Antiarrhythmic Drugs: Good for Premature Ventricular Complexes but Bad for Patients? ivi oricizine, a relatively new antiarrhythmic agent in the United States, was developed primarily because of its potent ability to suppress premature ventricular complexes (1). It shares these effects with other type IC antiarrhythmic agents such as encainide and flecainide. In this issue of Annals, two studies of the effects of moricizine in patients with sustained ventricular tachyarrhythmias are reported (2, 3). All but 1 of the 47 patients studied had sustained monomorphic ventricular tachycardia induced by electrophysiologic testing in the absence of antiarrhythmic drugs. Suppression of the inducible sustained ventricular tachycardia in response to moricizine was achieved in only three patients (6%). More striking was the high rate of exacerbation of the underlying arrhythmias: Eleven patients (23% overall) developed proarrhythmic responses, and relatively conservative definitions of this response were used. Similar effects have been noted in groups of patients studied with encainide and flecainide (4, 5). Some of the proarrhythmic responses observed in these patients seem very similar to the incessant, potentially lethal arrhythmias now well recognized to occur in some patients as a response to flecainide and encainide (6). Drugs like moricizine have in common the effect of 420
causing marked conduction slowing in all cardiac tissues while causing little alteration in refractoriness (7). Such conduction slowing may contribute to the initiation and maintenance of arrhythmias caused by reentry. Thus, facilitation of tachycardia induction by programmed stimulation and the occurrence of incessant tachycardias in response to agents causing marked conduction slowing is, in fact, not surprising in light of our knowledge of the characteristics of reentrant circuits causing sustained ventricular tachycardia in humans (810). Because of its ability to suppress premature ventricular complexes, moricizine, along with flecainide and encainide, was chosen by the National Institutes of Health to be tested in the Cardiac Arrhythmia Suppression Trial (CAST) (11). This study was designed to test the hypothesis that suppression of spontaneous ventricular premature complexes would reduce the risk for sudden death in survivors of acute myocardial infarction. In this trial, serial Holter monitors were used to judge the efficacy with which study drugs suppressed premature ventricular complexes. Seventy-five percent of the patients recruited demonstrated suppression and were randomly assigned to therapy with one of these
1 March 1992 • Annals of Internal Medicine • Volume 116 • Number 5
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agents or placebo. After an average follow-up of 10 months, patients treated with encainide or flecainide had a 3.6-fold increased risk for arrhythmic death compared with patients who received placebo. The placebo arm had an unexpectedly low arrhythmic event rate (1.2%), a finding that may be explained in part by the fact that the population tested was a relatively low risk group; only 48% had a left ventricular ejection fraction of less than 0.40, and only 20% had runs of nonsustained ventricular tachycardia on Holter monitoring. Therefore, in April 1989, the arm of the study involving encainide and flecainide was discontinued. Recently, the moricizine-placebo arm of the trial was discontinued when it became apparent that treatment with moricizine would not confer a survival advantage in comparison with the placebo. It is important to delineate what we have learned and have not learned from this trial. First, suppression of asymptomatic ventricular ectopy by a pharmacologic agent in a survivor of myocardial infarction does not indicate that this agent will reduce the risk for sudden cardiac death. Second, the CAST strategy of using Holter monitors to guide antiarrhythmic therapy will not reduce the risk for sudden cardiac death in survivors of myocardial infarction. However, it is inappropriate to conclude that the use of Holter monitors to identify high-risk patients after myocardial infarction is not justified. The CAST did not address this issue, and Holter monitoring remains an effective tool for risk stratification in patients who have had a myocardial infarction. The results of the CAST also do not prove that antiarrhythmic therapy in asymptomatic patients after myocardial infarction is not effective. For example, it is possible that if the same agents had been tested in the CAST population using an alternative method to judge the efficacy of therapy, such as electrophysiologic studies, evidence of inadequate drug effects would have been discovered in patients who subsequently developed sudden death. This trial also does not suggest that the agents tested cannot be used in patients with sustained ventricular tachyarrhythmias. Indeed, the two studies in this issue of Annals suggest that a small fraction of patients may benefit from therapy with agents such as moricizine when electrophysiologic testing is used to evaluate drug effects. Although there are many data documenting the ability of moricizine to suppress premature ventricular complexes, fewer data exist regarding the drug's effect on sustained ventricular tachyarrhythmias, especially when electrophysiologic studies are used to evaluate these effects. Therein lies the importance of the current studies (2, 3). Agents such as moricizine, which can effectively suppress spontaneous ventricular premature complexes, have a very low rate of preventing sustained ventricular tachycardia induction by electrophysiologic testing and a demonstrated inability to prevent sudden death after infarction when Holter monitoring is used to guide therapy. These facts suggest that 1) the mechanism underlying spontaneous ventricular premature complexes may be different from that causing sustained ventricular tachycardia in patients with chronic coronary artery disease and that 2) spontaneous ventricular
