Flecainide: Long-term treatment using a reduced dosing schedule

Flecainide: Long-Term Treatment Using a Reduced Dosing Schedule

DAVID FLOWERS, MD, DEBORAH O’GALLAGHER, RN, VILMA TORRES, MD,

DENNIS MIURA, MD, PhD, and JOHN C. SOMBERG, MD

Flecainide was initially prescribed at a dose of 200 mg twice daily, but after early toxicity in patients with ventricular tachycardia (VT), the dosage was reduced to 100 mg twice daily. The effects of flecainide were studied In 40 patients (29 men and 11 women, mean age 62 f 2 years, ejection fraction 45 f 3%) who underwent programmed electrical stimulation to determine the efficacy of flecainide in preventing VT chronically at the reduced dose. Sustained VT was induced in 21 patients and nonsustained VT in 19. Flecainide prevented VT induction in 26 patients (65%). At a mean dose of 1.5 f 0.1 mg/kg, prolongation occurred in the effective refractory period of the first (260 f 5 vs 249 f 5 ms) and second (254 f 6 vs 209 f 9 ms) extrastimuli (p <O.Ol). In the patients protected by flecainide,

the effective refractory periods increased by a 17 f 2% and 21 f 3%, in contrast to only a 7 f 3% and 6 f 4% increase in the nonprotected group (p <0.05), despite a higher mean dose (1.9 f 0.1 vs 1.35 f 0.1 mg/kg). Twenty-one patients were discharged on flecainide therapy, 100 mg twice daily, and were followed for a mean of 11 months. Sixteen patients are alive and well, 1 died suddenly, 1 died from a noncardiac cause and 1 had a “breakthrough” arrhythmia. Two were switched to quinidine therapy by their referring physicians, but were without problems while receiving flecainide. Thus, flecainide therapy guided by programmed electrical stimulation is effective at a reduced dose.

(Am J Cardiol 1965;55:79-63)

Flecainide acetate is an investigational antiarrhythmic agent developed by Barnitt et a1.l The efficacy of flecainide for the control of ventricular premature con- tractions (VPCs) in outpatients has been reported.2-g Initial studies have demonstrated the use of flecainide in therapy guided by programmed electrical stimulation and have shown a correlation between acute drug testing with the intravenous form and subsequent protection from ventricular tachycardia (VT) in long-term fol- 10w-up.~~J~ In these clinical studies, a total daily oral dose of 300 to 600 mg has usually been given in a twice-daily regimen. Several recent reports have documented various toxic effects of flecainide, including death, that have occurred at these dosing schedules with serum levels ranging from 500 to 2,200 ng/m1.12-l5 Several investigators have suggested that a lower daily dose may be effective, while reducing the incidence of toxicity to a more acceptable level.15 Forty patients who

From the Cardiac Arrhythmia Service, Departments of Medicine and Pharmacology, Albert Einstein College of Medicine, Bronx, New York. Manuscript received June 25, 1984; revised manuscript received and accepted August 20, 1984.

Address for reprints: John C. Somberg, MD, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Room 208 Forchheimer Building, Bronx, New York 1046 1.

were referred to the cardiac arrhythmia service for PES-guided therapy because of VT underwent intravenous drug testing with flecainide. We report on the acute drug testing results and long-term follow-up using a reduced dosage regimen of 100 mg of flecainide administered twice daily.

Methods All the patients were admitted to the coronary care unit 36

to 48 hours before PES studies. A baseline electrocardiogram (ECG), Holter ECG, x-ray, urinalysis, hematologic studies and chemistry profiles were performed. Each patient gave in- formed consent and PES was performed after the patient had discontinued taking all antiarrhythmic drug treatment for at least 5 half-lives.

During all the PES studies, before and after drug administration, surface electrocardiographic leads I, II, aVF and V5 were continuously monitored, stored on 8-channel magnetic tape and printed on a polygraph recorder along with intracardiac recordings. These data were recorded using a Siemens Elema Mingograf at paper speeds of 25 and 100 mm/s during induction of VT. The intracardiac electrograms were filtered between 50 to 200. Hz and then amplified using a Bloom As- sociates amplifier.

