorous and circumspect path. More in­ rhythmia; only relatively recently has therapy of ventricular formation is available to us so we can decide when and how arrhythmias been emphasized. In fact, significant pharma­ these agents should be employed. cologic treatment of ventricular arrhythmias was minimal Like all antiarrhythmic drugs of the first generation, the until routine use of quinidine and procainamide began in new agents have the potential to provoke or worsen ven­ the 1950s (1,2). The first generation oral antiarrhythmic tricular arrhythmias. These proarrhythmic effects vary in drugs, quinidine, procainamide and disopyramide, previ­ incidence and may present a major problem in certain patient ously constituted the principal antiarrhythmic agents for long­ groups such as those with sustained ventricular tachyar­ term treatment of ventricular arrhythmias in the United States. rhythrnias, reduced left ventricular function and conduction Compared with modem regulatory standards, the data on disturbances. In common with other antiarrhythmic drugs, which the use of these drugs was based were modest at best the second generation drugs have not been shown to prevent and rudimentary at worst. However, because good clinical sudden death in patients with ventricular ectopic activity. judgment compensates for a multitude of deficiencies, we These factors, along with efficacy and potential toxicity, have been able to provide effective antiarrhythmic therapy must be considered in selecting antiarrhythmic regimens for to many patients with this rather limited pharmacopoeia. an individual patient. Two beta-adrenergic blocking agents, propranolol and acebutolol, have been approved for the treatment of ven­ Tocainide tricular arrhythmias by the Food and Drug Administration. Unlike the first generation of antiarrhythmic drugs and the Efficacy. Tocainide hydrochloride, a class IB agent, has recently released agents which effect their antiarrhythmic electrophysiologic and antiarrhythmic characteristics similar action by direct alteration of electrophysiologic properties, to those of lidocaine, of which it is a congener; however, the beta-blockers presumably act indirectly by blunting sym­ it can be prescribed for oral administration. Tocainide is pathetic tone. Although they are effective, either alone or indicated for the "suppression of symptomatic ventricular as an adjunct to classic antiarrhythmic therapy, they will arrhythmias, including frequent premature ventricular con­ not be considered in this discussion of membrane-active tractions, unifocal or multifocal , couplets and ventricular antiarrhythmic agents. tachycardia" (3). It has been reported to significantly reduce In slightly more than 12 months, four new antiarrhythmic (decrease by at least 70% in frequency) ventricular pre­ drugs, tocainide, mexiletine, ftecainide and amiodarone, mature complexes in 20 to 50% of patients (4). When com­ have been released for the treatment of ventricular arrhyth­ pared with quinidine or procainamide, tocainide has been mias. A fifth drug, encainide, is likely to be released within less effective in suppressing ventricular premature com­ a year. These drugs are "second generation," not only plexes (5). In patients with malignant ventricular arrhyth­ because their electrophysiologic properties are new and in mias (ventricular tachycardia with hemodynamic compro­ mise or ventricular fibrillation) tocainide has been shown to be effective in 10 to 15% of patients; however, notable * Editorials published in Journal ofthe American College ofCardiology reflect the views of the authors and do not necessarily represent the views exceptions with higher efficacy rates have been reported (6). of JACC or the American College of Cardiology. These and other data provide support for the indications for From the Division of Clinical Cardiac Electrophysiology and Sudden tocainide. Death Prevention Program of the Likoff Cardiovascular Institute, Hah­ nemann University and Hospital, Philadelphia, Pennsylvania. Adverse effects. Tocainide commonly produces minor, Manuscript received March 4, 1986; revised manuscript received July transient, gastrointestinal and neurologic adverse effects. 