premature complexes are mechanistically unrelated to the ventricular tachyarrhythmias causing sudden cardiac death after myocardial infarction. What are the implications of the present studies and the CAST for the management of patients with ventricular arrhythmias today? First, the clinician must examine the indication for antiarrhythmic therapy. If the patient has a sustained tachyarrhythmia, treatment is usually indicated to relieve or eliminate symptoms. The next decision regards the type of therapy: pharmacologic or nonpharmacologic (catheter or surgical ablation, implanted antitachycardia device). The above studies provide further evidence of the potential risks of pharmacologic therapy. Finally, the clinician must decide what technique will be used to judge the efficacy of therapy. Electrophysiologic testing is probably the most reliable technique available today to evaluate the effect of pharmacologic and nonpharmacologic treatments for sustained arrhythmias that occur intermittently and unpredictably. However, the ESVEM trial (12), a randomized, controlled comparison of Holter monitoring and electrophysiologically guided therapy in patients with sustained ventricular tachyarrhythmias, is likely to provide the "final word" on this subject. The second potential indication for antiarrhythmic therapy is to reduce the risk for sudden cardiac death. In this case, the decision to treat must be based on knowledge of the degree of risk. Survivors of cardiac arrest are at especially high risk for recurrence (about 30% over 18 months), and treatment is clearly warranted for this reason. The patient who presents to the emergency room with sustained monomorphic ventricular tachycardia that has not precipitated a cardiac arrest is at a lower, but as yet undefined, risk for sudden death. It is also not yet known whether treatment prevents sudden death in such patients. The asymptomatic patient after acute myocardial infarction who has evidence of severe ventricular dysfunction (ejection fraction < 40%) remains at a relatively high risk for sudden cardiac death, and Holter monitoring is a valuable tool to identify a subgroup at significantly increased risk for sudden death (those patients with nonsustained ventricular tachycardia [5% to 10% yearly]). Whether current antiarrhythmic therapy will increase survival in such patients is the subject of several ongoing randomized, controlled trials evaluating the efficacy of electrophysiologic studies to guide both pharmacologic and nonpharmacologic therapy (implantable cardioverter-defibrillators). One must be careful in extrapolating the results of the present studies or CAST to other patient populations with different types of arrhythmias. For example, although little is known about the mechanisms causing sudden death in patients with cardiomyopathies, it is likely that they differ from those causing sudden death in patients with coronary artery disease. Thus, drugs that are generally ineffective or dangerous in patients with coronary disease may not prove to have the same properties in patients with nonischemic cardiomyopathies. Controlled trials addressing this question are desperately needed in these latter patients. Should moricizine and similar agents not be used by clinicians? I believe that in selected patients, when elec-
1 March 1992 • Annals of Internal Medicine • Volume 116 • Number 5 Downloaded from https://annals.org by Tulane University user on 01/17/2019
421
trophysiologic studies are used to test efficacy, drugs such as moricizine may be safe and occasionally effective. Flecainide and encainide are very effective against many types of supraventricular arrhythmias. Flecainide has recently been approved by the Food and Drug Administration for treatment of supraventricular arrhythmias in patients without structural heart disease. Moricizine too might prove to be a safe, effective agent for the treatment of supraventricular arrhythmias. For the present, these studies emphasize that all antiarrhythmic treatments have potentially serious risks and must be evaluated carefully in a controlled manner. As always, the treatment must be tailored to the individual patient to ensure that its risks do not exceed those of the underlying disease. Alfred E. Buxton, MD Hospital of the University of Pennsylvania and the University of Pennsylvania School of Medicine Philadelphia, PA 19104 Requests for Reprints: Alfred E. Buxton, MD, Cardiovascular Division, Hospital of the University of Pennsylvania, 9 Founders Pavilion, 3400 Spruce Street, Philadelphia, PA 19104.
