Propafenone for the Treatment of Refractory Complex Ventricular Ectopie Activity

Propafenone for the Treatment of Refractory Complex Ventricular Ectopie Activity STEPHEN C. HAMMILL, M.D., F.A.C.C, PATRICIA B. SORENSON, R.N., DOUGLAS L. WOOD, M.D., F.A.C.C, Division of Cardiovascular Diseases and Internal Medicine; DECLAIM D. SUGRUE, M.D., M.Sc, M.R.C.P., Resident in Cardiology*; MICHAEL J. OSBORN, M.D., F.A.C.C, BERNARD J. GERSH, M.B.,Ch.B., D.Phil., F.A.C.C, DAVID R. HOLMES, Jr., M.D., F.A.C.C, Division of Cardiovascular Diseases and Internal Medicine The results of therapy with propafenone were evaluated in 45 patients with complex ventricular ectopie activity that had been refractory to a mean of 3.8 antiarrhythmic drugs. The cardiac diagnoses were ischemie heart disease (in 16 patients), cardiomyopathy (in 7), mitral valve prolapse (in 7), idiopathic ventricular ectopie beats (in 6), valvular heart disease (in 5), and hypertension (in 4). The frequency of ventricular ectopie beats was established after therapy with antiarrhythmic agents had been discontinued. Patients then received propafenone during a dose-ranging protocol. An effective response was defined as a reduction in total ventricular ectopie beats of 80% or more. During dose ranging, therapy failed in four patients because of side effects, in eight because of a reduction in ventricular ectopie beats of less than 80%, and in three because of an aggravation of the arrhythmia. Thirty patients had a reduction in total ventricular ectopie beats of 80% or more. During a mean follow-up of 12.4 months, therapy failed in 1 patient because of sustained ventricular tachycardia and in 7 because of intolerable side effects; 22 patients continued to receive propafenone. PR and QRS intervals were significantly prolonged (P = 0.001 ), but the corrected QT interval and the heart rate were unchanged. The mean trough plasma level of propafenone associated with an effective response was 756 ng/ml, and that associated with intolerable side effects was 920 ng/ml. Thus, in patients with refractory complex ventricular ectopie beats, propafenone was effective and well tolerated initially in 67% of patients and during long-term administration in 49%, and toxicity was minor in most patients. Suppression of complex ventricular ectopie beats in patients with a history of recurrent ventricular tachycardia or ventricular fibrillation could potentially prevent sudden cardiac death. 1 No ideal antiarrhythmic drug has been identified; antiarrhythmic agents that are currently available have major disadvantages such as a high incidence of side effects and an unacceptable frequency of therapeutic failures. Consequently, new antiarrhythmic drugs are being developed and investigated in an attempt to find an agent that is effective, well tolerated, and not associated with serious side effects. Propafenone is a unique antiarrhythmic drug with local anesthetic (class *Mayo Graduate School of Medicine, Rochester, Minnesota. Address reprint requests to Dr. S. C. Hammill, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, MN 5590S. IC) and ß-adrenoreeeptor blocking effects that has been evaluated in Europe and is currently being investigated in the United States. In this article, we review our experience with the use of propafenone in patients with complex ventricular ectopie activity that was previously refractory to antiarrhythmic drugs. PATIENTS AND METHODS Patient Population. We examined 45 patients (34 men and 11 women) who were referred to our institution for control of ventricular arrhythmias that had been refractory to antiarrhythmic therapy. The mean age of the patients was 60 years (range, 34 to 86 years). The left ventricular ejection fraction was 40% or more in all the patients. All but 6 of the 45 patients had a cardiac abnormality: ischemie heart disease in 16, cardiomyop- Mayo Clin Proc 61:98-103, 1986 98

Mayo Clin Proc, February 1986, Vol 61 PROPAFENONE FOR REFRACTORY VENTRICULAR ECTOPIC BEATS 99 athy in 7, mitral valve prolapse in 7, valvular heart disease in 5, and hypertension in 4. Primary symptoms associated with the arrhythmia included intolerable palpitations in 15 patients, syncope in 10, near-syncope in 7, and light-headedness in 6; 7 of the patients were asymptomatic. Previous treatment had been attempted with a mean of 3.8 antiarrhythmic agents (range, 2 to 8 agents) that either were ineffective in controlling the ventricular arrhythmia or were poorly tolerated. Previous antiarrhythmic drugs were deemed ineffective only if the ventricular arrhythmia persisted even though "therapeutic" blood levels were present or the patient had been treated by the referring physician with adequate therapeutic doses. Previously, therapeutic failures had been experienced with use of quinidine (in 43 patients), procainamide (in 41), ß-adrenoreceptor blocking agents (in 36), disopyramide (in 26), mexiletine (in 12), lidocaine (in 9), phenytoin (in 2), and tocainide (in 1). Baseline 24-hour monitoring, after therapy with antiarrhythmic drugs had been discontinued