Second Generation Antiarrhythmic Agents: Have We Reached Antiarrhythmic Nirvana?

JACC Vol. 9. NO.2 459 February 1987:459-63

EDITORIAL REVIEWS

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

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 indicated. turbances must be carefully observed for the development of worsening of these abnormalities. Flecainide F1ecainide acetate, a class IC agent, markedly depresses Encainide the sodium channel and is the first released agent of a group Encainide hydrochloride also markedly slows intracar of agents with potent negative dromotropic effects which diac conduction and is classified as a class IC antiarrhythmic have been classified as IC agents. agent. Its antiarrhythmic effects are similar to those of fle Efficacy. Flecainide is indicated for the "treatment of cainide. Encainide was recommended for approval by the documented life-threatening ventricular arrhythmias, such Cardio-renal Advisory Committee in July 1985 and is in the as sustained ventricular tachycardia" and "symptomatic latter stages of the Food and Drug Administration's review nonsustained ventricular tachycardia and frequent premature process. It will probably be released within a year. ventricular complexes" (11). More than 80% of patients Efficacy. Encainide will be indicated for the treatment will achieve greater than 75% suppression of ventricular of ventricular arrhythmias similar to those for which fle premature complexes, or elimination of ventricular tachy- cainide is indicated. The efficacy of encainide in suppressing JACC Vol. 9. NO.2 HOROWITZ AND MORGANROTH 461 February 1987:459-63 EDITORIAL REVIEW

both ventricular premature complexes and malignant ven patients who will have nonlife-threatening recurrent ar tricular arrhythmias is similar to that of flecainide. It produces rhythmia (27,28). adequate suppression of ventricular premature complexes in Toxicity and adverse effects. Because its use is accom approximately 80% of patients and complete abolition in 30 panied by substantial toxicity, amiodarone is indicated only to 40% of patients (16,17). Encainide is more effective than for use in patients with life-threatening ventricular arrhyth quinidine in suppressing ventricular premature complexes mias. Amiodarone has several potentially lethal toxicities, (18). When evaluated by electrophysiologic techniques. it the most notable of which is pulmonary toxicity. Although has been reported to be effective in approximately 25% of the incidence of this adverse effect is debated, rates between patients with malignant ventricular arrhythmias (19). 5 and 15% have been routinely reported and death may Adverse effects. The adverse effects produced by en occur from this complication in as many as 10% of those cainide during long-term oral use are predominantly neu with the adverse effect. It may cause a worsening of conges rologic. Blurred vision, dizziness and ataxia are reported in tive heart failure and arrhythmias. Moreover, amiodarone 10 to 20% of patients. poses major management problems because of its unusual Encainide will probably carry a proarrhythmia warning pharmacokinetics and other less severe adverse effects. similar to that in the flecainide package insert. A proar Amiodarone has been reported to cause hepatic injury, cor rhythmic effect has been reported in 5 to 10% of patients neal microdeposits and uncommonly, impairment of vision, receiving encainide, most commonly in patients with left cutaneous photosensitivity, thyroid abnormalities and a ventricular dysfunction and malignant ventricular arrhyth number of drug interactions. It has significant interactions mia (20,21). This proarrhythmic effect may also be dose with other antiarrhythmic drugs. digitalis and warfarin an related (22). Like flecainide, encainide may depress sinus ticoagulants. node function and AV conduction particularly in patients with preexisting disturbances. It is not expected that en cainide will carry a warning relative to heart failure because Antiarrhythmic Therapy in 1986 minimal hemodynamic effects have been reported and heart Clinical approach to antiarrhythmic therapy. Have failure uncommonly complicates the use of encainide even we, therefore, entered antiarrhythmic nirvana? Can we and in patients with preexisting heart failure (23). should we abandon the use of first generation antiarrhythmic agents because newer drugs are now available? What is the role of these new agents and where do they fit in the ther apeutic algorithm for patients with ventricular arrhythmia? Amiodarone Clearly we have not attained perfection in antiarrhythmic Amiodarone, a benzofuran derivative, was initially in therapy. All of the second generation agents have limitations troduced as a coronary vasodilator for treatment of angina and thus. none is the perfect antiarrhythmic agent. Such an pectoris but was found to have antiarrhythmic properties. "ideal" antiarrhythmic agent would have minimal adverse Amiodarone increases the action potential duration and pro effects and be effective in the majority of patients, partic longs repolarization. In addition, it is a noncompetitive ad ularly those with malignant ventricular arrhythmias. Its me renergic antagonist. tabolism and pharmacokinetics would be simple and un Efficacy. Because of its potentially life-threatening side varying in different patient populations. It would be nice if effects and the substantial management difficulties associ it were effective in treating supraventricular arrhythmias as ated with its use, amiodarone is indicated for the treatment well! We do not have and probably are not likely to have of "documented, life-threatening recurrent ventricular ar such an agent. The advantage of having twice as many rhythmias [recurrent ventricular fibrillation and recurrent agents available is that there is a greater variety from which hemodynamically unstable ventricular tachycardia]. when to match an individual patient with a specific regimen and these have not responded to documented adequate doses of there are more choices from which to select an effective other adequate available antiarrhythmics or when alternative regimen that is well tolerated by the patient. It has recently agents could not be tolerated" (24). Because of its sub been emphasized (29) that the selection of an antiarrhythmic stantial toxicity, amiodarone should not be used for the regimen is more commonly based on consideration of tox treatment of ventricular premature complexes, even when icity profiles rather than on the relative efficacies of the these occur in repetitive forms. The efficacy of amiodarone various agents. It is now encumbent on us to develop rational in the treatment of sustained life-threatening ventricular ar and clinically useful approaches to the use of this larger rhythmias ishighly variable, ranging from 30t080%(25-28). number of antiarrhythmic agents (Table I). Controversy continues regarding the utility of electrophys The use of first generation antiarrhythmic drugs should iologic testing in evaluating amiodarone. Considerable re not be abandoned. Quinidine and procainarnide, in partic cent evidence suggests that it may be useful in identifying ular, are useful in the treatment of supraventricular arrhyth patients who will not have recurrent arrhythmia and those mias. and all of these agents are useful in the treatment of 462 HOROWITZ AND MORGANROTH lACC Vol. 9. No.2 EDITORIAL REVIEW February 1987:459-63