1,1986, accepted July 21,1986. These side effects have been reported in 30 to 40% of Address for reprints: Leonard N. Horowitz, MD. Philadelphia Heart Institute, Presbyterian-University of Pennsylvania Medical Center, 39th patients. Intolerable adverse reactions may require discon­ and Market Streets, Philadelphia, Pennsylvania 19104. tinuation of tocainide therapy in 10 to 20% of patients. The © 1987 by tbe American College of Cardiology 0735-1097/87/$3.50 460 HOROWITZ AND MORGANROTH lACC Vol. 9. No.2 EDITORIAL REVIEW February 1987:459-63 manufacturer has warned that blood dyscrasias, which are cardia, or both, during flecainide therapy, and the median possibly drug related, have been reported in patients re­ reduction in ventricular premature complexes for all patients ceiving tocainide, and frequent monitoring of hematologic approximates 95% (12). F1ecainide has been shown to be variables is recommended. Pulmonary fibrosis has also been more effective than quinidine in suppressing ventricular pre­ reported. Tocainide has produced minimal negative ino­ mature complexes (12). In patients with refractory life­ tropic effects and most patients, even those with evidence threatening ventricular arrhythmias, it has been effective in of significant left ventricular dysfunction, can tolerate to­ 25% of patients evaluated by noninvasive or invasive tech­ cain ide without worsening of congestive heart failure. More­ niques, or both (13,14). Although flecainide has not been over, tocainide can be administered with other cardioactive directly compared with first generation antiarrhythmic drugs medications without significant interactions. in this latter group of patients, in most of the patients treated with flecainide previous therapy with first generation agents had been unsuccessful. Mexiletine Adverse effects. The most common adverse effects noted Efficacy. Mexiletine hydrochloride, a class IB agent, is with patients treated with flecainide have been central ner­ structurally similar to lidocaine and tocainide and has similar vous system disturbances. These occur in 10 to 20% of antiarrhythmic potency. Mexiletine is indicated for patients. Discontinuation of treatment because of these ef­ "suppression of symptomatic ventricular arrhythmias in­ fects has been reported in 5 to 10% of patients (11,15). cluding premature ventricular contractions, unifocal or mul­ The manufacturer has warned that flecainide can cause tifocal, couplets and ventricular tachycardia" (7). Mexile­ new or worsened arrhythmias. This proarrhythmic effect tine has been effective in reducing the frequency of ventricular has been reported in 7O/c of the patients treated with fle­ premature complexes in 30 to 50% of patients (6-8). Com­ cainide and its frequency appears to be related to the dose, parisons with procainamide, quinidine and disopyramide the method of dose titration and the underlying cardiac dis­ have shown no significant difference in efficacy. In patients ease. The incidence of proarrhythrnic effect is highest among with more serious ventricular arrhythmias evaluated by non­ patients who have sustained ventricular tachycardia or whose invasive methods, the efficacy of mexiletine has been re­ dose is rapidly titrated upward, or both. When high initial ported to be good (8). However, in patients with sustained doses and rapid upward titration were used in early studies ventricular tachycardia evaluated by electrophysiologic test­ of patients with sustained ventricular tachycardia, a proar­ ing, mexiletine when used alone has generally been reported rhythmic event occurred in 26% of patients, and in 10% of to have minimal efficacy (9). In this group of patients, the patients treated, a proarrhythmic event resulted in death. however, the combination of mexiletine with procainamide With the current dosing recommendations, however, the or quinidine has been shown to be very effective (10). incidence of proarrhythmic events resulting in death has Adverse effects. Mexiletine commonly produces gas­ decreased to 0.5%. Thus, it is extremely important to follow trointestinal and neurologic adverse reactions. Upper gas­ the recommended dosing schedule. trointestinal distress has been reported in more than 40% of In addition. flecainide has a negative inotropic effect and patients and light-headedness, tremor and coordination dif­ can cause or worsen congestive heart failure. This effect ficulties have been reported in 10 to 20% of patients (7). is particularly noted in patients with cardiomyopathy or The manufacturer has noted that liver injury and elevation preexisting severe heart failure. Because flecainide has po­ of certain hepatic enzymes have been noted in a small num­ tent depressant effects on cardiac conduction, patients with ber of patients treated with mexiletine and may be related sinoatrial node and atrioventricular (AV) conduction dis­ to it. Appropriate clinical follow-up is