for at least the duration of four half-lives before monitoring, demonstrated the following mean ventricular ectopie counts per 24 hours: total ventricular ectopie beats, 13,989 (range, 463 to 49,053); paired ventricular ectopie beats, 1,321 (range, 0 to 15,488); and runs (three or more beats) of ventricular tachycardia, 81 (range, 0 to 820, with 22 patients having at least one three-beat or longer run of ventricular tachycardia). The 24-hour recordings were quantified by using a reference laboratory (Cardio-Data Systems, Haddonfield, New Jersey). Dose-Ranging Protocol. After the baseline frequency of ventricular ectopie beats had been established, propafenone was administered in an initial dosage of 150 mg every 8 hours; this dosage was increased to 150 mg every 6 hours, 300 mg every 8 hours, or 300 mg every 6 hours, the chosen regimen depending on side effects and efficacy. An effective response was defined as an 80% or more reduction in total ventricular ectopie beats during a 24-hour recording period (compared with the baseline frequency) after achieving a steady state. 2 Trough and peak blood levels were determined when a dose was effective or associated with major side effects. At examination every 3 months, 24-hour ambulatory monitoring and electrocardiography were performed, and hématologie data, renal and hepatic function, and antinuclear antibodies were assessed to determine the continued effectiveness of the propafenone and the presence of toxicity. The baseline electrocardiographic intervals were hand measured at a paper speed of 25 mm/s. The corrected QT interval (QTc) was calculated by the following formula: QTc = QT/ VRR. Aggravation of arrhythmia was defined as a fourfold increase in the frequency of ventricular ectopie beats or the first emergenceof sustained ventricular tachycardia. 3 Statistical analysis was performed by using Student's two-tailed t test for paired data, and P<0.05 was accepted as the limit of significance. RESULTS Dose Ranging. During the dose-ranging protocol, propafenone was effective and well tolerated in 30 patients (Fig. 1). The drug was ineffective in eight patients, the arrhythmia was worse in three patients, and early toxicity occurred in four patients. Of the three patients whose complex ventricular ectopie activity became worse with use of propafenone, two experienced a 400% increase in the absolute number of ventricular ectopie beats and one had the onset of sustained ventricular tachycardia. During the dose-ranging protocol, the administration of propafenone was discontinued in four patients because of the following manifestations of toxicity: constipation, rash, nausea, and light-headedness; these symptoms resolved promptly after the propafenone therapy had been discontinued. Not effective 8 Ä Arrhythmia B^iär^ worse Effective ^^lillillilll^i'ï's^^^ toxicity response ^lilöw" ' "; / Fig. 1. Responses of 45 patients to propafenone during dose-ranging protocol. A response was considered effective if the patient had at least an 80% reduction in total ventricular ectopie beats (compared with the baseline frequency) during a 24-hour recording period. Worsening of arrhythmia was defined as a fourfold increase in frequency of ventricular ectopie beats or the first emergence of sustained ventricular tachycardia. The 30 patients who responded to propafenone (80% or more reduction in the total ventricular ectopie beats) had a substantial decrease in the frequency of ectopie beats (Fig. 2). The mean number of ventricular ectopie beats per 24 hours was reduced from a baseline value of 15,770 (range, 1,093 to 49,053) to 827 (95% reduction). The mean number of paired premature ventricular complexes per 24 hours was reduced from a baseline determination of 1,711 (range, 0 to 15,488) to 34 (98% reduction). Finally, the mean number of runs of ventricu-

100 PROPAFENONE FOR REFRACTORY VENTRICULAR ECTOPIC BEATS Mayo Clin Proc, February 1986, Vol 61 16000 Total PVCs Paired PVCs 1ΠΠ VT Runs 1600 12000 80 Mean 1200 60 m^ number per 24hrs 8000 800-40 4000 400 20 0 95% Baseline Propafeno ne 0 98% Baseline Propafenone 95% Baseline Propafenone Fig. 2. Reduction (%) in total and paired premature ventricular complexes (PVCs) and runs of ventricular tachycardia (VT) in 30 patients who responded to propafenone during dose-ranging protocol. lar tachycardia per 24 hours was reduced from a baseline 0.001), but it did not affect the heart rate (68 ± 11 versus value of 99 (range, 0 to 820) to 5 (95% reduction). 68 ± 10 beats/min) or the QTc interval (0.43 ± 0.03 Propafenone significantly prolonged the PR interval versus 0.44 ± 0.03 second) (Fig. 3). (0.17 ± 0.04 to 0.20 ± 0.03 second; P = 0.001) and the Theeffectivedailydoseof propafenone was 600 mg in QRS duration (0.10 ± 0.01 to 0.12 ± 0.02 second; P = 8 patients, 900 mg in 19 patients, and 1,200 mg in 3 Fig. 3. Effect of therapy on heart rate (HR) and electrocardiographic intervals in 30 patients who responded to propafenone during dose-ranging protocol. BPM = beats per minute; NS = not significant; QTc = corrected QT interval.