Annals of Internal Medicine. 1992;116:420-422. References 1. The Cardiac Arrhythmia Pilot Study (CAPS) Investigators. Effects of encainide, flecainide, imipramine and moricizine on ventricular arrhythmias during the year after acute myocardial infarction. The CAPS. Am J Cardiol. 1988;61:501-9.
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of Internal
Medicine
2. Damle R, Levine J, Matos J, Greenberg S, Brooks R, Frumkin W, et al. Moricizine in inducible sustained ventricular tachycardia. Ann Intern Med. 1992;116:375-81. 3. Powell AC, Gold MR, Brooks K, Garan H, Ruskin JN, McGovern BA. Electrophysiologic response to moricizine in patients with sustained ventricular arrhythmias. Ann Intern Med. 1992;116:382-7. 4. Weintraub AR, Manolis AS, Estes NA. Electrophysiologic and electrocardiographic effects, efficacy and safety of encainide in malignant ventricular arrhythmias associated with coronary artery disease. Am J Cardiol. 1990;66:947-53. 5. Herre JM, Titus C, Oeff M, Eldar M, Franz MR, Griffin JC, et al. Inefficacy and proarrhythmic effects of flecainide and encainide for sustained ventricular tachycardia and ventricular fibrillation. Ann Intern Med. 1990;113:671-6. 6. Winkle RA, Mason JW, Griffin JC, Ross D. Malignant ventricular tachyarrhythmias associated with the use of encainide. Am Heart J. 1981;102:857-61. 7. Wyndham CR, Pratt CM, Mann DE, Winkle RA, Somberg J, De Maria AN, et al. Electrophysiology of ethmozine (Moricizine HC1) for ventricular tachcyardia. Am J Cardiol. 1987;60:67F-72F. 8. Almendral JM, Stamato NJ, Rosenthal ME, Marchlinski FE, Miller JM, Josephson ME. Resetting response patterns during sustained ventricular tachycardia: relationship to the excitable gap. Circulation. 1986;74:722-30. 9. Kay GN, Epstein AE, Plumb VI. Incidence of reentry with an excitable gap in ventricular tachycardia: a prospective evaluation utilizing transient entrainment. J Am Coll Cardiol. 1988;11:530-8. 10. Stamato NJ, Frame LH, Rosenthal ME, Almendral JM, Gottlieb CD, Josephson ME. Procainamide-induced slowing of ventricular tachcyardia with insights from analysis of resetting response patterns. Am J Cardiol. 1989;63:1455-61. 11. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: Effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med. 1989;321:406-12. 12. The ESVEM Investigators. The ESVEM Trial: Electrophysiologic study versus electrocardiographic monitoring for selection of antiarrhythmic therapy of ventricular tachyarrhythmias. Circulation. 1989;79:1354-60. © 1992 American College of Physicians
• Volume 116 • Number 5
Downloaded from https://annals.org by Tulane University user on 01/17/2019
causing marked conduction slowing in all cardiac tissues while causing little alteration in refractoriness (7). Such conduction slowing may contribute to the initiation and maintenance of arrhythmias caused by reentry. Thus, facilitation of tachycardia induction by programmed stimulation and the occurrence of incessant tachycardias in response to agents causing marked conduction slowing is, in fact, not surprising in light of our knowledge of the characteristics of reentrant circuits causing sustained ventricular tachycardia in humans (810). Because of its ability to suppress premature ventricular complexes, moricizine, along with flecainide and encainide, was chosen by the National Institutes of Health to be tested in the Cardiac Arrhythmia Suppression Trial (CAST) (11). This study was designed to test the hypothesis that suppression of spontaneous ventricular premature complexes would reduce the risk for sudden death in survivors of acute myocardial infarction. In this trial, serial Holter monitors were used to judge the efficacy with which study drugs suppressed premature ventricular complexes. Seventy-five percent of the patients recruited demonstrated suppression and were randomly assigned to therapy with one of these
1 March 1992 • Annals of Internal Medicine • Volume 116 • Number 5
Downloaded from https://annals.org by Tulane University user on 01/17/2019
agents or placebo. After an average follow-up of 10 months, patients treated with encainide or flecainide had a 3.6-fold increased risk for arrhythmic death compared with patients who received placebo. The placebo arm had an unexpectedly low arrhythmic event rate (1.2%), a finding that may be explained in part by the fact that the population tested was a relatively low risk group; only 48% had a left ventricular ejection fraction of less than 0.40, and only 20% had runs of nonsustained ventricular tachycardia on Holter monitoring. Therefore, in April 1989, the arm of the study involving encainide and flecainide was discontinued. Recently, the moricizine-placebo arm of the trial was discontinued when it became apparent that treatment with moricizine would not confer a survival advantage in