Table 1. Characteristics of Current Antiarrhythmic Agents*

Incidence of Efficacy Proarrhythmia (%)t Effect on Incidence of Significant Drug VPCs MVA LV Function VPCs MVA Noncardiac Side Effects (%)

Quinidine +++ ++ 0 3 7 25 Procainamide +++ ++ t 3 7 25 Disopyramide ++ ++ t t t 3 7 35 Tocainide ++ + 0 2 3 40 Mexiletine ++ + 0 2 3 40 Flecainide ++++ ++ t t

ventricular arrhythmias, both ventricular premature com patients be quantitatively evaluated and the patients be fol plexes and malignant or life-threatening ventricular arrhyth lowed closely. mias. The addition of the new agents allows better tailoring In this group of patients, the reported efficacy of class of antiarrhythmic regimens for individual patients. IA (quinidine-like) agents and class IC (flecainide-like) agents Patients with benign ventricular premature com is similar; however, class IB agents (mexiletine or tocainide) plexes or potentially lethal ventricular arrhythmias (30). are less often effective alone. The selection of which agent In these patients antiarrhythmic regimens should be selected is the first choice for treatment requires weighing the risk after consideration of the goals of antiarrhythmic therapy, and benefit of a specific regimen in an individual patient. efficacy and toxicity of specific agents in this patient group The key is individualization of therapy. Quinidine or pro and the individual patient's previous drug history and clin cainamide is effective in approximately 25% of these pa ical status. In patients with few complicating factors, fle tients but each has frequent noncardiac toxic effects that cainide or encainide would be appropriate as a first choice may cause discontinuation of treatment in as many as one because of their higher efficacy and lower incidence of tox third of patients. Flecainide and encainide, similarly, are icity. In patients with conduction disturbances, quinidine or effective in 25% of patients in this group but have a greater procainamide might be better initial choices. In patients with proarrhythmic potential, and flecainide can worsen left ven severely depressed left ventricular function or severe tricular function. In patients with left ventricular dysfunction congestive heart failure, the choice of an agent that has and congestive heart failure or severe conduction distur minimal or only modest negative inotropic potential, such bance, quinidine and procainamide should be evaluated ini as encainide, tocainide, mexiletine or quinidine, would be tially. Adjunctive use of mexiletine or tocainide augments appropriate. Subsequent choices should be based on the efficacy with these agents and should also be considered. patient's response, particularly side effects, to previously Even in patients with malignant ventricular arrhythmias evaluated drugs. Thus, for patients with ventricular pre without complicating heart failure or conduction abnor mature complexes, therapy should be guided by a consid malities, ftecainide and encainide should not be considered eration of the adverse effects of the available agents and the initially because of their probably higher proarrhythmic po appropriate selection of initial therapy can be made by a tential. Particularly in patients with severe heart failure, knowledge of the patient's clinical status and the effects of encainide should be used before ftecainide. Clinical judg the antiarrhythmic drugs. ment is required in making the initial choice in therapy for Patients with life-threatening or malignant ventricu these highest risk patients, and one must weigh the clinical lar arrhythmias. In these patients the complicating car toxicity of the quinidine-like and lidocaine-like drugs against diovascular factors are usually many. Most of these patients the probably higher potential of proarrhythmia of encainide have left ventricular dysfunction and conduction distur and ftecainide and heart failure of ftecainide. The approach bances and the use of concomitant medications is common. in using this larger array of drugs should not be hierarchical. Because of the severity of the arrhythmia, no argument The choice of ftecainide for initial therapy does not mean exists regarding whether these patients should be treated. that a first generation agent will not be effective if ftecainide Whether they are evaluated by noninvasive or invasive tech proves unsuitable and vice versa. niques, it is critical that the antiarrhythmic regimens in such Before initiating amiodarone therapy in patients with ma- lACC Vol. 9, No.2 HOROWITZ ANDMORGANROTH 463 February 1987:459~63 EDITORIAL REVIEW

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