A Proposal for the Clinical Use of Flecainide
JEFFREY L. ANDERSON, MD, JAMES R. STEWART, MD, and BARRY J. CREVEY, MD
Effective antiarrhythmic therapy requires a carefully sponse rate is observed in preventing induction of considered approach, including an understanding sustained ventricular tachycardia, and these pa- of the arrhythmia, the underlying cardiac disease tients should be carefully selected. Flecainide is and the drug’s pharmacokinetics. Flecainide is a promising in the treatment of supraventricular new antiarrhythmic drug that may soon be released tachycardias using atrioventricular nodal or extra- for general use. Flecainide demonstrates unsur- nodal reentrant pathways, although this use is still passed efficacy in chronic ventricular arrhythmias investigational in the United States. The drug’s use in stable patients and may become a first-choice for arrhythmias during acute myocardial infarction drug because of its ease of administration, efficacy requires further study. Flecainide possesses modest and favorable tolerance. Twice-daily dosing with negative inotropic potential. Proarrhythmic or other 100 to 200 mg usually provides effective therapy. adverse reactions have occurred primarily in set- Clinical experience suggests flecainide to be indi- tings of high drug level, poor ventricular function cated in the treatment of uniform and multiform or refractory, malignant arrhythmias, suggesting ventricular premature complexes, coupled ven- caution in these groups. tricular premature complexes, and episodes of nonsustained ventricular tachycardia. A lower re- (Am J Cardiol 1984;53:1128-1198)
Effective therapy of cardiac arrhythmias requires a coronary artery disease, complex ventricular arrhyth- carefully considered approach.’ The first step in ar- mias may be associated with an increased risk of mor- rhythmia management is an accurate cardiac diagnosis, tality, particularly from sudden death due to ventricular which includes documentation and identification of the fibrillation.2p3 Studies documenting the ability of anti- arrhythmia and evaluation of underlying heart disease. arrhythmic therapy to reduce this excessive risk are Specific initiating factors should be identified. Elec- incomplete. However, a carefully applied approach trolyte, acid base and other metabolic derangements, appears to hold promise.4 Therapy for ventricular ar- neuroendocrine factors or adverse drug interactions rhythmias is indicated in the following settings: (1) should be addressed. Antiarrhythmic goals should be primary ventricular fibrillation unprovoked by myo- specified in advance and may include elimination of cardial infarction; (2) complex ventricular arrhythmias symptoms (palpitation), suppression of ectopic ven- (pairs, runs, R-on-T complexes and high frequency ar- tricular complexes, elimination of repetitive complexes rhythmia) after myocardial infarction, particularly or prevention of ventricular tachycardia and fibrillation. during the first year; (3) complex arrhythmias in asso- Drug administration should be based on sound clinical ciation with ischemia; (4) ventricular tachycardia, and pharmacologic principles. Disease states may alter particularly in coronary artery disease; (5) syncope as- drug effects and disposition. Once therapy has begun, cribed to ventricular tachycardia of any origin; (6) ar- careful follow-up should be undertaken, including rhythmias causing significant clinical symptoms (pal- documentation of antiarrhythmic effects, observation pitation, dyspnea, fatigue and dizziness).315 for adverse effects and, when appropriate, drug plasma An ideal antiarrhythmic drug should possess a high concentration. degree of effectiveness, a low level of toxicity with a wide In association with organic heart disease, particularly therapeutic range and prolonged antiarrhythmic ac- tion.6 The clinical management of ventricular ar- rhythmias remains problematic, however, because of the frequent failure of standard drugs which may be at- tributable to inadequate antiarrhythmic activity, in- From the University of Utah College of Medicine, Division of Cardiology, tolerable adverse effects or compliance problems. In this Salt Lake City, Utah, and University of Michigan School of Medicine, regard, flecainide acetate possesses several favorable Ann Arbor, Michigan. properties compared with available antiarrhythmic Address for reprints: Jeffrey L. Anderson, MD, University of Utah College of Medicine, c/o LDS Hospital, 325 8th Avenue, Salt Lake City, agents: excellent ant&rhythmic potency per milligram, Utah 84143. effectiveness against ventricular arrhythmias in a high
1128 February 27, 1984 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 53 1138 percentage of patients, a low incidence of major adverse TABLE I Clinical Pharmacoloav of Oral Flecainide effects, and a long half-life, which favors patient com- Bioavailability:>90% pliance and continuous antiarrhythmic action.7 Minimum effective plasma concentration range: 200 to 1,000 We are presenting a long-term patient experience, ng/ml (mean 506) Elimination half-life: 20 hours (range 12 to 27) reviewing important investigative observations (many Elimination: Renal detailed in this symposium), and formulating guidelines Plasma protein binding: 40 % for the initial clinical application of flecainide. Active metabolites: None of significance
