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Effects of Flecainide and Propafenone on Systolic Performance in Subjects With Normal Cardiac Function* Vincenzo Igino Santinelli, Oppo, Stefania Maione, Giunta, Flecainide and both their effects. the effects and are is often study was ance. limited (ejection shortening rameters (28 normal tolic were and blood drugs. systolic pressure internal percent FS (th) oth propafenone and in a on selected 12 women; structure and indexes of global [EF] and percentage mean did not diameter in was observed after (p<O.OO1), flecainide EF and (p<0.0Ol), acetate 1C antiarrhythmic left and agents of ventricular 1 However, other antiarrhythmic agents, related side effects. The flecainide are well known,’2 percent after are thick- are class effective in the and supraventricular their efficacy, like is often limited proarrhythmic as demonstrated tachythat of by doseeffects of by the possibility to increase the arrhythmic deaths tients with ventricular ectopy and ischemic disease (Cardiac Arrhythmic Suppressor in paheart 3 In addition to the proarrhythmic effects, flecainide has been shown to induce a slightly negative inotropic effect on significant function.’5 the left ventricle’ that becomes in patients with compromised Even if the risk of this latter adverse effect for example, *From the diography, Manuscript appears to be small, it is not Haissaguerre et a116 noted Laboratory of Clinical Electrophysiology clinically ventricular significant negligible; new-onset and I Clinica Medica, University of Naples, Italy. received April 28; revision accepted October Reprint requests: Dr Santinelli, Department ofCardiology, sity ofNaples, 80131 Naples, Italy 1068 FS from 37 was percent to 13 percent; from EF 65 percent patient after percent to recorded. moderate to 17 percent from These EF from reversible 58 percent reduction of 42 and in one (percent FS from 30 to 35 percent). that both intravenous flecainide mild negative inotropic effects and from to 40 percent respectively) propafenone 15 percent; and 55 percent to 35 percent, intravenous We conclude none exhibit left and propafeleading to a ventricular sys- tolic performance; however, impairment of systolic pump in some cases, a dramatic function may occur, suggesting careful first-line use of both subjects; finally, the drugs true as incidence agents ofthis is still unknown. EF of flecainide propafenone that propafenone) also in normal deleterious (Chest 1993; effect 103:1068-73) both decrease PW (p<O.00l after after ventricular both flecainide a significant PWex sys[ex]) after, randomized Heart rate change (p<O.00l) simultaneously (p<O.00l), management significantly paleft and (percent and perform- as monodimensional septum (IVS) p<0.0l changes were comparable and promptly reversible. In analyzing individual data, a marked systolic dysfunction was observed in two patients after intravenous flecainide percent systolic pump of fractional (15 mm) after or propafenone. increase propafenone; ening men recovery flecainide A significant and and side wail the early of either and noninvasively (PW) contractility (percent [percent th] and systolic excursion in all subjects at baseline, immediately thickening assessed and in injection dose-related indices cardiac fraction posterior by flecainide [percent FS]) as well of the interventricular ventricular B with in suppressing to evaluate function Echocardiographic function M.D.; M.D.; tachyarrhythmias, performed of intravenous 25 years) Palma, effective supraventricular left ventricular systolic population of 40 subjects age, Arnese, M.D.; F. C. C. F; Mario propafenone efficacy This , Mariarosaria Matarazzi, M.D. ventricular but Crescenzo ; M. D. andAnna , F. C. C. F; Al. D. M. D. Echocar7. Univer- ejection fraction; ex excursion; FS fractional shorten. 1VS = interventricular septum; LVIDd left ventricular end-diastolic dimension; LYIDs left ventricular endsystolic dimension; PW posterior wall; th thickening = ing; congestive with heart failure flecainide; in similarly, their overall in a recent experience editorial ment, Benditt et al’7 outlined that the of flecainide are becoming increasingly com- adverse apparent. effects 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. ‘ These cardiac side effects usually occur advanced heart disease, and they dependent. Thus, like flecainide, quires patients close monitoring with congestive in patients appear to be propafenone of left ventricular heart failure, during the first weeks of was designed to compare the intravenously flecainide none ively The study 