Summary of efficacy and safety of flecainide for supraventricular arrhythmias

Summary

of Efficacy and Safety of Flecainide Supraventricular Arrhythmias

for

Jeffrey L. Anderson, MD, Dan M. Jolivette, MD, and Patricia A. Fredell, BA

This report provides an overview of the safety and efficacy of flecainide for supraventricular tachyarrhythmias (SVT) based on a review of the world literature. This review provided 107 entries, but 5 were review articles and 22 were articles not translated into English. The remaining 80 articles or published abstracts form the basis for this report. A total of 1,371 courses of therapy with intravenous or oral flecainide, or both, were represented. Efficacy was defined by each investigator. Intravenous flecainide was successful in terminating ongoing tachycardias in 81% of reported cases of atrioventricular (AV) nodal reentrant tachycardias, 88% of AV reentrant tachycardias and 100% of atrial tachycardias. Atrial fibrillation or flutter was terminated by intravenous flecainide in 62% of cases and arrhythmias associated with Wolff-ParkinsonWhite syndrome in 73%. Oral flecainide was successful in longer-term management of arrhythmia in 74 and 81% of patients with AV nodal and AV reentrant tachycardia, respectively, and in 83% with atrial tachycardia. Atrial flutter or fibrillation responded to oral drug in 61% of cases and arrhythmias related to Wolff-Parkinson-White syndrome in 61%. Adverse experiences were reported in studies totaling 695 patients (designated “at-risk patients”). They were not commented on in studies with the remaining 594 patients. Overall, a total of 6.9% of at-risk patients (3.7% of total patients) reported cardiac adverse experiences; 19% of at-risk patients (10% of total patients) reported at least 1 noncardiac adverse effect. Cardiac adverse events included worsened arrhythmias in 26, conduction disturbances in 15 and congestive heart failure in 5. The most frequent noncardiac adverse experiences were paresthesia and visual disturbance. In conclusion, flecainide provides effective therapy for SVT in two-thirds to three-fourths of patients, most of whom had no success with standard therapies, and is generally well tolerated. Patients with AV and AV nodal reciprocating tachycardias and atrial tachycardias are particularly responsive (>SO%). Two-thirds of patients with Wolff-Parkinson-white syndrome-related SVT and recent-onset atrial fibrillation had successful results. Insufficient data with chronic atrial fibrillation are available to assess the use of flecainide. This experience suggests that flecainide represents an important addition to the treatment of symptomatic SVT. (Am J Cardiol 1988;62:62D-6613) 62D

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he focus of antiarrhythmic therapy trials in the United States is perceptibly shifting from ventricular to supraventricular arrhythmias. Although the risk of ventricular arrhythmias in the setting of organic heart diseaseis well documented,‘-3 the potential of antiarrhythmic agentsother than p blockers4-’to reduce this excessiverisk hasnot yet beenshown.8The potential risks of antiarrhythmic therapy for ventricular arrhythmias have also becomeincreasingly recognized in recent years. Supraventricular tachyarrhythmias (SVT) have received less attention in clinical trials than ventricular arrhythmias; however, they are frequently symptomatic and often difficult to treat. The effects of SVT therapy on symptom reduction and quality of life have alsonot been adequately studied. However, promising new drugs and new study designshave presenteda goldenopportunity to increasesubstantially the understanding of SVT and its treatment. Electrophysiologic methodsapplied to animal modelsand patients have led to much progressin understanding its pathogenesisand assessingnew therapies, including therapy with flecainide.9J0Pritchett et al” presentedin this supplementa natural history study of paroxysmal SVT and a model for quantitating symptomatic episodesand evaluating outpatient therapy with antiarrhythmic agents.What remainsis to demonstratequantitatively in placebo-controlled,long-term outpatient trials that antiarrhythmic therapy can indeed improve the quality of life by reducing symptomatic arrhythmia episodeswithout causing significant adverse reactions. Substantial clinical experience has already been gained with the useof intravenous flecainide for therapy of spontaneousor electrophysiologically induced SVT and with oral therapy for long-term arrhythmia control. The purposeof this report is to provide an overview of the safety and efficacy of flecainide for SVT basedon reports from the world literature available asof September 1987.

T

METHODS Major medical and specialty journals in both English and foreign languageswere reviewed for the past 10years by the Medical Literature Service of 3M Riker, United States and United Kingdom. The searchprograms used provided on-line international data bases from Iowa Drug Information Service (157 journal review); Medline, Bethesda, Maryland (3,200 journal review); and Excerpta Medica, EMBASE, Amsterdam, The NetherFrom the University of Utah, Salt Lake City, Utah, and 3M Riker, St. Paul, Minnesota. Address for reprints: Jeffrey L. Anderson, MD, Division of Cardiology, Latter Day Saints Hospital, Eighth Avenue and C Street, Salt Lake City, Utah 84143.

