Flecainide

Flecainide and propafenone are effective in suppressing both ventricular and supraventricular tachyarrhythmias, but their efficacy is often limited by dose-related side effects. This study was performed to evaluate noninvasively the effects of intravenous flecainide and propafenone on left ventricular systolic function indices in a selected population of 40 subjects (28 men and 12 women; mean age, 25 years) with normal cardiac structure and performance. Echocardiographic indexes of global systolic pump function (ejection fraction [EF] and percentage of fractional shortening [percent FS]) as well as monodimensional parameters of the interventricular septum (IVS) and left ventricular posterior wall (PW) contractility (percent systolic thickening [percent th] and systolic excursion [ex]) were assessed in all subjects at baseline, immediately after, and in the early recovery (15 min) after randomized injection of either flecainide or propafenone. Heart rate and blood pressure did not significantly change after both drugs. A significant increase (p<0.001) in left ventricular systolic internal diameter was observed after both flecainide and propafenone; simultaneously a significant decrease of percent FS (p<0.001), EF (p<0.001), PW percent thickening (th) (p<0.001), and PWex (p<0.001 after flecainide and p<0.01 after propafenone) was recorded. These changes were comparable and promptly reversible. In analyzing individual data, a marked systolic dysfunction was observed in two patients after intravenous flecainide (percent FS from 37 percent to 17 percent and from 42 percent to 13 percent; EF from 55 percent to 40 percent and from 65 percent to 35 percent, respectively) and in one patient after intravenous propafenone (percent FS from 30 percent to 15 percent; EF from 58 percent to 35 percent). We conclude that both intravenous flecainide and propafenone exhibit mild negative inotropic effects leading to a moderate and reversible reduction of left ventricular systolic performance; however, in some cases, a dramatic impairment of systolic pump function may occur, suggesting careful use of both drugs as first-line agents also in normal subjects; finally, the true incidence of this deleterious effect is still unknown.

Both flecainide acetate and propafenone are class 1C antiarrhythmic agents that are effective in the management of ventricular and superventricular tachyarrhythmias.[1-11] However, their efficacy, like that of other antiarrhythmic agents, is often limited by dose-related side effects. The proarrhythmic effects of flecainide are well known,[12] as demonstrated by the possibility to increase the arrhythmic deaths in patients with ventricular ectopy and ischemic heart disease (Cardiac Arrhythmic Suppressor Trial).[13] In addition to the proarrhythmic effects, flecainide has been shown to induce a slightly negative inotropic effect on the left ventricle[14] that becomes clinically significant in patients with compromised ventricular function.[15] Even if the risk of this latter significant adverse effect appears to be small, it is not negligible; for example, Haissaguerre et al[16] noted new-onset congestive heart failure in their overall experience with flecainide; similarly, in a recent editorial comment, Benditt et al[17] outlined that the adverse effects of flecainide are becoming increasingly apparent.

Propafenone is a recently released antiarrhythmic drug that shares many clinical characteristics with flecainide. The overall incidence of cardiovascular side effects during propafenone therapy has been reported to be approximately 13 percent.[18] These cardiac side effects usually occur in patients with advanced heart disease, and they appear to be dose dependent. Thus, like flecainide, propafenone requires close monitoring of left ventricular function in patients with congestive heart failure, particularly during the first weeks of therapy.[19] The present study was designed to compare the inotropic effects of intravenously administered flecainide and propafenone on left ventricular systolic function, noninvasively assessed by two-dimensional echocardiography. The study was performed in a selected population of 40 subjects with normal cardiac structure and performance at rest, the majority of whom required antiarrhythmic therapy because of superventricular tacharrhythmias.

MATERIAL AND METHODS

Patients

The studied population consisted of 40 nonconsecutive patients (28 men and 12 women whose range in age varied from 17 to 56 years; mean age, 25 years) selected from those referred to our department between September 1989 and March 1991 because of recurrent episodes of symptomatic paroxysmal tachycardias. Inclusion criteria were the absence of structural heart disease as assessed by clinical and instrumental (12-lead ECG, two-dimensional and Doppler echocardiography, chest radiograph) examination and the presence of adequate echocardiographic recordings. No patient had clinical history of essential hypertension or coronary artery disease; in addition, in the oldest patients (8 men older than 40 years and 2 women older than 45 years), thallium-201 exercise myocardial scintigraphy did not detect any perfusion defect. All patients underwent an electrophysiologic study: 14 patients had an atrioventricular reentry tachycardia due to accessory pathway; 34 had an atrioventricular nodal reentry tachycardia, 1 had an ectopic atrial tachycardia, and the last 1 had a benign ventricular tachycardia.

Treatment with all previous antiarrhythmic agents was discontinued for at least five half-lives. The nature of the procedure was explained and informed consent was obtained.