Application of Clinical Pharmacology Only by applying a thorough understanding of a belongs to the membrane-stabilizing (class I) group of drug’s unique pharmacologic characteristics can max- antiarrhythmic agents; however, it has its own charac- imal therapeutic benefit be realized (Table I). teristic electrophysiologic profile.12J” In humans, fle- Metabolism in humans? After oral administration, cainide depresses conduction in all parts of the heart, the absorption of flecainide is nearly complete, and with greatest effects on the His-Purkinje system. Effects presystemic (first-pass) metabolism is negligible, re- on refractory periods are less pronounced and primarily sulting in systemic bioavailability of more than 90%. limited to the ventricle.‘” Sinus node recovery times are Peak plasma drug levels occur at about 3 hours (range usually unaffected except in certain patients with sick 1 to 6). Food does not deter the rate or extent of fle- sinus syndrome, in whom flecainide occasionally may cainide absorption. Increases in oral dosage lead to in- result in pronounced lengthening.14 Prolongation of PR creases in plasma level in a linear fashion. and QRS intervals is greater during treatment with The mean plasma elimination half-life in patients flecainide than with standard drugs?J5J6 but effects with ventricular arrhythmias as determined in several on the QT interval are small15 (Table II). Increases in studies averages about 20 hours (range 12 to 27).7,gJo PR and QRS intervals of about 20% commonly occur at This result is somewhat longer than the 14-hour mean doses of 400 mg/day, and are usually not a cause for half-life noted after single oral doses given to healthy concern.7J3J5 Those with initially increased PR and persons.” Minimum therapeutic plasma concentrations QRS intervals are not disproportionately affected.‘” associated with greater than 90% suppression of ven- Similar electrocardiographic changes also are noted with tricular premature complexes (VPCs) in responding encainide.17p18 Clinically, an increase in electrocardio- patients range from 200 to 1,000 ng/ml (mean 500). In graphic intervals of more than 50%, substantial in- patients with advanced cardiac disease, major adverse creases in corrected QT intervallg or the development cardiac effects have usually occurred in association with of new bundle branch block should raise a clinical con- plasma levels greater than 1,000 to 1,500 ng/ml. Because cern, particularly in patients with advanced disease. The antiarrhythmic effects are related to parent drug, development of bifascicular block or second-degree or plasma determinations of flecainide may provide useful greater heart block is an indication for drug reduction clinical information. Elimination of flecainide is pri- or discontinuation unless a pacemaker is present to marily renal, consisting of unchanged drug and 2 major sustain rhythm. urinary metabolites with little or no antiarrhythmic Hemodynamic considerations: Flecainide has been activity. Plasma protein binding is low (about 40%) and well tolerated hemodynamically. Blood pressure is independent of plasma drug levels. Drug interactions typically unchanged. Small increases have occasionally of consequence have not been observed. Despite the been noted, and rarely increases in antihypertensive high percentage of flecainide circulating as free drug, therapy are needed. Heart rate is unchanged, although its large volume of distribution (about 10 liters/kg) rarely bradycardia or tachycardia may be seen. Among precludes effective removal of flecainide by hemo- antiarrhythmic drugs, flecainide appears to have in- dialysis. termediate negative inotropic potential. In stable pa- Urinary excretion in moderate renal failure is only somewhat less than that in healthy subjects; in contrast, urinary elimination may be markedly lower with end- stage renal disease. Observation suggests a decrease of TABLE II Cardiovascular Effects of Oral Flecainide about 25% in the rate of flecainide elimination from Blood pressure: - (*t) plasma in patients with congestive heart failure (New Heart rate: - Electrocardiogra hit intervals’: York Heart Association class III or IV). Drug interac- APR: 0.04 s ( f 23%), p
TABLE III Efficacy of Oral Flecainide
Summary of Representative Trials
% Responders % VPC Suppression % Suppression Mean Dose (mg/day) Study (n) (>80% VPC Suppression) (Mean Frequency Reduction) Couplets, Runs (Range) Multicenter 97 (32/33) 97% >99% 400 dose ranging (n = 33)‘1~-‘~ Flecainide-quinidine 85 95 % , mean 100% reduction in 75% (20:~0600) comparison (n = 233)15 (99G;$+median) 80% reduction in 90% Flecainide, mexiletine, 82 (9/l 1) . 0 98.8% (40:oo600) propafenone comparison (n = 12)22 VPC = ventricular premature complexes.