TABLE I Overview Tachycardia Diagnosis (No. of Pts) AVN RT (200) AVRT(217) AT (46) AF/AFL (577) Chronic AF (23) WPW (224) Total

in Supraventricular

TABLE II Review Experiences

No. of Trials Effective

Total No. of Trials

Noncardiac Adverse Experiences

n

% of At-Risk Patients

% of Total Patients

111

137

81..0

50 138 64 34 24 211 137 0 7 107 81 601 363

68 157 79 34 29 341 225 7 16 146 132 822 549

73.5 87.9 81.0 100.0 82.8

Paresthesia Visual disturbance Hypotension

49 21 12

7.1 3.0 1.7

3.8 1.6 0.9

of Flecainide

Route IV PO IV PO IV PO IV PO IV PO IV PO IV PO

Efficacy

%

61.9

60.9 0.0 43.8 73.3 61.4 73.1 66.1

AF/AFL = atrial fibrillation/atrial flutter: AT = atrial tachycardia; AVNRT = atnoventricular nodal reentrant tachycardia; AVRT = atrwentricular reentrant tachycardia; IV = intravenous; PO = oral; W?W = Wolf-Parkmson-White syndrome.

lands (4,000 journal review). To confirm the completeness of this search, a retrospective literature search was also run using the program of ADIS Press, Auckland, New Zealand. Literature entries were selected by providing key words such as flecainide, R-818, Tambocor@, SVT and atria1 tachycardia. Of these, all studies dealing with therapy of supraventricular arrhythmias were retrieved by the investigators for further review. An attempt was made to identify obvious duplications in reported studies, such as when a full manuscript followed an identical abstract, and the most recent report was used for analysis. However, overlap in studies could not always be excluded, i.e., when a single center published multiple distinct reports. Two investigators independently reviewed each report for safety and efficacy results using a prospectively defined approach. Results of the 2 reviews were then compared and any differences resolved by direct discussion. Efficacy was evaluated separately for intravenous and oral drug trials in each of 6 separate diagnosis categories. Adverse experiences were placed in cardiac and noncardisc categories. Because adverse experiences were not reported in every study, their incidence was assessed based on both the number of patients in studies reporting adverse experiences (“at-risk patients”) and the number of patients from all studies (“total patients”). RESULTS

The literature provide 107entries for the useof flecainide in SVT, but 5 were review articles and 22 were articles not translated into English. The remaining 80 articles or published abstracts form the basisof this report.* A total of 1,371 treatment trials with intravenous or oral flecainide were represented. Overview of flecainide efficacy in supraventricular tachycardia (Table I): Overall efficacy: Overall, flecai-

nide waseffective in 70% (964) of the 1,371trials in 1,289 patients. Intravenous therapy wasjudged effective in 73% * A listing of studies reviewed Riker, St. Paul, Minnesota.

is available

on request

from

3M

of Most

Common

Noncardiac

Adverse

of trials (601 of 822) and oral therapy in 66% (363 of 549). Atrioventricular nodal reentrant tachycardia: Flecainide was used to treat a total of 200 patients with atrioventricular (AV) nodal reentrant tachycardia. Intravenous flecainide, used to terminate spontaneous or induced AV nodal reentrant tachycardia, was successful in 81% (111 of 137) of trials. Oral therapy was reported to be successful in 74% (50 of 68). Atrioventricular reentrant tachycardia: A total of 217 patients with AV reentrant tachycardia were treated with flecainide. Again, therapy was highly successful. Intravenous therapy for ongoing (spontaneous) and induced tachycardia was successful in 88% (138 of 157) of trials. Oral therapy was also highly effective, with a success rate of 81% (64 of 79). Atrial tachycardia: A relatively small but promising experience was reported for patients whose arrhythmias were classified as atria1 tachycardia. Forty-six patients were treated. All 34 intravenous trials were judged effective, and 24 of 29 (83%) of oral trials were successful. Atrialflutter or fibrillation: A total of 577 patients who received intravenous or oral flecainide, or both, in this arrhythmia category were evaluated. Overall, intravenous trials were successful in establishing sinus rhythm in 62% (211 of 341) of trials. Oral therapy was judged successful in 61% (137 of 225). A small number of patients (n = 23) were treated for “chronic atria1 fibrillation.” The definition used for “chronic” was not always given. Intravenous therapy was not effective in 7 trials; oral therapy was effective in 7 of 16 (44%) of trials. Although this experience is insufficient, the response, as expected, appears to be less than in patients whose atria1 fibrillation is not designated as chronic. Supraventricular tachycardia related to the WolffParkinson-White syndrome: Two hundred twenty-four patients with Wolff-Parkinson-White syndrome-related SVT were treated with intravenous or oral flecainide, or both. Intravenous trials were successfulin 73% (107 of 146) of patients and oral therapy in 61% (81 of 132) of patients. Overview of safety and adverse experiences: Adverse experienceswere reported in studies totaling 695 patients (designated the population of at-risk patients). Adverse experienceswere not commented on in studies involving the remaining 594 patients. It could often not be determined whether the lack of reported adverseeffects was due to their absenceor to failure to report safety information. Noncardiac adverseexperiences:A total of 19%(132 of 695) of at-risk patients (10% of total patients) reported THE AMERICAN