Echocardiographic Study

Baseline echocardiographic examination was performed in the standard manner by means of a phased array system (HP 770 20 AC), with a 2.5 or 3.5 MHz transducer. Parasternal short axis view at the midventricular level was used to obtain left ventricular end-diastolic (LVIDd) and end-systolic dimension (LVIDs) as well as diastolic and systolic thickness of the interventricular septum (IVS) and left ventricular posterior wall (PW), according to the American Society of Echocardiography recommendations.[20] The left ventricle was also visualized in a standardized short-axis scan at various levels between the base and apex, in the four-chamber and two-chamber apical view, to assess qualitatively the regional contractility. During the test, the different myocardial regions were identified by moving the transducer through various positions rapidly. The systolic contractility of the IVS and left ventricular PW was quantified by M-mode assessment of both percent systolic thickening (percent th) and systolic excursion (ex); percent fractional shortening of left ventricle (percent FS) and ejection fraction (EF), calculated by ellipse biplane method, were assumed as indices of overall systolic left ventricular pump function.

Echocardiograms were analyzed independently by two experienced observers who were blinded to the drug given to the patients. All measurements were expressed as mean value of at least three cardiac cycles. Intraobserver and interobserver agreements about M-mode and two-dimensional measurements were 92 percent and 88 percent, respectively. [TABULAR DATA OMITTED]

Treatment Protocol

Once the baseline studies were completed, all patients were randomized in a single-blind fashion to receive either flecainide or propafenone as first drug; they were then crossed over to the other agent after a 48-h drug-free period. Flecainide (2 mg/kg) and propafenone (2 mg/kg) were injected intravenously at a constant rate during 10 min. Both ECG and echocardiogram were continuously recorded. In addition, systemic arterial pressure was monitored in all patients by means of a standard sphygmomanometer. Echocardiographic measurements were made at baseline, immediately after the infusion, and in the early (15 min) and late (30 min) recovery phase.

Statistical Analysis

All values are expressed as mean values [+ or -] SD. Student's t test for paired and unpaired (when indicated) samples was performed to compare the data. A p<0.05 was considered significant.

RESULTS

No significant changes in heart rate were observed after injection of both drugs. Systolic blood pressure showed a slight but not significant decrease after both flecainide (from 115 [+ or -] 15 to 105 [+ or -] 10 mm Hg) and propafenone (from 110 [+ or -] 17 to 105 [+ or -] 12 mm Hg).

Mean values of echocardiographic parameters before and after injection of both flecainide and propafenone after both flecainide and propafenone; vice versa, both drugs induced a significant increase of LVIDs. A significant reduction of both indices of global systolic pump function, EF and percentage of FS, was observed after flecainide and propafenone (Table 1). Two-dimensional images of the left ventricle at peak of drug injections clearly demonstrated a uniformly distributed depression of ventricular function, which may be quantified in a fall of about 12 percent in the EF and 25 percent in FS after both drugs.

The percentage of systolic th of the left ventricular PW showed a decrease of about 27 percent after flecainide and of 23 percent after propafenone, while its systolic ex was reduced to 32 percent after flecainide and to 25 percent after propafenone.

The systolic ex of the interventricular septum fell significantly (25 percent after flecainide and propafenone); also, the IVS systolic th showed a trend toward a decrease after injection of drugs, without reaching significant values.

The hemodynamic changes induced by flecainide and propafenone on left ventricular systolic function were comparable and promptly reversible within 15 min. In analyzing the individual data, we observed dramatic impairment of systolic function in two patients after flecainide (a 23-year-old woman and a 20-year-old man): percentage of FS fell from 30 percent to 17 percent in one patient (Fig 1A) and from 35 percent to 13 percent in the other (Fig 1B) and EF from 55 percent to 40 percent and from 65 percent to 35 percent, respectively. Similarly, a marked negative inotropic effect was observed after propafenone in one patient (male, 26 years old) in whom percentage of FS decreased from 30 percent to 15 percent and EF from 58 percent to 35 percent (Fig 2A). In these three patients, dyspnea occurred at the end of the injection. It is of interest to note that after crossing these three patients over the other drug (propafenone and flecainide, respectively) the changes in systolic pump function indices were similar to those detected in the whole study group (Fig 2B).

Finally, in the patient with propafenone-induced systolic dysfunction, blood

pressure decreased from 105/75 mm Hg to 85/70 mm Hg while in the other two patients with flecainide-induced systolic dysfunction, the BP remained unchanged.

In these three patients, the family and clinical history were unremarkable; laboratory findings were all normal (including thyroid hormone profile); two of three patients had episodes of supraventricular tachycardia while the other one had brief runs of benign ventricular tachycardia (Fig 1B).