comparison with the placebo. It is important to delineate what we have learned and have not learned from this trial. First, suppression of asymptomatic ventricular ectopy by a pharmacologic agent in a survivor of myocardial infarction does not indicate that this agent will reduce the risk for sudden cardiac death. Second, the CAST strategy of using Holter monitors to guide antiarrhythmic therapy will not reduce the risk for sudden cardiac death in survivors of myocardial infarction. However, it is inappropriate to conclude that the use of Holter monitors to identify high-risk patients after myocardial infarction is not justified. The CAST did not address this issue, and Holter monitoring remains an effective tool for risk stratification in patients who have had a myocardial infarction. The results of the CAST also do not prove that antiarrhythmic therapy in asymptomatic patients after myocardial infarction is not effective. For example, it is possible that if the same agents had been tested in the CAST population using an alternative method to judge the efficacy of therapy, such as electrophysiologic studies, evidence of inadequate drug effects would have been discovered in patients who subsequently developed sudden death. This trial also does not suggest that the agents tested cannot be used in patients with sustained ventricular tachyarrhythmias. Indeed, the two studies in this issue of Annals suggest that a small fraction of patients may benefit from therapy with agents such as moricizine when electrophysiologic testing is used to evaluate drug effects. Although there are many data documenting the ability of moricizine to suppress premature ventricular complexes, fewer data exist regarding the drug's effect on sustained ventricular tachyarrhythmias, especially when electrophysiologic studies are used to evaluate these effects. Therein lies the importance of the current studies (2, 3). Agents such as moricizine, which can effectively suppress spontaneous ventricular premature complexes, have a very low rate of preventing sustained ventricular tachycardia induction by electrophysiologic testing and a demonstrated inability to prevent sudden death after infarction when Holter monitoring is used to guide therapy. These facts suggest that 1) the mechanism underlying spontaneous ventricular premature complexes may be different from that causing sustained ventricular tachycardia in patients with chronic coronary artery disease and that 2) spontaneous ventricular
premature complexes are mechanistically unrelated to the ventricular tachyarrhythmias causing sudden cardiac death after myocardial infarction. What are the implications of the present studies and the CAST for the management of patients with ventricular arrhythmias today? First, the clinician must examine the indication for antiarrhythmic therapy. If the patient has a sustained tachyarrhythmia, treatment is usually indicated to relieve or eliminate symptoms. The next decision regards the type of therapy: pharmacologic or nonpharmacologic (catheter or surgical ablation, implanted antitachycardia device). The above studies provide further evidence of the potential risks of pharmacologic therapy. Finally, the clinician must decide what technique will be used to judge the efficacy of therapy. Electrophysiologic testing is probably the most reliable technique available today to evaluate the effect of pharmacologic and nonpharmacologic treatments for sustained arrhythmias that occur intermittently and unpredictably. However, the ESVEM trial (12), a randomized, controlled comparison of Holter monitoring and electrophysiologically guided therapy in patients with sustained ventricular tachyarrhythmias, is likely to provide the "final word" on this subject. The second potential indication for antiarrhythmic therapy is to reduce the risk for sudden cardiac death. In this case, the decision to treat must be based on knowledge of the degree of risk. Survivors of cardiac arrest are at especially high risk for recurrence (about 30% over 18 months), and treatment is clearly warranted for this reason. The patient who presents to the emergency room with sustained monomorphic ventricular tachycardia that has not precipitated a cardiac arrest is at a lower, but as yet undefined, risk for sudden death. It is also not yet known whether treatment prevents sudden death in such patients. The asymptomatic patient after acute myocardial infarction who has evidence of severe ventricular dysfunction (ejection fraction < 40%) remains at a relatively high risk for sudden cardiac death, and Holter monitoring is a valuable tool to identify a subgroup at significantly increased risk for sudden death (those patients with nonsustained ventricular tachycardia [5% to 10% yearly]). Whether current antiarrhythmic therapy will increase survival