tients, electrocardiographic ejection fraction does not Couplets were eliminated in 70% of patients treated change during maintenance therapy.7sgJ0 Twelve pa- with flecainide; quinidine eliminated the couplets in tients with compromised left ventricular function were only 41% (p TABLE IV Experience with Long-Term Therapy No. of Age (yr) Arrhythmia Previous Follow-Up Pt & Sex Cardiac Diagnosis Complexity Drugs l (mo) Outcome 1 62F ASD Couplets 28 Successful (X28 mo); MVP, MR late failure (see text) 56F MVP Runs Successful G 49F Normal Couplets z: Successful 4 55F AVD Multiform Successful 52F Normal Runs 1: Successful : 61M CAD, old MI Runs 3 Failure (exercise VT) 43F Normal Runs 10 Failure (exercise VT) 1: 69M AS, CM Runs 21 Successful (X21 mo); late failure (VT) 9 70F Normal Runs 16 Successful 10 67M CAD, old Ml Runs 9 Successful lsustalned VT) * Includes disopyramide (5 patients), lidocaine (1 patient), phenytoin (2 patients), procainamide (6 patients), propranolol (6 patients), quinidine (8 patients) and tocainide (1 patient). AS = aortic stenosis; ASD = atrial septal defect; AVD = aortic valve disease (biscuspid); CAD = coronary artery disease; CM = cardiomyopathy; Ml = myocardial infarction; MR = mitral regurgitation; MVP = mitral valve prolapse. TABLE V Experience with Long-Term Therapy Average VPCs/Hour Plasma Flecainide (ng/ml) Dose Pt (mgfday) Baseline 14 Days 4-a MO 18-36 MO 14 Dayst 6 Mo’j 30 MO* 1 400 125 1 16 921 1,160 400 2,544 8 0 544 892 ‘$63 x 600 636 25: 74 1,291 1,589 1,444 4 400 264 10: 0 357 1,284 1,476 400 3,468 18 0 777 967 727 2 500 144 1,615 400 1,854 8 743 1:421 ::: 3 400 1,302 11: 897 1,047 300 1,478 : 129’ ...... 1,012 ... 1: 400 8.1OOt 127 33 ...... 845 l After attempted dosage reduction. r Sustained ventricular tachycardia, 136 beats/min t Predose (trough). * Random. on the same dose of medication and were followed 7 ventricular tachycardia also occurred during treadmill monthly for 4 months and bimonthly thereafter. His- exercise. Most recent levels in the 4 patients in whom tory, examination, la-lead electrocardiography with tachyarrhythmias developed were in excess of 1,000 l-minute rhythm strip and blood chemistry tests were ng/ml (mean 1,300). performed at each visit and 24-hour ambulatory (Hol- Side effects were minor. Symptoms occurred early in ter) electrocardiographic recordings at 4-month inter- the course of treatment and did not progress during vals. follow-up. Seven patients complained of intermittent The follow-up period ranged from 3 months in a pa- visual blurring and 2 noted a metallic taste. No hema- tient with early treatment failure to 37 months, with a tologic or blood biochemistry abnormalities were ob- median of 25 months (Tables IV and V). In the 9 pa- served. Electrocardiographic changes, including mod- tients successfully treated at 6 months, geometric mean erate increases in PR and QRS intervals of 10 to 20%, VPC frequency was 8.0/hour (range 0 to 258), repre- remained stable. senting 99% suppression with respect to baseline. An In summary, flecainide has remained highly effective additional treatment failure occurred between 6 and 12 in reducing VPC frequency in these patients for as long months, and 1 each during the second and third treat- as 37 months (median 25) and is symptomatically well ment years. During successful treatment at 18 to 36 tolerated.25 However, spontaneous ventricular tachy- months (n = 7), geometric mean VPC frequency was cardia may still occur in some patients. Disease pro- 6.2/hour (range 0 to 781, representing 99.6% continued gression or high plasma levels may have contributed to VPC suppression. these failures. Exercise testing was useful in assessing Treatment failures included ventricular tachycardia proarrhythmic potential. in 3 instances and supraventricular arrhythmia in 1. In Granrud, et alz6 reported preliminary results of Patients 6,7 and 8, spontaneous episodes of more sus- long-term follow-up in 27 patients treated with fle- tained ventricular tachycardia developed despite con- cainide. Treatment was stopped in 4 patients, because tinued reduction of VPC frequency. In Patients 6 and of sudden death in 1, heart failure in 1, right bundle 1168 CLINICAL USE OF FLECAINIDE TABLE VI Dosage Recommendations for Oral Flecainide patients have required higher doses, but a dose of 600 Therapy mglday should not be exceeded. Usual dosage: 200-400 mg/day Dosage increases greater than 400 mglday should not initial dose: 200 mg be made in patients at