After PES studies were complete, patients were observed in the coronary care unit for 48 hours and clinical laboratory

79

80 CHRONIC REDUCED DOSE FLECAINIDE

TABLE I Comparison of Electrophysiologic Measurements for All Patients Tested with Flecainide

Mean BP HR QRS QT s3

(mm W (beatsimin) (FE, (W (ms) 0-M

No therapy 94 f 3 76 f 3 169 f 5 94 f 4 366 f 7 249 f 5 208 f 9 Flecainide 91 f3 73 f 2 190 f 5” 100 f 4 400 f 7 280 f 5t 254 f 6t

(1.5 f 0.1 mg/kg)

Significant difference from the group off therapy: * p <0.05; t p <O.Ol. BP = blood pressure; HR = heart rate; Sp = shortest interval from end of the pacing train that the first extrastimulus causes a ventricular

depolarization; Ss = shortest interval between the first and second extrastimulus that causes a ventricular depolarization after the second extrastimulus.

tests, 12-lead ECGs and physical examinations were re- peated.

Flecainide was given intravenously by an intermittent bolus of 20 mg every 5 minutes to a dose of 1 mg/kg; the patient then underwent PES. If this dose was not protective, additional boluses were given to a total of 2 mg/kg and testing was re- peated. Heart rate, blood pressure, PR, QRS and QT intervals were measured every 5 minutes. Drug administration was terminated if severe nausea or hypotension developed or if QRS or QT intervals were prolonged more than 50% over baseline values. Plasma levels were determined immediately after the PES festing.

PES was performed using a hexapolar pacing catheter introduced through the right internal jugular vein to the apex of the right ventricle. In patients in whom VT could not be induced from the right ventricular apex, the catheter was re- positioned to the right ventricular outflow tract. A digital stimulator (Bloom Associates) was used to deliver square- wave electrical impulses of 2.0 ms in duration, with amplitude set at twice diastolic threshold. The right ventricle was driven with a pacing train of 6 beats at a cycle length of 500 ms, with an intertrain interval of 8 seconds.

Single premature ventricular stimuli (Sz) were delivered in late diastole starting at 500 ms from the end of the pacing train and progressively introduced earlier by 20-ms decrements. The shortest interval at which Sz evoked a depolarization was termed the refractory period. The stimulus was brought out 10 ms further from the end of the pacing train, then a second extrastimulus was introduced at the sum of the SlSl and SlSg intervals and introduced at 20-ms decrements. This programmed introduction of premature stimuli was performed until VT (10 or more beats) was obtained or until 4 premature stimuli were introduced.

Nonsustained VT was defined as at least 10 beats of VT that terminated spontaneously and sustained VT was defined as VT that lasted 30 seconds or required either pacing techniques or defibrillation for termination. A patient was considered protected if 4 stimuli failed to induce more than 3 ventricular beats beyond the last extrastimulus.

Patients: Forty patients underwent electrophysiologic testing to determine if flecainide acetate was an effective antiarrhythmic agent. Twenty-nine were men and 11 were women, mean age 61 f 2 years. The mean nuclear ejection fraction as determined by nuclear ventriculography performed before flecainide loading was 45 f 3% (range 25 to 79%). Seven patients presented with a cardiac arrest, 1 patient had syncope with suspected VT as a cause (although not documented on Holter), 20 patients had symptomatic VT (VT associated with syncope, confusion, dizziness, angina or symptoms of congestive heart failure causing presentation at a hospital), and 12 had asymptomatic, nonsustained VT documented on the Holter monitoring. Twenty-nine patients had coronary artery disease, 1 patient had mitral valve prolapse, 2 had dilated cardiomyopathy, and 8 had no apparent structural heart disease detected by routine screening studies. They had failed an average of 1.9 f 0.2 drugs clinically before being referred

to the electrophysiology laboratory, although usually they had received low doses of conventional agents.

Statistical methods: Values are presented as the mean f the standard error of the mean and were compared using a l-way analysis of variance for groups and Dunnett’s test to differentiate individual means. A Student t test was used to compare values between 2 samples; results were considered significant at the p <0.05 level.

Results Acute electrophysiologic data: Twenty-one pa-

tients had sustained VT and 19 had nonsustained VT provoked during the control electrophysiologic study. Sustained VT was terminated by pacing in 40% of patients and by electrical cardioversion in 60%. Of the total group of 40 patients tested, 26 (65%) were protected by flecainide and in 14 (35%), VT was inducible despite the drug treatment. The electrophysiologic findings are listed in Table I. Patients were given a mean dose of 1.5 f 0.1 mg/kg of flecainide, which resulted in a plasma level of 230 f 20 rig/ml. There was a 12% increase in the PR interval (p <0.05) and a 12% and 22% increase in the refractory periods of the first and second extrastimuli, respectively (p <O.Ol) for all 40 patients tested. Com- paring the percent change in refractory periods while receiving the antiarrhythmic agent to the initial de- termination for each patient, flecainide caused a significant increase in the refractory period of the first and second extrastimuli for the protected patients (17 f 2% and 21 f 3%), in contrast to only a 7 f 3% and 6 f 4% increase in the nonprotected patients (p <0.05), despite a higher mean dose (1.9 f 0.1 nonprotected vs 1.35 L 0.1 mg/kg protected).