Mayo Clin Proc, February 1986, Vol 61 PROPAFENONE FOR REFRACTORY VENTRICULAR ECTOPIC BEATS 101 2000 1600 - Steady-state 1200 mean plasma concentration (ng/ml) 800 1 1 1 1 400-600 900 1200 (N = 40) (N = 26) (N = 4) Total daily propafenone dose (mg) Fig. 4. Mean steady-state plasma propafenone concentrations during dose ranging. Vertical lines denote standard deviations. patients. The mean trough plasma level of propafenone associated with an effective response was 756 ng/ml (range, 110 to 1,900 ng/ml). The mean plasma level of the drug associated with intolerable side effects was 920 ng/ml (range, 90 to 2,369 ng/ml). Total daily propafenone doses were associated with the following mean plasma levels: 600-mg dose, 490 ng/ml (range, 110 to 1,780 ng/ml); 900-mg dose, 1,098 ng/ml (range, 370 to 2,370 ng/ml); and 1,200-mg dose, 1,567 ng/ml (range, 1,300 to 1,790 ng/ml) (Fig. 4). Long-Term Follow-Up. During a mean follow-up of 12.4 months (range, 1 to 22 months) for the 30 patients who responded to propafenone during the dose-ranging protocol, the administration of propafenone was effective and well tolerated in 22 patients (73%), was discontinued'because of side effects in 7 patients (23%), and was discontinued because of the occurrence of ventricular tachycardia in 1 patient (4%) (Fig. 5). The side effects that necessitated discontinuation of therapy during follow-up were rash in two patients and weakness, ataxia, headache, light-headedness, and hyponatremia in one patient each. The patient with hyponatremia had a serum sodium concentration of 120 meq/liter, which promptly returned to normal after therapy with propafenone was discontinued. This patient was not subjected to a rechallenge trial with propafenone and was subsequently found to have the syndrome of inappropriate antidiuretic hormone secretion. Five patients described tolerable side effects and continued to receive medication; these side effects included rash that resolved spontaneously, constipation, and a metallic taste. All routine laboratory values remained unchanged except for the leukocyte count, which decreased significantly (6,800 ± 1,800 to 5,900 ± 1,500/mm 3 ; P = 0.002) at the time of administration of the maximal dosage and remained lowduringfollow-up(5,900 ± 1,400/mm 3 ata mean of 12.4 months). Effective and well-tolerated Stopped due to side effects Ventricular tachycardia Fig. 5. Results of long-term follow-up (mean, 12.4 months; range, 1 to 22 months) in 30 patients who responded to propafenone during dose-ranging protocol.