40 subjects formance Effects administered on left assessed ventricular systolic by two-dimensional was performed with at of Flecainide rest, normal the and Propafenone majority on Systolic Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21669/ on 05/13/2017 function particularly in The present study inotropic effects of and propafe- function, noninvasechocardiography. in a selected cardiac with dose re- population of structure and of required whom Performance (Santinelli per- et a!) antiarrhythmic tachyarrhythmias. therapy because of NI-mode supraventricular and 88 percent, Treatment MATERIAL AND Once studied men population and years; age, department sion clinical presence instnimental older did not trict,lar reentry nodal tachycardia, and Treatment for Baseline five with a 2.5 and also view, was used thickness apex, the the different myocardial regions through of the IVS assessment th) and systolic ventricle various and excursion (percent biplane FS) and pump Echocardiograms who measurements cycles. Table 1 -Mean blinded expressed Intraohserver Values as mean and cm cm % FS, EF, % % IVSth, % IVSex, mm PWth, % PWex, by mm text for abbreviations; the two sets observed The two experi- but 3.4±0.6 <0.01 42.4±7.2 32.1±10.7 <0.001 62.9±7.0 54.2±6.8 <0.001 were for to observed pressure after both did not change vice versa, both of LVIDs. A of global percentage and images quantified and 25 sys- of FS, propafenone of the left in a fall percent of systolic and a decrease of and of23 percent ex was reduced to 25 percent in ventricle a func- of about FS after 12 both after propafenone, to 32 percent after after at Baseline NS 5.2±0.2 5.0±0.4 2.9±0.4 3.3±0.5 40±5.0 33.4±7.1 60.5±5.3 18.9 52.9±15.9 <0.001 72.9±17.3 by F and basal values; P on all parameters p Value NS <0.01 <0.001 16.4 NS 2.9±0.8 NS 55.8±14.3 <0.001 3.8±0.8 no significant were 1V After <0.001 31.2± 5.1±0.7 <0.001 vs respective and 54±5.4 41.4± 73.1±20.4 (B) Studied* P 3.9±1 while flecai- propafenone. Parameters Subjects th of the left ventricular about 27 percent after B NS induced t test peformed blood indices and pVah,e 10.9 changes rate flecainide be percentage showed <0.001 changes was decrease both EF EF 2.9±0.9 The Student Systolic significant of may the 3.9±1.1 P values. (30 mm) drug injections clearly demonstrated distributed depression of ventricular in nide 3.6±0.9 not after which about 5.0±0.7 F and imme- late significant. in heart function, of flecainide its systolic 2.9±0.47 to drug-induced and ± SD. considered 1). Two-dimensional three patients. 5.0±0.35 refer moni- at baseline, samples drugs. reduction was PW F p values continuwas drugs. b B 5.3±0.6 *See was changes Two-Dimensional Echocardiographic (F) and Propafrnone (P) in the 32.2± and sphygmomanometer. (15 mm) values indicated) of both a slight pump systolic agreements and mg/kg) pressure made earls’ as mean A p<O.O5 significant percent of left of at least ofFlecainide 18.3 data. tolic tion, (percent to the in the or other at a constant were arterial were and (2 echocardiogram of a standard (when injection at peak uniformly systolic quantified by value (± SD) ofM-Mode 44.6± ofhaseline by moving calculated given interobserver Injection LVDId, drug means infusion, unpaired the (Table During of overall independently to the and systemic are expressed and significant levels The (EF), as indices by Flecainide to the intravenously fenone are reported in Table 1. LVIDd after both flecainide and propafenone; drugs induced a significant increase as (IVS) shortening fraction 20 view two-chamber was ECC over flecainide (from 115±15 to 105±10 mm Hg) and propafenone (from 1 10 ± 17 to 105 ± 12 mm Hg). Mean values of echocardiographic parameters before and after injection of both flecainide and propa- ventricle thickening fractional assumed analyzed were were cardiac LVDIs, after function. were observers PW period. crossed RESULTS end- at various identified Both then were flecainide Analysis No well contractility systolic ejection left rapidly. ventricular axis septum and were patieIlts phase. compare to the American scan either measurements the All values paired in the as The were percent were and an 770 ventricular according all to receive injected In addition, after Statistical 2 was (lIP (LVIDs) regional percent (ex); method, ventricular left positions left of both in all patients discontin- short four-chamber qualitatively tored completed, were atrial performed system short-axis in the 10 mm. recorded. Echocardiographic patients procedure interventricular to assess M-mode was recommendations.