higher risk for toxicity (heart Initial maintenance dose: 100 mg every 12 hours failure, renal failure with creatinine clearance 120 Dose increments: 50 mg every 12 hours, every 4 days as needed Usual effective regimens: ml/min/m2, the very elderly and weight less than 50 kg) 100, 150, and 200 mg every 12 hours unless guided by plasma drug concentrations. Again, Alternative: 100 mg every 8 hours 12 Maximum dosage: 300 mg every 12 hours (600 mg/day) initial dosage should not exceed 100 mg every hours Conditions of altered dosage: and increments should be made cautiously, at 4- to 1. End-stage renal disease (creatinine clearance 120 ml/min/ 7-day intervals, allowing for steady-state plasma levels m2) 2. Advanced ventricular dysfunction, heart failure and unstable to be reached. Studies to determine the effect of hepatic rhythms impairment on flecainide elimination have not been 3. Recommend: Schedule hospital administration: begin 100 mg completed. every 12 hours: increments L every 4 to 7 days, maximum 200 mg every 12 hours; follow plasma levels if possible. Some patients may be intolerant to or not adequately controlled by a dose given every 12 hours. In these cases, the daily dose may be divided into 8-hour intervals. The long half-life of flecainide suggests the possibility of once-daily dosing in certain patients, but this possibility branch block in 1 and inadequate efficacy in 1. Side has not been studied. effects were minor. At 18 to 20 months, mean percent suppression of VPCs and ventricular pairs was 88% and Recognizing and Dealing with suppression of ventricular tachycardia 83% (23 pa- Adverse Reactions (Table VII) tients). The average dose of flecainide was reduced to a mean of 320 mglday during chronic therapy, resulting Flecainide is well tolerated, although minor adverse in an average plasma drug level of 577 ng/ml. Flecainide effects may be seen. About 30% of patients receiving an was well tolerated. average dose of 400 mg/day or greater have visual dis- turbance (blurred vision and difficulty in accommo- Drug Dosage dation, particularly on lateral gaze) or dizziness Dosing recommendations (Table VI): Most studies (lightheadedness and unsteadiness).7~s~1c~1sJ5 These with flecainide have used an average starting dose of 200 effects most often occur after dosing, during the period mg every 12 hours, and this dose has been effective and of expected drug peak. Complaints of nausea and well tolerated in most patients. Because of the long headache may occur in 5 to 10% on larger doses. Infre- half-life of flecainide, it is likely that even smaller doses quent effects (incidence of less than 5%) include flush- (100 to 150 mg every 12 hours) will provide antiar- ing, chest pain, dyspnea, nervousness, palpitation, rhythmic efficacy in many patients. Therefore, it is tremor, paresthesia, fatigue, asthenia and metallic taste. recommended that after a loading dose (200 mg), ther- These effects are minor, transient and well tolerated in apy be initiated at 100 mg every 12 hours. This dose may most patients. In 1 large study,15 13% of patients dis- be increased in increments of 50 mg twice daily every continued flecainide because of adverse effects. How- 4 days until efficacy has been achieved or until 400 ever, dosages of 400 to 600 mglday were used, and mg/day (200 mg twice daily) has been reached. A few down-titration was not allowed. Experience in chronic studies indicates that adverse effects may be relieved while efficacy is maintained by downward dose ad- justments.26 Intolerance should force discontinuation TABLE VII Adverse Reaction Profile in less than 10%. Flecainide has not caused biochemical or hematologic abnormalities. Neurocirculatory: Hemodynamic and rhythm effects form the other Common: Dizziness, blurred vision (~30%) Comment: Usually minor; may decrease with time; usually basis for potential adverse reactions. Worsening of heart responds to dosage reduction if needed failure may occur in approximately 2% of the patients. Occasional: Headache and nausea (5 to 10 % ); asymptomatic lo atrioventricular block First-degree atrioventricular (AV) block is seen fre- Uncommon: Flushing, chest pain, anxiety, tremor, palpitation, quently, but is usually benign. QRS widening may rarely altered taste, paresthesia, fatigue, asthenia and progress to bundle branch block, usually asymptomatic. hypertension Proarrhythmic: Sinus bradycardia, sinus pause, sinus arrest or more Increased VPCs: <5 to 10% of patients advanced AV block