DISCUSSION

In agreement with previous observations,[14,15,21-23] our study confirms that flecainide induces a negative inotropic effect leading to a moderate and reversible impairment of left ventricular systolic performance; comparable effects were induced by propafenone and it appears to be interesting because controversial data still exist about the inotropic properties of propafenone.

In particular, negative inotropic effects of high concentrations of propafenone have been recognized in vitro[24] as well as in animal studies,[25] in addition, clinical studies have demonstrated a reduction of EF by oral propafenone in patients with either minimally decreased[26] or clearly impaired ventricular function.[27] However, other clinical studies[28,29] on propafenone have found no further decrease in EF in patients whose initial systolic pump function had been impaired.

Two observations should be emphasized in our experience. First, there are no significant differences in the negative inotropic effects of flecainide and propafenone on left ventricular systolic pump function. Second, both drugs are able to induce a severe albeit promptly reversible impairment of systolic function in some young and healthy patients with otherwise normal ventricles.

The latter effect does not appear to be dose related; therefore, we believe that this may be considered a serious and unpredictable hemodynamic adverse effect of both flecainide and propafenone. It is important to outline that in the two patients with flecainide-induced dramatic impairment of systolic function, propafenone caused only minor hemodynamic changes, comparable to those observed in all the remaining patients. On the other hand, similar findings were observed after flecainide in the patient with propafenone-induced marked systolic dysfunction. This observation permits us to rule out the presence of an underlying subclinical cardiomyopathy as a cause of the left ventricular functional alterations observed in these patients, although we cannot definitely exclude this condition because a myocardial biopsy was not performed. However, the complete absence of abnormalities in clinical and instrumental examination as well as the different responses observed in the same patient after flecainide and propafenone may suggest that the drug by itself is responsible for the observed effects. It may be hypothesized that, like the well-known proarrhythmic effect[12,13] observed in some otherwise healthy subjects, flecainide and propafenone exhibit a primary adverse hemodynamic effect in some subjects with normal cardiac anatomy and contractility, leading to severe and dramatic depression of left ventricular pump function.

The results of our study further support previous clinical observations of new-onset congestive heart failure by Haissaguerre et al[16] in their overall experience with flecainide. In addition, in a recent editorial on the implications of CAST, Gottlieb[30] suggests that type 1 antiarrhythmic agents like flecainide may actually have important adverse hemodynamic effects in patients with heart failure and that these effects may not be appreciated because during long-term oral administration, the clinical deterioration may be misinterpreted as a worsening of the underlying disease.

Our disquieting observations mandate that these agents be cautiously injected as first-line agents not only in patients with heart failure, but also in subjects without clinical evidence of left ventricular impairment.

A limitation of this study is the relatively small number of subjects that does not allow us to draw a definitive conclusion about the true incidence of this phenomenon. Further studies are needed to elucidate the incidence, time course, and physiopathologic mechanisms of such alterations because even a rare but severe adverse reaction in a set of young patients without clinically underlying structural heart disease is dramatic.

Thus, we believe that more knowledge of these new and incompletely defined antiarrhythmic class 1C drugs is needed before they are widely accepted for clinical use.

CONCLUSIONS

Intravenous flecainide and propafenone exhibit mildly negative inotropic effects in subjects with normal ventricles. The negative inotropic effects of the two drugs are comparable. Both flecainide and propafenone may sometimes cause a dramatic but promptly reversible impairment of systolic pump function; thus, cautious intravenous use of both drugs is desirable as first-line agents also in subjects with normal cardiac function.

REFERENCE

[1] Anderson JL, Stewart JR, Perry BA, Van Hamersveld DD, Johnson TA, Conard GJ, et al. Oral flecainide acetate for the treatment of ventricular arrhythmias. N Engl J Med 1981; 305:473-77

[2] Duff HJ, Roden DM, Maffucci RJ, Vesper BS, Conard GJ, Higgins SB, et al. Suppression of resistant ventricular arrhythmias by twice daily dosing of flecainide. Am J Cardiol 1981; 48:1133-40

[3] Neuss H. Long term use of flecainide in patients wih supraventricular tachycardia. Drugs 1985; 29(suppl 4):21-5

[4] Kimm SS, Lal R, Ruffy R. Treatment of paroxysmal reentrant supraventricular tachycardia with flecainide acetate. Am J Cardiol 1986; 58:80-5

[5] Crozier IG, Ikram H, Kenealy M, Levy L. Flecainide acetate for conversion of supraventricular tachycardia to sinus rhythm. Am J Cardiol 1987; 59:607-09

[6] Henthorn RW, Waldo AL, Anderson JL, Gilbert EM, Alpart BL, Bhandary AK, et al. Flecainide acetate prevents recurrence of symptomatic paroxysmal supraventricular tachycardia. Circulation 1991; 83:119-25