Of the 7 patients who presented with a cardiac arrest, 6 (85%) were protected by flecainide and 4 (57%) by procainamide therapy. Sixty-five percent. of the patients with symptomatic VT were protected by flecainide and the same number by procainamide therapy. Forty-eight percent of the patients with asymptomatic VT were protected by flecainide at acute drug testing and 57% by procainamide. The 1 patient who presented with syncope of uncertain cause was protected by treatment with both drugs at PES studies.

The number of stimuli required to induce VT and the presenting arrhythmia are listed in Table II. Among patients with what might be considered the greater risk for electrical instability (cardiac arrest), VT was inducible in most cases by 2 stimuli, whereas the symptomatic VT and asymptomatic VT groups were very similar in their pattern of inducibility. With flecainide therapy, the threshold for inducibility was higher in 5

January 1, 1985 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 55 81

TABLE II Number of Stimuli Required for induction of Ventricular Tachycardia (VT)

TABLE IV Electrocardiographic Changes During Chronic Flecainide Therapy

Extrastimuli 1 2 3 4 Off Drug 1 mo. 3 mo. 6 mo.

Cardiac arrest* 8 4 (57%) 1(14%) 0 Syncope l(lOO%) 0 Symptomatic VT

: (20%)

Asymptomatic VT 1(6%)

l In 2 additional patients VT was induced with ventricular burst pacing.

patients, did not change in 2, and was lower in 6. One patient had a clear arrhythmogenic response to the drug: Spontaneous VT developed during the loading period and required defibrillation. The runs of VT subsided within 6 hours after drug administration was terminated.

Comparison with procainamide: Thirty patients were also tested with procainamide as a reference agent. Procainamide was administered intravenously, 100 mg every 5 minutes to a total dose of 1,000 mg, and if this did not provide protection at PES, an additional 500 mg was administered in a similar manner. Procainamide concentration was 7.8 f 0.4 pg/ml (8.4 f 0.3 for the protected and 7.2 f 0.5 for the nonprotected group). Only patients who did not have a clinical event on procainamide or intolerable side effects were studied with this agent in the laboratory. A comparison of the electrophysiologic data only for patients tested with both drugs is given in Table III. In the group of patients tested with both drugs, 63% of the patients tested with flecainide were protected from VT, compared with 60% protected by procainamide.

Long-term follow-up: Of the 26 patients protected by flecainide during the acute electrophysiologic testing, 21 were discharged from the hospital with flecainide therapy. Five of these 21 patients had presented with a cardiac arrest, 11 with symptomatic VT and 5 with asymptomatic VT. All patients initially received 100 mg twice daily and 18 patients were discharged with this dose. In 2 patients the dosage was increased to 100 mg 3 times daily, and in 1 patient to 200 mg twice daily because of inadequate plasma levels (<200 rig/ml) or because of continued high-grade ventricular ectopy. There was an 85% reduction in ventricular ectopic ac- tivity and complete abolition of all VT events at these doses. The patients were followed for a mean of 11 f 1.5 months. During this period, 2 have died: 1 died suddenly (flecainide level-peak 772 rig/ml and trough 644 rig/ml)

Heart rate (beats/min) 72 f 2 74 f 3 62 f 3 79 f 6 PR interval 17lf9 194f7 176fll 192fl2 QRS interval 61 f3 95f7” 102f 10” lOOf5’ QT interval 369 f a 387 f 7 382 f 11 387 f lo

Significant increase from initial value off drug: l p <0.05.

and 1 died from a noncardiac cause. One patient had several runs of breakthrough VT at a flecainide dose of 100 mg twice daily, with peak serum concentrations of 990 rig/ml and trough of 679 rig/ml. She was switched to high-dose procainamide treatment and has since died. The patient who died suddenly originally presented with asymptomatic VT on Holter, 9 months after a subendocardial myocardial infarction; the patient who had breakthrough arrhythmias originally had had near-syncope from sustained VT. Two patients have been switched to quinidine treatment by their referring physicians because of unease at continuing an experi- mental drug, despite continued efficacy. Sixteen patients continue to receive flecainide without problems. Thus, of the patients who continued to receive flecainide treatment, 2 of 19 (11%) have had a breakthrough arrhythmia while receiving chronic therapy, although they were protected during acute testing. None of the patients who presented with a cardiac arrest have had recurrent VT or a repeat arrest.