#{176} and during were fashion they (2 mg/kg) showed array (PW), after ously recover 34 had was of the to obtain of the drug-free tachycardia. dimension wall a 48-h had and an ectopic Parasternal in a standardized base contractility enced obtained. end-systolic posterior transducer ellipse nature was transducer. level and visualized test, All MHz systolic the apical pathway; agents The ageilt myocardial All ventricular drug; diately had an atrioven- 1 had of a phased of Echocardiography between the 3.5 or 92 percent disease; 40 years defect. examination means ventricular Society was by (LVIDd) left than exercise antiarrhythmic consent midventricular diastolic artery studies as first the Study manner diastolic left baseline in a single-blind propafenone rate and and No patient to accessory half-lives. informed of as assessed recordings. 14 patients a benign echocardiographic standard and 1 had all previous at least and last Echocardiographic the the propafenone Inclu- or coronary tachycardia, our because examination perfusion due 1991 disease older study: reentry the with explained at the any tachycardia atrioventricular AC), detect to two-dimensional thallium-201 an electrophysiologic underwent ECC, (8 men years), 17 to 56 tachycardias. radiograph) patients 45 from referred heart hypertension oldest than scintigraphy March echocardiographic in the women ued (12-lead ofessential in addition, and paroxysmal cilest of adequate history those of structural patients varied from 1989 the absence and in age selected echocardiography, clinical range years) of symptomatic were Doppler of 40 nonconsecutive September episodes criteria by whose 25 between recurrent consisted 12 women mean were Protocol randomized The ineastrements METHODS Ihtients (28 two-dimensional respectivel) differences <0.01 were found comparing comparable. CHEST Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21669/ on 05/13/2017 I 103 I 4 I APRIL, 1993 1069 2A and FIGURE the changes recordings were similar to those recordings a marked observed in Figure in the same subject after detected (IVS = interventricular obtained (bottom) it appears still exist B. M-mode echocardiographic (26-year-old man) showing left) in a patient (A, were fiecainide septum; to be interesting because controversial data about the inotropic properties of propafe- before (top) and after (bottom) IV propafenone drug-induced impairment of systolic function: 1A and B. In B (right) the echocardiographic are shown; only minor changes in systolic function PW = posterior wall). The latter therefore, serious none. In particular, negative inotropic concentrations of propafenone in vitro24 as well as in animal clinical studies by oral propafenone decreased have effects have been studies;23 demonstrated a reduction in patients or clearly of with impaired either ventricular high recognized in addition, of EF minimally and does believe not that unpredictable fect ofboth flecainide to outline that in induced dramatic propafenone changes, remaining function.27 effect we caused comparable patients. only after paired. ofan subclinical experience. in the First, albeit tion normal there negative propafenone lion. should are inotropic on Second, left both promptly in some be ventricles. significant effects ventricular drugs reversible young no emphasized and are of to induce impairment healthy pump patients ofsystolic with dude a severe func- this condition because a ef- hemodynamic observed in all the hand, similar findings patient with dysfunction. the presence cardiomyopathy and related; It is important with flecainidesystolic function, flecainide in the marked systolic permits us to rule out of the left ventricular functional in these patients, although we func- otherwise underlying dose considered adverse minor our differences flecainide systolic able in be hemodynamic to those On the other were observed propafenone-induced This observation observations to be may and propafenone. the two patients impairment of However, other clinical studies on propafenone have found no further decrease in EF in patients whose initial systolic pump function had been imTwo appear this as a cause alterations observed cannot definitely ex- 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 CHEST Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21669/ on 05/13/2017 I 103 I 4 I APRIL 1993 1071 2A and FIGURE the changes recordings were similar to those recordings a marked observed in Figure in the same subject after detected (IVS = interventricular obtained (bottom) it appears still exist B. M-mode echocardiographic (26-year-old