in such patients is the subject of several ongoing randomized, controlled trials evaluating the efficacy of electrophysiologic studies to guide both pharmacologic and nonpharmacologic therapy (implantable cardioverter-defibrillators). One must be careful in extrapolating the results of the present studies or CAST to other patient populations with different types of arrhythmias. For example, although little is known about the mechanisms causing sudden death in patients with cardiomyopathies, it is likely that they differ from those causing sudden death in patients with coronary artery disease. Thus, drugs that are generally ineffective or dangerous in patients with coronary disease may not prove to have the same properties in patients with nonischemic cardiomyopathies. Controlled trials addressing this question are desperately needed in these latter patients. Should moricizine and similar agents not be used by clinicians? I believe that in selected patients, when elec-
1 March 1992 • Annals of Internal Medicine • Volume 116 • Number 5 Downloaded from https://annals.org by Tulane University user on 01/17/2019
421
trophysiologic studies are used to test efficacy, drugs such as moricizine may be safe and occasionally effective. Flecainide and encainide are very effective against many types of supraventricular arrhythmias. Flecainide has recently been approved by the Food and Drug Administration for treatment of supraventricular arrhythmias in patients without structural heart disease. Moricizine too might prove to be a safe, effective agent for the treatment of supraventricular arrhythmias. For the present, these studies emphasize that all antiarrhythmic treatments have potentially serious risks and must be evaluated carefully in a controlled manner. As always, the treatment must be tailored to the individual patient to ensure that its risks do not exceed those of the underlying disease. Alfred E. Buxton, MD Hospital of the University of Pennsylvania and the University of Pennsylvania School of Medicine Philadelphia, PA 19104 Requests for Reprints: Alfred E. Buxton, MD, Cardiovascular Division, Hospital of the University of Pennsylvania, 9 Founders Pavilion, 3400 Spruce Street, Philadelphia, PA 19104.
Annals of Internal Medicine. 1992;116:420-422. References 1. The Cardiac Arrhythmia Pilot Study (CAPS) Investigators. Effects of encainide, flecainide, imipramine and moricizine on ventricular arrhythmias during the year after acute myocardial infarction. The CAPS. Am J Cardiol. 1988;61:501-9.
422
1 March 1992 • Annals
of Internal
Medicine
2. Damle R, Levine J, Matos J, Greenberg S, Brooks R, Frumkin W, et al. Moricizine in inducible sustained ventricular tachycardia. Ann Intern Med. 1992;116:375-81. 3. Powell AC, Gold MR, Brooks K, Garan H, Ruskin JN, McGovern BA. Electrophysiologic response to moricizine in patients with sustained ventricular arrhythmias. Ann Intern Med. 1992;116:382-7. 4. Weintraub AR, Manolis AS, Estes NA. Electrophysiologic and electrocardiographic effects, efficacy and safety of encainide in malignant ventricular arrhythmias associated with coronary artery disease. Am J Cardiol. 1990;66:947-53. 5. Herre JM, Titus C, Oeff M, Eldar M, Franz MR, Griffin JC, et al. Inefficacy and proarrhythmic effects of flecainide and encainide for sustained ventricular tachycardia and ventricular fibrillation. Ann Intern Med. 1990;113:671-6. 6. Winkle RA, Mason JW, Griffin JC, Ross D. Malignant ventricular tachyarrhythmias associated with the use of encainide. Am Heart J. 1981;102:857-61. 7. Wyndham CR, Pratt CM, Mann DE, Winkle RA, Somberg J, De Maria AN, et al. Electrophysiology of ethmozine (Moricizine HC1) for ventricular tachcyardia. Am J Cardiol. 1987;60:67F-72F. 8. Almendral JM, Stamato NJ, Rosenthal ME, Marchlinski FE, Miller JM, Josephson ME. Resetting response patterns during sustained ventricular tachycardia: relationship to the excitable gap. Circulation. 1986;74:722-30. 9. Kay GN, Epstein AE, Plumb VI. Incidence of reentry with an excitable gap in ventricular tachycardia: a prospective evaluation utilizing transient entrainment. J Am Coll Cardiol. 1988;11:530-8. 10. Stamato NJ, Frame LH, Rosenthal ME, Almendral JM, Gottlieb CD, Josephson ME. Procainamide-induced slowing of ventricular tachcyardia with insights from analysis of resetting response patterns. Am J Cardiol. 1989;63:1455-61. 11. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: Effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med. 1989;321:406-12. 12. The ESVEM Investigators. The ESVEM Trial: Electrophysiologic study versus electrocardiographic monitoring for selection of antiarrhythmic therapy of ventricular tachyarrhythmias. Circulation. 1989;79:1354-60. © 1992 American College of Physicians
• Volume 116 • Number 5
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