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TABLE Cardiac Adverse

FOCUS

Ill Review

ON FLECAINIDE

of Cardiac

Adverse

Experiences

TABLE

% of At-Risk Patients (n = 695)

% of Total Patients (n = 1,289)

4.0 2.2

2.2 1.2

0.7

0.4

Experiences

n

Worsened arrhythmia Conduction disturbance Bradycardia alone BBB or IVCD SA block Second-degree AV block Third-degree AV block Heart failure

28 15 5 6 1 1 2 5

AV = atrioventricular; BBB = bundle delay: SA = sinoatnal.

branch block; IVCD = intraventricular

IV Advantages

and Problems

of Literature

Reviews

Advantages Pooling minimizes pitfalls of drawing inappropriate conclusions from small, selected studies Allows evaluation of therapy for uncommon types of supraventricular tachyarrhythmias Provides a better evaluation of overall efficacy, tolerance and safety Problems Inhomogeneous patient groups, selection criteria Differing routes, doses, duration of therapy Varying criteria for efficacy Inconsistent reporting of adverse effects

conduction

Advantages and limitations of pooling results: Both advantagesand disadvantagesof pooling studiesfrom the literature are apparent (Table IV). By combining data at least 1 potential noncardiac adverse experience. The most frequent noncardiac adverse experiences were parfrom a large number of smaller studies,inappropriate or spuriousconclusionsarising by chanceor bias from indiesthesia (49 patients) and visual disturbance (21 patients). Hypotension after intravenous drug administravidual studiescan be minimized. Pooling also allows an tion was reported in 12 patients (Table II). assessmentof therapeutic potential for uncommon arCardiac adverse experiences: Cardiac adverse experirhythmias. The risk of common adverse events and the ences were reported by 6.9% (48 of 695) of patients at risk possibility of uncommon events can be better assessed (3.7% of total patients) (Table III). Worsened arrhythfrom large populations. On the other hand, limitations mias were reported in 28 trials (4.0% of at-risk, 2.3% of also apply to pooled studies.Patient groups may not be total patients). Conduction disturbances occurred in 15 homogeneous,selectioncriteria may differ, dosing regipatients and congestive heart failure in 5. No deaths were mensmay vary and criteria for establishingefficacy may reported to result from adverse reactions to therapy. not be the same.Potential inconsistenciesin assessing and reporting adverse experienceshave already been menDISCUSSION tioned. However, taken as a whole, the literature review Review summary: The literature review revealsa sub- complementsthe information derived from the more instantial experience with the use of flecainide for SVT. depth individual studies. Flecainide was effective in about two-thirds to threeSummary of individual symposium studies: Hellefourths of patients with SVT, many of whom had unsuc- strand15found intravenous flecainide to be successfulin cessful results with standard therapies. Flecainide was terminating ongoing AV nodal reentrant tachycardia also generally well tolerated; a low incidence of noncar- (88%, 30 of 34 patients). Reinitiation of SVT wasusually disc and cardiac adverse effects was reported. Therapy prevented (73%, 28 of 40 patients). Similarly, Neuss16 was particularly effective for AV nodal reentrant, AV found intravenous flecainide to be effective in 30 of 36 reciprocating and atria1 tachycardias (>SO% response). (86%) of these patients. Over two-thirds of those with paroxysmal atria1 fibrillaIn both studies,termination usually occurred by block tion responded.Many patients had SVT (AV reentry or in the retrogradely conducting pathway. Neussalsoevalatria1 fibrillation, or both) associatedwith a diagnosisof uated the long-term effectiveness of therapy in 31 patients treated with an average of 250 mg/day over a Wolff-Parkinson-White syndrome,and most (about twothirds) were successfullytreated. This overall experience period of 23 months.Therapy continued to be effective in suggeststhat flecainide is an important addition to the 24 patients, or 77% (65% of the total group), and waswell tolerated. Studies by Hellestrand,r5 Neuss16and Zeetherapy for symptomatic SVT. The review also suggeststhat flecainide is generally Cheng et alI7 showa similar high efficacy rate for treatwell tolerated in patients with SVT. Noncardiac adverse ment of AV reciprocating tachycardia using a retroexperiences,primarily lightheadedness,paresthesiaor vigradely conducting bypass tract. Intravenous flecainide terminated ongoingAV reentrant tachycardia in 32 of 38 sual disturbance, were observed in about 10% of total patients. This percentagewasasanticipated from trials in (84%) of patients treated by Hellestrand,15and electroventricular arrhythmias. I2 Cardiac adverse effects oc- physiologicreinitiation of SVT wasusually prevented (27 curred in about 7%, divided among those causing ar- of 41,66%). Neussi6observedtermination of reciprocatrhythmia worsening (4%), conduction disturbance (2%) ing tachycardia in 30 of 43 patients (70%) (41 with orthoand congestive heart failure (about 0.7%). Arrhythmia dromic tachycardia). During long-term follow-up (mean aggravation appearsto occur lessfrequently and be gen- 21 months), over 75%continued to be effectively treated. Zee-Cheng et all7 treated 18 patients in whom AV reenerally lessseverethan in patients treated for ventricular arrhythmias.t3,t4 As for other antiarrhythmic drugs, fle- trant tachycardia was induced electrophysiologically. In cainide may posea higher risk for adverserhythm effects 11 patients (61%), SVT could not be reinduced after in elderly patients with sick sinussyndrome. Intravenous intravenous flecainide. As in the other studies,the main therapy should be monitored for the occasional occur- effect of flecainide was depressionof retrograde conducrence of hypotension. tion in the bypasstract, resulting in ablation of reentry or 64D