is rare, but may occur with preex- Comment: More common at subtherapeutic dosage; if so, may istent conduction system disease. Proarrhythmic effects decrease with therapeutic dosage Facilitation of VT: (1) on ambulatory monitoring (may be independent are discussed herein. of total VPC response), (2) at electrophysiologic induction, and Precautions: Important drug interactions with fle- (3) exercise-induced spontaneous. Incessant VT or VF (difficult to resuscitate): Very rare. cainide have not been apparent. There has been no ex- Comment: Associated with high plasma drug levels (>l,OOO perience with co-administration of flecainide and either ng/ml), poor ventricular function (ejection fraction <30%), disopyramide or verapamil. There is little rationale to history of malignant arrhythmias and f concurrent antiar- rhythmic use; avoid, by careful patient selection and dosage co-administer disopyramide, particularly in view of the increments, careful monitorina negative inotropic properties of each drug. In appro- VF = ventricular fibrillation; VPC = ventricular premature complexes; priate patients, co-administration of verapamil and VT = ventricular tachycardia. flecainide may be indicated when the potential benefit February 27, 1984 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 53 1178 outweighs the risk (negative inotropy and decreased AV TABLE VIII Indications for Clinical Use conduction). Hiahlv effective:* Flecainide has not been shown to be carcinogenic in -1. ‘Uniform and multiform VPC animal studies.“7 There are no adequate and well-con- 2. Coupled VPC 3. Runs of VPC (nonsustained VT) trolled studies in pregnancy. Therefore, the drug should Selectedf prophylactic efficacy: be used in pregnancy only if benefit justifies the un- Sustained VT, VF (includes electrophysiologic guided therapy) known risk to the fetus. Teratogenic effects were noted Investigational applications: 1. Supraventricular tachycardiasx in large doses in 1, but not another, strain of rabbit. A. AV nodal reentry Effects on human labor and delivery, and excretion in B. AV bypass tract reentry (concealed or overt WPW syn- drome) human milk of flecainide have not been studied. Safety 2. Arrhythmias during myocardial infarction and effectiveness of flecainide have not been established l May be agent of choice for chronic VPCs; little experience to date in children younger than 18 years of age. In view of fle- with acute VPCs during myocardial infarction. cainide’s modest negative inotropic effects, it should be + Younger patients without advanced ischemic heart disease or used cautiously in patients with a history of congestive ventricular dysfunction may do better. t Little experience for atrial flutter or fibrillation. heart failure. AV = atrioventricular; VF = ventricular fibrillation; VPC = ventricular Contraindications: As with other class I antiar- premature complex; VT = ventricular tachycardia; WPW = Wolff- rhythmic drugs, flecainide should be considered con- Parkinson-White syndrome. traindicated in patients with preexisting second- or third-degree AV block or with bifascicular or trifascic- fractory condition, an extremely cautious approach, or ular bundle branch block unless a pacemaker is present alternative therapy, is indicated. that can sustain cardiac rhythm should complete AV block occur. Flecainide is contraindicated in the pres- Clinical Proposal for initial Drug Use ence of cardiogenic shock. Flecainide’s safety, unsurpassed efficacy and near- Proarrhythmic effects: a clinical caution: A clear ideal pharmacokinetics in patients with chronic stable understanding of the potential of antiarrhythmic agents ventricular arrhythmias suggest that it will frequently to produce proarrhythmic effects is essential to their be the drug of choice when medical treatment is indi- safe and rational administratiorG$ such is also the case cated. Studies summarized herein indicate that fle- for flecainide.29 Substantial proarrhythmic effects have cainide will result in greater suppression of ventricular been observed with all antiarrhythmic drugs, with an ectopy, including pairs and runs in these patients, than incidence of about 5 to 15% using ambulatory electro- will the standard drugs (quinidine and disopyramide), cardiographic recording28 and about 10 to 30% during and the newer lidocaine congeners (i.e., mexiletine and programmed stimulation.aO There is also concern with tocainide) soon due for general release in the United class IC agents.17x1sJ1 