102 PROPAFENONE FOR REFRACTORY VENTRICULAR ECTOPIC BEATS Mayo Clin Proc, February 1986, Vol 61 DISCUSSION Clinical Efficacy. The results of this study demonstrate that propafenone is effective and well tolerated initially in 67% of patients and during long-term administration in 49% of patients. Podrid and Lown 4 evaluated the effectiveness of propafenone in 30 patients with sustained hemodynamically unstable ventricular tachyarrhythmia. Drug efficacy was determined on the basis of ambulatory electrocardiographic monitoring and exercise stress testing. Sixteen patients (53%) responded to propafenone therapy with a 99% decrease in couplets, the complete abolition of paroxysms of ventricular tachycardia, and a 93% reduction in the frequency of premature ventricular complexes. Kingma and associates 5 studied the effects of propafenone in 28 patients with either ventricular tachycardia or ventricular fibrillation by using invasive electrophysiologic testing. Intravenously administered propafenone was effective in preventing the induction of ventricular arrhythmias in 11 of 13 patients, and orally administered propafenone prevented the induction of the arrhythmia in 15 of 17 patients. Of 27 patients who were followed up, 25 remained free of arrhythmia during a mean interval of 6 months. In contrast, Prystowsky and associates 6 studied 26 patients who had inducible ventricular tachycardia in the electrophysiology laboratory, 21 of whom continued to have inducible tachycardia after therapy with orally administered propafenone. The propafenone was associated with a decrease in the rate of tachycardia, and 11 of 1 7 patients who received longterm treatment with propafenone remained free of tachycardia during a mean follow-up period of 11 months. Electrophysiologic and Antiarrhythmic Effects. Propafenone is a membrane-stabilizing or local anesthetic type of antiarrhythmic drug (class IC) with ß-adrenoreceptor blocking action and calcium antagonist activity. 7 " 10 The ß-adrenoreceptor blocking action is 40 times lower than that of propranolol; 9 however, the clinically effective plasma concentration of propafenone is at least 50 times higher than that of propranolol. 10 This difference suggests that the ß-adrenoreceptor action of propafenone is a substantial mechanism of the antiarrhythmic effect of the medication, but this theory must be evaluated further. We noted no change in the resting heart rate of patients after they had been given propafenone. The calcium antagonist activity of propafenone is weak approximately a hundredth the potential of verapamil. 8 Studies to date have not indicated that the calcium antagonist action of propafenone contributes substantially to the antiarrhythmic effects of the drug in the range of concentrations noted clinically. Pharmacokinetics. After oral administration of propafenone, maximal plasma concentrations occur between 2 and 3 hours, and the bioavailability is dose dependent. 11 ' 2 As observed in this study and by previous authors, 12 the relationship between the dose and the plasma levels is nonlinear a twofold increase in dose results in a threefold increase in the concentration of propafenone in plasma. The mean steady-state plasma propafenone levels obtained in this study are similar to the levels reported by Connolly and associates. 12 The drug is extensively metabolized in the liver by hydroxylation and conjugation, 13 and the major metabolite, 5-hydroxypropafenone, has an antiarrhythmic effect independent of the parent compound. 14 Patients are either extensive or poor metabolizers of propafenone; those who are poor metabolizers accumulate low concentrations of the metabolite and higher concentrations of propafenone, and those who are rapid metabolizers will have steady-state concentrations of 5-hydroxypropafenone that exceed those of propafenone. 13 The mean elimination half-life in normal volunteers is 2.5 hours (range, 2 to 4 hours), and that in patients with cardiac rhythm disturbances is 5 to 8 hours. 11 ' 3 Patients who are poor metabolizers of propafenone have an appreciably prolonged elimination half-life (up to 32 hours). 11 As demonstrated in this study, the blood level of propafenone that achieves a significant reduction in frequency of arrhythmia varies greatly. A satisfactory antiarrhythmic effect has been noted with a blood level as low as 60 ng/ml or as high as 3,200 ng/ml. 12 " 15 Thus, a therapeutic range cannot be delineated. Hemodynamic Effects. The effect of propafenone on left ventricular function was not assessed in this study because previous studies 4 ' 15,16 have demonstrated no clinically significant alteration of ejection fractions in patients with ejection fractions that exceeded 40%. No patient had symptoms that suggested a worsening of ventricular function. A decrease in ejection fraction of approximately 5% in patients with depressed left ventricular function has previously been associated with the use of propafenone. 2 ' 15 Side Effects. In our study, therapy with propafenone had to be discontinued because of side effects in 4 (9%) of the 45 patients during the initial dose-ranging protocol and in 7 (23%) of the 30 patients who underwent longterm follow-up. These rates are higher than those of previous reports, in which 2 to 10% of the patients had to discontinue therapy because of side effects. 17 The side effects were transient and reversible when the dose of propafenone was reduced or treatment was discontinued. The overall incidence of side effects from propafenone reported in the literature is 15 to 30% 4 ' 12 ' 15,17 and was 24% in our study.