Long-term electrophysiologic data: The PR, QRS, and QT intervals at acute testing and at 1 month, 3 months and 6 months of follow-up are listed in Table IV. Flecainide had no effect on heart rate or PR or QT intervals; however, it did cause a 24% widening of the QRS complex during long-term therapy (p <0.05). No trend toward further widening was noted during follow-up, and there were no apparent clinical complica- tions from the increased QRS interval. Plasma levels of the group that received chronic therapy were 536 f 77 at 1 month, 525 f 95 at 3 months and 704 f 178 at 6 months of follow-up. Four patients have required a gradual reduction in flecainide dosage over several months because of increases in the serum concentration, QRS widening, heart rate slowing, confusion, and dizziness, from 100 mg twice daily to 50 mg 3 times daily or 50 mg twice daily. Despite the smaller daily dosages, the plasma levels have remained between 500 and 700

TABLE Ill Comparison of Electrophysiologic Measurements for the Groups Not Receiving Antiarrhythmic Therapy

HR PR (beats/min) (ms)

QRS (ms) (2,

No therapy Flecainide

19 protected 11 not protected

Procainamide

76 f 3 168f 5 93 f 5 387 f 7 249 f 5 213 f 11

73 f 3 190 f 7” 93 f 3 386 f 7 283 f 5” 259 f 5” 74 f 4 187fa 114f9 415 f 9” 275 f 17 263 f 24

16 protected 74 f 2 la9 f 6* a9 f 3* 398 f 12 291 f 6’” 25af7** 12 not protected 72 f 4 la9 f 6” 116f8” 435 f 13” 300f9”” 261 f 32”

Significant difference compared to patients off therapy: * p <0.05; t p <O.Ol.

02 CHRONIC REDUCED DOSE FLECAINIDE

rig/ml. All 4 of these patients clinically have signs of congestive heart failure (New York Heart Association class II), although their mean ejection fraction was 33%.

Adverse reactions: Few adverse reactions have been noted in the patients discharged with flecainide treatment using the lower dosage. One patient has complained of mild neurologic symptoms, primarily dizziness, vague paresthesias and nausea. Two patients had plasma flecainide levels of greater than 1,000 rig/ml before their daily dosage was reduced; both complained of feeling distinctly unwell, with confusion and dizziness. The flecainide levels were 1,081 and 1,099 rig/ml and the symptoms disappeared when the dosage was reduced. One patient had gastrointestinal discomfort with oral flecainide administration.

Serious sinus dysfunction with bradycardia developed in 4 patients predisposed to this problem by evidence of asymptomatic sick sinus syndrome. None of these patients had had significant sinus pauses while receiving previous antiarrhythmic therapy (2 patients receiving procainamide and 2 receiving quinidine) and none had required temporary or permanent pacing. When given flecainide, all 4 required placement of a permanent pacemaker for prolonged sinus pauses (from 2.0 to 3.7 seconds) with nodal or ventricular escape beats developing within 3 days after being started on a dose of flecainide, 100 mg twice daily. After continued ob- servation over the next few days, pauses of longer than 3.5 seconds or paroxysmal atria1 tachycardia with 7:l block and a ventricular response of 31 were noted and a permanent pacemaker was needed in each case. Two other patients had chronic atria1 fibrillation but no evidence of “tachy-brady” syndrome; neither of these patients required pacing. None of the other 15 patients with clinically normal sinus node function have demonstrated any instances of sinus or atrioventricular block.

Discussion Flecainide has been reported to cause a marked re-

duction in VPC frequency.3-s This suppression in VPC frequency is also noted with other class IC drugs such as encainide.16 These data suggest that flecainide may be a useful new agent for the treatment of VPCs. Less information is known regarding the efficacy of flecainide in patients with life-threatening arrhythmias and in patients undergoing electrophysiologic studies.rOpil

We studied the effects of flecainide treatment in 40 patients with serious ventricular arrhythmias, all of whom had VT provoked at electrophysiologic testing without antiarrhythmic medication. With an ejection fraction of 45 f 3% and having only failed 1.9 f 0.2 drugs before referral, this group of patients would not be considered “drug-resistant,” and therefore may be more representative of the usual patient who receives antiarrhythmic therapy for life-threatening arrhythmias. In this group, flecainide protected 65% of the patients. To allow comparison to other centers with a different referral population, we report data on the 30 patients tested with both procainamide and flecainide. Flecainide was as effective as procainamide treatment,

63% vs 60%. In populations with lower ejection fractions or who have failed treatment with more antiarrhythmic drugs, the absolute numbers will be lower, but we be- lieve that flecainide is an effective agent that should be tested.