The risk of proarrhythmic effects States. Convenience of dosing (twice-daily schedule) from flecainide appears to be similar: In a survey of 588 exceeds that of these other drugs, and adverse effects patients, 8% (44 patients) were believed to have such jeopardizing continued therapy are low. effects. In studies in which only stable patients were Proposed indictions for clinical use (Table VIII): recruited, proarrhythmic effects were noted in about 4%, Flecainide is proposed for suppression and prevention whereas in studies in which unstable patients with ad- of uniform and multiform ventricular premature com- vanced disease were recruited, the percentage was 12% plexes, coupled ventricular premature complexes, and (personal communication, Riker Laboratories). Ar- runs of ventricular tachycardia. If the tachycardia is rhythmias associated with a long QT syndrome, noted nonsustained, response is followed primarily by am- commonly with quinidine,s2 appear to be rare with fle- bulatory monitoring; if sustained, therapy may also be cainide and are associated with toxic doses.19 Proar- directed by programmed electrical stimulation. The rhythmic effects may take the form of an increased response rate of sustained VT is lower and dependent frequency of VPC. If facilitation is mild and occurs in on patient selection; younger patients without coronary stable patients at subtherapeutic levels, a dosage in- disease or, if they have coronary disease, with reason- crease may be considered. Otherwise, alternative ther- ably well-preserved ventricular function respond most apy should be used. An increase in repetitive beats favorably. ls The same may be said for other antiar- (pairs and runs) irrespective of effects on total VPC rhythmic drugs. 23,24Experience to date is greatest for should be a stronger indication for alternative therapy. chronic arrhythmias. Class I antiarrhythmics are usually Inducibility of ventricular tachycardia at electrophys- not effective in treating arrhythmias associated with iologic study in nonresponding patients is unpredictable digitalis intoxication; therefore, flecainide is not rec- and may be better, worse or unchanged.13 The most ommended for such cases. Although effects of the QT serious arrhythmogenic effects have included rare in- interval are less than those after quinidine, flecainide stances of unresuscitable ventricular tachycardia or has not been determined to be useful in the treatment fibrillation. A recent review among flecainide investi- of arrhythmias associated with a long QT interval. Ef- gators pointed to a potential role of excessive drug levels fects of flecainide in patients with supraventricular (>l,OOO ng/ml) in patients with advanced disease (left arrhythmias or acute myocardial infarction have not ventricular ejection fraction <30%, previous infarction, been adequately studied to provide usage recommen- history of sustained ventricular tachycardia or con- dations at this time. In patients with advanced heart comitant treatment with other class I antiarrhythmic disease, including multiple arrhythmia mechanisms, drugs). In these very ill patients with a frequent re- conduction system disease or advanced ventricular 1168 CLINICAL USE OF FLECAINIDE dysfunction, the increased risks of flecainide’s mild electrophysiologic study. Flecainide may also be useful negative inotropic effects and potential proarrhythmic in other supraventricular arrhythmias, but further effects should be carefully weighed against those of documentation will be required. There is little experi- other therapeutic alternatives.:‘“-:36 ence in the prevention or treatment of atria1 fibrillation Clinical approach: Flecainide, like other antiar- or flutter with flecainide. The therapeutic use of com- rhythmic drugs, should be started during inhospital bining flecainide with other antiarrhythmic drugs or observation. Most adverse effects of drug occur within nondrug management (pacemakers and internal defi- a few days of initial administration. In patients with brillators) requires exploration. stable arrhythmias without a history of sustained Acknowledgment: We acknowledge Terri Johnson, RN, tachycardia, a carefully designed outpatient plan forms and Joan Lutz, RN, for excellent and ongoing patient care. We an alternative approach. Weekly outpatient visits in- thank Marian Curfew and Sandi Olson for typing this man- cluding ambulatory electrocardiographic recording and uscript. symptom assessment may be undertaken until a suc- References cessful regimen is obtained. Thereafter, the patient may be seen at monthly intervals for 3 months, and 3-month 1. Anderson JL. Harrison DC. Meffin PJ. Winkle RA. Antiarrhvthmic druas: clinical pharmacology and therapeutic uses. Drugs 1978; 15:271-309.