Mayo Clin Proc, February 1986, Vol 61 PROPAFENONE FOR REFRACTORY VENTRICULAR ECTOPIC BEATS 103 CONCLUSION Propafenone is a new, unique antiarrhythmic drug of the local anesthetic type and, in addition, displays ß-adrenoreceptor blocking ability. The drug effectively reduces the frequency of complex ventricular ectopie beats and is not associated with serious side effects in most patients. Intolerable side effects resolve promptly after use of propafenone is discontinued. Arrhythmia was worsened in 3 (7%) of our 45 patients, an indication that drug efficacy should be established in patients who receive propafenone, as in those who receive other antiarrhythmic agents. REFERENCES 1. Craboys TB, Lown B, Podrid PJ, DeSilva R: Long-term survival of patients with malignant ventricular arrhythmia treated with antiarrhythmic drugs. Am ] Cardiol 50:437-443, 1982 2. Morganroth J, Michelson EL, Horowitz LN, Josephson ME, Pearlman AS, Dunkman WB: Limitations of routine long-term electrocardiographic monitoring to assess ventricular ectopie frequency. Circulation 58:408-414, 1978 3. Velebit V, Podrid P, Lown B, Cohen BH, Craboys TB: Aggravation and provocation of ventricular arrhythmias by antiarrhythmic drugs. Circulation 65:886-894, 1982 4. Podrid PJ, Lown B: Propafenone: a new agent for ventricular arrhythmia. J Am Coll Cardiol 4:117-125, 1984 5. Kingma H, Brugada P, PaulussenC, Wei lens HJJ: Intravenous and oral propafenone in patients with ventricular tachycardia or fibrillation (abstract). Circulation 70 Suppl 2:55, 1984 6. Prystowsky EN, Heger )J, Chilson DA, Miles WM, Hubbard J, Zipes DP: Antiarrhythmic and electrophysiologic effects of oral propafenone. Am ) Cardiol 54:26D-28D, 1984 7. Dukes ID, Vaughan Williams EM: The multiple modes of action of propafenone. Eur Heart) 5:115-125, 1984 8. Ledda F, Mantelli L, Manzini S, Amerini S, Mugelli A: Electrophysiological and antiarrhythmic properties of propafenone in isolated cardiac preparations. ) Cardiovasc Pharmacol 3:1162-1173, 1981 9. McLeod AA, Stiles GL, Shand DG: Demonstration of beta adrenoceptor blockade by propafenone hydrochloride: clinical pharmacologie, radioligand binding and adenylate cyclase activation studies. J Pharmacol Exp Ther 228:461-466, 1984 10. Müller-Peltzer H, Greger G, Neugebauer G, Hollmann M: Betablocking and electrophysiological effects of propafenone in volunteers. Eur) Clin Pharmacol 25:831-833, 1983 11. Siddoway LA, Roden DM, Woosley RL: Clinical pharmacology of propafenone: pharmacokinetics, metabolism and concentrationresponse relations. Am J Cardiol 54:9D-12D, 1984 12. Connolly S), Kates RE, Lebsack CS, Harrison DC, Winkle RA: Clinical pharmacology of propafenone. Circulation 68:589-596, 1983 13. Gill is AM, Kates RE: Clinical pharmacokinetics of the newer antiarrhythmic agents. Clin Pharmacokinet 9:375-403, 1984 14. Kretzschmar R, Gries ), Hofmann HP, Muller D, Philipsborn G, Raschack M, Teschendorf H): Pharmacological studies with 5-hydroxy-propafenone, an active metabolite of propafenone (abstract). Naunyn Schmiedebergs Arch Pharmacol 324 Suppl:R32, 1983 15. Salerno DM, Granrud G, Sharkey P, Asinger R, Hodges M: A controlled trial of propafenone for treatment of frequent and repetitive ventricular premature complexes. Am J Cardiol 53:77-83, 1984 16. Baker BJ, Dinh HA, Kroskey D, de Soyza NDB, Murphy ML, Franciosa JA: Effect of propafenone on left ventricular ejection fraction. Am J Cardiol 54:20D-22D, 1984 17. Seipel L, Breithardt G: Propafenone a new antiarrhythmic drug. Eur Heart J 1:309-313, 1980