The correlation between success at acute testing and protection from clinical events in long-term follow-up appears good. In 11 months, 2 patients (11%) had an arrhythmia breakthrough during flecainide therapy, which resulted in 1 (5%) sudden death. This is consis- tent with results from other PES studiesi and is con- sistent with the high risk of this population, which in- cluded 7 patients with previous cardiac arrest and 11 with hemodynamically significant, sustained VT. Without a concurrent control group, these numbers are difficult to interpret, but appear to be an improvement over mortality observed with historic controls, especially because none of the patients who had had a cardiac arrest before therapy have died.17-20

Flecainide appears to be a well tolerated drug, especially at the reduced doses used in this study. We had only 3 instances of central nervous system and gastrointestinal toxicity in our patients; all of these side effects have been noted by other investigators.21r22 Four patients had a history of intermittent episodes of atria1 fibrillation, flutter or supraventricular tachyarrhyth- mias and pauses suggestive of sick sinus syndrome. None of these patients had had sinus pauses during previous, ineffective antiarrhythmic therapy (procainamide in 2 patients and quinidine in 2) and none had required temporary or permanent pacing. When given flecainide, all 4 required placement of a permanent pacemaker for prolonged sinus pauses, which occurred within 3 days of oral therapy. Hellestrand et a123 described sinus node function in 10 patients tested with flecainide during electrophysiologic studies. Although there were no statistically significant increases in the sinus node recovery times in either the patients with normal or abnormal sinus node function, 1 patient had a marked prolongation of her corrected sinus node recovery time, from 3,885 to 18,195 ms. They concluded that flecainide should be used with caution in patients with abnormal sinus node function. Vik-Mo, Ohm and Lund-Johansen24 studied 11 patients with sinus node dysfunction and found a significant increase in the corrected sinus node recovery time, from 875 f 181 to 1,727 f 507 ms (p <0.05). They also advised caution in using flecainide therapy in patients with sick sinus syndrome. Pacemaker thresholds appear to increase by as much as 200% with chronic oral flecainide therapy.23 This may further increase the risk of patients with a sick sinus who are treated and later require a permanent pacemaker. These considerations should not decrease the utilization of this highly effective agent, but rather caution the prescriber to be observant for the patient who may require pacemaker implantation with flecainide therapy.

Dosage considerations are also important. Toxicity is increased when the level is increased over 1,000 rig/ml. Four patients required a reduction in their maintenance therapy or their plasma level would have gone into the toxic range. Besides the central nervous system and

January 1, 1985 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 55 83

gastrointestinal symptoms that could be avoided, levels over 1,000 ng may be more likely associated with arrhythmias. Because of a previous report of a case of flecainide toxicity that led to death,12 we were cautious not to obtain high plasma levels and an associated increase in QRS duration. Flecainide in excessive concentrations may cause a wide complex tachycardia, leading to ventricular fibrillation or asystole unre- sponsive to defibrillation and pacing.i2 The known el- evation in pacing thresholdz3 and the probable increase in defibrillation threshold emphasizes the need for moderate plasma levels. Frequent early blood level monitoring during the first month and every 3 months thereafter can be of great help in this regard. Further- more, evidence from the present study suggests that a subpopulation of patients with clinical symptoms of congestive heart failure may show a rise in flecainide plasma concentrations over time; these patients require more careful monitoring.25

Mechanism of action: The current study suggests that flecainide is effective in patients in whom it causes a significant prolongation in myocardial refractoriness as measured by the extrastimulus technique. Although intravenous flecainide therapy causes prolongation in the effective refractory period of the first extrastimulus in all patients tested (12 f 3%), the change is not di- rectly related to dose. In fact, patients protected by flecainide treatment had a 17 f 2% increase in the first extrastimulus refractory period with a dose of 1.35 f 0.1 mg/kg, whereas the nonprotected patients only had a 7 f 3% increase, but received a higher mean dose of 1.9 f 0.1 mg/kg. Of all the drugs studied in our laboratory, flecainide most clearly shows this differential prolongation in refractoriness between the patients in whom it was effective and ineffective. However, excessive prolongation of refractoriness could also be arrhythmogenic, as noted both in a previous report of a toxicity in a patient12 as well as possibly explaining the flecainide toxicity in patients studied by Reid et all4

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Flecainide: Long-term treatment using a reduced dosing schedule