- intervals during the first year or as otherwise indicated 2. Ruberman W, Weinblatf E, Goldberg JD, Frank CW, Shapiro S. Ventricular by the patient’s condition. Ambulatory electrocardio- premature beats and mortality afler myocardial infarction. N Engl J Mecl 1977;297:750-757. graphic recordings are obtained until an effective re- 3. Lown B. Sudden cardiac death: the major challenge confronting contem- oorarv cardioloav. Am J Cardiol 1979:43:313-326. sponse has been achieved, in the presence of recurrent 4. Grabdys TS, Lo&t B! P&M PJ, DeSilia RA. Long-term survival of patients symptoms or dose adjustment or at about 6-month in- with malignant ventrtcular arrhythmia treated with antiarrhythmic agents. Am J Cardiol 1982;50:437-443. tervals during at least the first 1 to 2 years. 5. Anderson JL. Manaaina cardiac arrhvthmias: an empiric approach. Mod For patients with a history of, or who have potential Med Nov. 1981;76-92.- 6. Drellus LS, Ogawa S. Quality of the ideal antiarrhythmic drug. Am J Cardiol for, malignant arrhythmias (sustained ventricular 1977;39:466-468. 7. Anderson JL, Stewart JR, Perry BA, Van Hamersveld DD, Johnson TA, tachycardia, ventricular fibrillation, poor ventricular Conard GJ, Chang SF, Kvam DC, Pltt B. Oral flecainide acetate for the function and advanced age), inhospital titration (be- treatment of ventricular arrhvthmias. N Enal J Med 1961:305:473-477. 6. Riker Laboratories. Proposed package-insert. Flecainide. February ginning with 100 mg every 12 hours) should be obliga- 1963. tory. Continuous inhospital ambulatory electrocar- 9. Duff HJ, Roden Dhl, Maffucci RJ, Vesper BS, Canard GJ, Higgins SE, Oates JA, Smffh RF, Woosley RL. Suppression of resistant ventricular arrhythmias diographic recording and predischarge exercise testing by twice daily dosing with flecainide. Am J Cardiol 1961;46:1133-1140. to a symptomatic end point by treadmill or bicycle er- 10. Hodges M, Haugland JM, Granrud G, Conard GJ, Aslnger RW, Mlkelt FL, Krejci J. Suppression of ventricular ectopic depolarization by flecainide gometry are performed. Patients with a history of sus- acetate, a new antiarrhythmic agent. Circulation 1962;65:679-665. 11. Conard GJ, Carlson GL, Frost JW, Ober RE. Human plasma pharmacoki- tained ventricular tachycardia are usually tested with netics of flecainide acetate (R-616), a new antiarrhythmic. following single programmed electrical stimulation, particularly if oral and intravenous doses (abstr). Clin Pharmacol Ther 1979;25:216. 12. Akeda N, Davis L, Hauswirfh 0, Singh BN. Flecainide: electrophysiologic spontaneous arrhythmia episodes are infrequent. Blood profile in isolated cardiac muscle of an antiarrhythmic with differential ef- level monitoring is encouraged when doses of 400 fects in ventricular muscle and Purkinje fibers (abstr). Circulation 1962; 66:suppl ll:ll-379. mglday or greater are administered and for patients 13. Anderson JL, Lutz JR, Allison SD. Electrophysiologic and antiarrhythmic with compromised physiologic findings. effects of oral flecainide in patients with inducible ventricular tachycardia. J Am Coll Cardiol 1983;2:1b5-114. 14. Vlk-Mo H, Ohm O-J, Lung-Johansen P. Electrophysiologic effects of fle- Investigational Use (Table VIII) cainide acetate in patients with sinus nodal dysfunction. Am J Cardiol 1962;50:1090-1094. Flecainide is 1 of 4 new antiarrhythmic drugs being 15. Flecainide-Quinidine Research Group. Flecainide versus quinidine for treatment of chronic ventricular arrhythmias: a multicenter clinical trial. tested in the National Institutes of Health-sponsored Circulation 1963;67:1117-1123. 16. Ross DL, Sre DY, Keefe DL, Swerdlow CD, Echt DS, Griffin JC, Wlnkie Cardiac Arrhythmia Pilot Study (CAPS), which began RA. Mason JW. Antiarrhvthmic drua combinations in the treatment of in July 1983. This study in patients with complex ar- ventricular tachycardia. C’lrculation 1>62;66:1205-1210. 