[7] Singh BN, Kaplinsky E, Kirsten E, Guerrero J. Effects of propafenone on ventricular arrhythmias: double-blind, parallel, randomized, placebo-controlled dose-ranging study. Am Heart J 1988; 116:1542-51

[8] Hartel G. Efficacy of oral propafenone on chronic ventricular arrhythmias: a placebo controlled cross-over exercise study. Fur Heart J 1985; 6:123-29

[9] Hammill SC, McLaren CJ, Wood DL, Osborn MJ, Gersh BJ, Holmes DR. Double blind study of intravenous propafenone for paroxysmal supraventricular reentrant tachycardia. J Am Coll Cardiol 1987; 9:1364-68

[10] Coumel P, Leclercq JF, Assayag P. European experience with the antiarrhythmic efficacy of propafenone for supraventricular and ventricular arrhythmias. Am J Cardiol 1984; 54:60D-6D

[11] Kerr CR, Klein GJ, Axelson JE, Cooper JC. Propafenone for prevention of recurrent atrial fibrillation. Am J Cardiol 1988; 61:914-16

[12] Monganroth J, Horowitz LN. Flecainide: its proarrhythmic effect and expected changes on the surface electrocardiogram. Am J Cardiol 1984; 53:89B-94B

[13] 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

[14] Serruys PW, Vanhaleweyk G, Van der Brand M, Verdouw P, Lubsen J, Hugenholtz PG. The haemodynamic effect of intravenous flecainide acetate in patients with coronary artery disease. Br J Clin Pharmacol 1983; 16:51-9

[15] Josephson MA, Ikeda N, Singh BH. Effects of flecainide on ventricular function: clinical and experimental correlations. Am J Cardiol 1984; 53:95B-100B

[16] Haissaguerre M, Warin JF, Benchimal D, Le Matayer P, Regandia JJ, Blanchot P. La flecainide oral dans le traitement des arythimies rebelles: suivi a long term de 98 patients. Arch Mal Coeur 1987; 80:357-63

[17] Benditt DG, Dunningam A, Buetikofer J, Milstein S. Flecainide acetate for long term prevention of paroxysmal supraventricular tachyarrhythmias. Circulation 1991; 83:345-49

[18] Shlepper M. Propafenone: a review of its profile. Eur Heart J 1987; suppl A:27-32

[19] Funck-Brentano C, Kroemer HK, Lee JJ, Roden DM. Propafenone. N Engl J Med 1990; 22:518-25

[20] Sahn DJ, De Maria A, Kisslo J, Weyman A. The Committee on M-mode Standardization of the American Society of Echocardiography. Recommendations regarding quantitation of M-mode echocardiography: results of a series of echocardiographic measurements. Circulation 1978; 58:1072-83

[21] Legrand V, Vandormael M, Collignon P, Kulbertus HE. Hemodynamic Effects of a new antiarrhythmic agent, flecainide (R-818), in coronary heart disease. Am J Cardiol 1983; 51:422-26

[22] Jackson NC, Verma SP, Silke B, Nelson GIC, Hussain M, Taylor SN. Hemodynamic effects of flecainide in acute myocardial infarction (MI) [abstract]. Eur Heart J 1984; 5:289

[23] Silke B, Verma SP, Nelson GIC, Hussain M, Taylor SK. Haemodynamic effects of infused flecainide acetate in myocardial infarction. Eur Heart J 1984; 5(B):113

[24] Haefeli W, Vozeh S, Ha HR, Oti K, Follath F. Pharmacological activity of 5-hydroxypropafenone, a major metabolite of propafenone in man [abstract]. Clin Res 1988; 36:364A

[25] Katagueuztan HS, Katoh T, McCullen A, Mandel WJ, Peter T. Electrophysiologic and hemodynamic effects of propafenone: a new antiarrhythmic agent on the anesthetized, closed chest dog: comparative study with lidocaine. Am Heart J 1984; 107:418-24

[26] 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 1984; 53:77-83

[27] Dinh H, Baker BJ, de Soyza N, Murphy ML. Sustained therapeutic efficacy and safety of oral propafenone for treatment of chronic ventricular arrhythmias: a two-year experience. Am Heart J 1988; 115:92-6

[28] Baker BJ, Dinh H, Kroskey D, de Soyza ND, Murphy ML, Franciosa JA. Effect of propafenone on left ventricular ejection fraction. Am J Cardiol 1984; 54:20D-2D

[29] Brodsky MA, Allen BJ, Abate D, Henry WL. Propafenone therapy for ventricular tachycardia in the setting of congestive heart failure. Am Heart J 1985; 110:794-99

[30] Gottlieb SS. The use of antiarrhythmic agents in heart failure: implications of CAST. Am Heart J 1989; 118:1074-77

COPYRIGHT 1993 American College of Chest Physicians
COPYRIGHT 2004 Gale Group