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prolongation of the tachycardia cycle length. Results of oral flecainide therapy were concordant with intravenous treatment. Subsequent outpatient experience was excellent in responding patients. The therapeutic potential of flecainide in conversion of recent-onset atria1 fibrillation and in prevention of recurrences of paroxysmal or sustained atria1 fibrillation is borne out by detailed studies in this symposium.i5,’ 8-2o Goy et al’s administered intravenous flecainide followed by oral flecainide to 69 patients with atria1 fibrillation and observed restoration of sinus rhythm in 49 (71%). Higher conversion rates were observed in patients with atria1 fibrillation of shorter duration (
controlled trials. Two suchmulticenter trials are currently underway in the United States. The first is a double-blind, placebo-controlled, crossover study of maximally tolerated dosesof flecainide for symptomatic SVT (paroxysmal supraventricular tachycardia [PSVT] or paroxysmal atria1 fibrillation/flutter [PAF]) using transtelephonic monitoring. Patients with frequent, symptomatic PSVT first undergo a qualifying baseline period, followed by open-label drug titration. During this phase,flecainide is given in increasing dosagestwice daily, each dosagefor 1 week, to the maximally tolerated dosage.A double-blind, crossoverphasethen begins. Flecainide, given in the tolerated dosagedetermined in the open-labelphase,or its matching placebo,is given for 8 weeks or until 4 episodesof PSVT or PAF occur. Therapy is then crossedover. Recruitment in this study has been completed, and a preliminary analysisof the results has been made.23,24 A secondongoing, controlled, U.S. study of flecainide in PSVT or PAF is designedto define more clearly the effective dosing range. This study is double-blind and involves five 4-week dosing periods. During the initial qualifying period, patients must transmit at least 2 symptomatic episodesof PSVT or PAF by transtelephonic monitor. Patients then enter consecutive periods of increasingdosagesof oral flecainide (25, 50, 100 and 150 mg twice daily), with placebo interspersed at random during the study. This study should determine which dosagesof flecainide are relatively ineffective, which provide effectivenesswith low-adverse effect potential and which, if any, may be effective but associatedwith increasedadverse potential. Favorable and well-documented results from these trials, together with the substantialexperiencefrom acute interventional and long-term observational studies reviewed, shouldprovide a firm data basefor submissionof an application for a new drug indication and for subsequent broad clinical usage. We thank Keith D. Green for typ-

Acknowledgment:

ing the manuscript.

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