17. Anderson JL, Stewart JR, Johnson TA, Lutz JR, Pitt B. Response to en- rhythmias in the early period after myocardial infarc- cainide of refractory ventricular tachycardia: clinical application of assays tion will compare the effectiveness of selected antiar- for parent drug and metabolites. J Cardiovasc Pharmacol 1962;4:812- 819. rhythmic drugs in suppressing complex ventricular 16. Mason JW, Peters FA. Antiarrhythmic efficacy of encainide in patients with arrhythmias and evaluate their safety. If the results of refractory, recurrent ventricular tachycardia. Circulation 1981;63:670- 675. CAPS are promising, a full-scale trial is proposed to test 19. Lul HG, Lee G, Dletrlch P, Low RI, Mason DT. Flecainide-induced QT prolongation and ventricular tachycardia. Am Heart J 1962;103:567- the hypothesis that elimination of ventricular ar- 569. rhythmias may reduce the excessive risk of sudden 20. Lul HK, Lee G, Stobbe D, Harris FJ, Mason DT. Effect of flecainide on ieft ventricular function (abstr). Clin Res 1963;31:13A. death in this patient group. On the basis of current as- 21. Pedrid PJ, Schoeneberger A, Lown 8. Congestive heart failure caused by oral disoovramide. N Enal J Med 1980:302:614-617. sessment, flecainide appears to be an excellent candi- ---r. ~~ 22. Klempt HW, Nayebagha-A, Fabry E. Antiarrhythmic efficacy of mexiletine. date drug for such an application. propafenone and flecainide in ventricular premature beats. A comparative Another application of great interest includes the use ;sF in patients after myocardial infarction. 2 Kardiol 1962;71:340- of flecainide for treatment of reentrant supraventricular 23. Swerdlow CD, Gong G, Echt DS, Winkle RA, Grlffln JC, Ross DL, Mason JW. Clinical factors predicting successful electrophysiologic pharmacologic arrhythmias, including those associated with AV bypass study in patients with ventricular tachycardia. J Am Coll Cardiol 1963;l: tracts as seen in the Wolff-Parkinson-White syndrome. 409-416. 24. Splelman SR, Schwarlz JS, McCarthy DM, Horowitz LN, Greenspan AM, Preliminary indications suggest that flecainide is an Sadowski LM, Josephson ME, Waxman HL. Predictors of the success or excellent drug in these applications. Hellestrand et a137 failure of medical therapy in patients with chronic recurrent sustained ventricular tachycardia: a discriminant analysis. J Am Coll Cardiol 1983; found flecainide to be effective in treating 12 of 14 cases 1:401-406. 25. Van Hamersveld DD, Stewart JR, Johnson TA, Andsrson JL. Oral flecainide of AV bypass tract reentrant tachycardia and 8 of 9 acetate for long-term treatment of ventricular arrhythmias in man (abstr). cases of AV nodal reentrant tachycardia evaluated by Circulation 1961;64:suppt IV:IV-316. February 27, 1984 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 53 1198 28. Granrud G, Salerno D, Hodges M, Kre)ci J, Lebens P, Aslnger R. Long-term 057Q364. flecainide is effective and well tolerated (abstr). Circulation 1982;66:suppl 32. Reynolds EW, VanderArk CR. Quinidine syncope and the delayed repo- ll:ll-1 l-11-69. larization syndromes. Mod Concepts Cardiovasc Dis 1976;45:117-122. 27. Schmid JR, Seebeck BD, Henrie CL, Banitt EH, Kvam DC. Some antiar- 33. O’Rourke RA, Horwitr LD. Effects of chronic oral quinidine on lefl ventricular rhythmic actions of a new compound, R-818, in dogs and mice (abstr). Fed performance. Am Heart J 1981;101:769-773. Proc 1975;34:775. 34. Giardina EV, Bigger JT. Antiarrhythmic effect of imipramine hydrochloride 28. Velebit V, Podrid P, Lown 8, Cohen BH, Graboys TB. Aggravation and in oatients with ventricular oremature comolexes without osvcholoaic.I _ de- provocation of ventricular arrhythmias by antiarrhythmic drugs. Circulation prkssion. Am J Cardiol 1962;50:172- 179.’ 1982;65:886-893. 35. Nademanee K, Hendrickson JA, Cannon DS, Goldreyer BN, Singh BN. 29. Nathan A, Hellestrand K, Bexton R, Banim S, Spurrell R, Cannon J. The Control of refractors life-threatenino ventricular arrhvthmias bv amicdarone. proarrhythmic effects of the new “antiarrhythmic” drug flecainide acetate Am Heart d 1981;iO1:759-768. - (abstr). J Am Coil Cardiol 1983;1:709. 36. Morady F, Scheinman MM, Hess DS, Sung RJ, Shen E, Shapiro W. Elec- 30. Poser R, Lombard1 F, Podrid P, Lown B. Aggravation of induced arrhythmias trophysiologic tasting in the management of survivors of out-of-hospital with antiarrhythmic drugs during electrophysiologic testing (abstr). J Am cardiac arrest. Am J Cardiol 1983;51:85-89. Coll Cardiol 1983;1:709. 37. Hellestrand K, Nathan AW, Bexton RS. Effect of flecainide on anomalous 31. Winkle RA, Mason JW, Grilfin JC, Ross D. Malignant ventricular tachyar- pathways and reentrant junctional tachycardia (abstr). Circulation 1982; rhythmias associated with the use of encainide. Am Heart J 1981;102: 66:suppl ll:ll-69