man) showing left) in a patient (A, were fiecainide septum; to be interesting because controversial data about the inotropic properties of propafe- before (top) and after (bottom) IV propafenone drug-induced impairment of systolic function: 1A and B. In B (right) the echocardiographic are shown; only minor changes in systolic function PW = posterior wall). The latter therefore, serious none. In particular, negative inotropic concentrations of propafenone in vitro24 as well as in animal clinical studies by oral propafenone decreased have effects have been studies;23 demonstrated a reduction in patients or clearly of with impaired either ventricular high recognized in addition, of EF minimally and does believe not that unpredictable fect ofboth flecainide to outline that in induced dramatic propafenone changes, remaining function.27 effect we caused comparable patients. only after paired. ofan subclinical experience. in the First, albeit tion normal there negative propafenone lion. should are inotropic on Second, left both promptly in some be ventricles. significant effects ventricular drugs reversible young no emphasized and are of to induce impairment healthy pump patients ofsystolic with dude a severe func- this condition because a ef- hemodynamic observed in all the hand, similar findings patient with dysfunction. the presence cardiomyopathy and related; It is important with flecainidesystolic function, flecainide in the marked systolic permits us to rule out of the left ventricular functional in these patients, although we func- otherwise underlying dose considered adverse minor our differences flecainide systolic able in be hemodynamic to those On the other were observed propafenone-induced This observation observations to be may and propafenone. the two patients impairment of However, other clinical studies on propafenone have found no further decrease in EF in patients whose initial systolic pump function had been imTwo appear this as a cause alterations observed cannot definitely ex- 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 CHEST Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21669/ on 05/13/2017 I 103 I 4 I APRIL 1993 1071 effects. It may known proarrhythmic be hypothesized that, effect12”3 like the well- in some observed otherwise healthy subjects, flecainide and none exhibit a primary adverse hemodynamic in some subjects with norma] cardiac The results of our clinical observations failure by Haissaguerre ence with flecainide. on the implications type study agents the clinical as a worsening disquieting agents be like adverse failure because cautiously only in patients without clinical BL, previous flecainide mandate with heart evidence as first-line failure, of left agents but also ventricular 11 randomized, acetate to sinus rhythm. JL, Gilbert acetate EM, prevents supraventricular Alpart recurrence tachycardia. Cir- placebo-ntrolled Kirsten E, J. Cuerrero arrhythmias: Effects double-blind, dose-ranging of parallel, study. Am Heart C. Efficacy of oral a placebo J 1985; Hammili SC, McLaren CJ, Double Wood blind 1987; chronic ventricular exercise study. Eur Osborn MJ, of intravenous reentrant Cersh BJ, propafenone J tachycardia. for Am Coll 9:1364-68 P, Leclercq the antiarrhvthmic and ventricular JF, Assayag efficacy Klein CJ, P European experience of propafenone arrhvthmias. CR, DL, study supraventricular Coumel on cross-over 6:123-29 DR. Kerr propafenone controlled J Am Axelson of recurrent JE, atrial with for supraventricular Cardiol 1984; Cooper JC. fibrillation. 54:60D-6D Propafenone J Am for Cardiol 1988; 61:914-16 limitation of this of subjects definitive study that conclusion phenomenon. the incidence, mechanisms is does about Further time of such but severe adverse without clinically not the studies course, alterations reaction underlying the relatively allow true small us to draw incidence 12 a of this Am are needed to elucidate and physiopathologic because even a rare 13 The in a set of young structural heart patients disease Thus, we believe incompletely drugs is needed clinical that more knowledge defined antiarrhythmic before they are widely accepted 15 flecainide inotropic 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 normal cardiac intravenous use of both agents also in subjects drugs with 1984; infarction. PW, J, venous flecainide disease. Br 17 function: 1984; des arvthimies Mal Coeur 1987; 19 20 function. JL, Johnson Stewart TA, treatment JR. Conard of GJ, ventricular BA, Oral Van Hamersveld flecainide acetate N J arrhythmias. EngI DD, for Med 22 HJ, SB, Higgins mias Roden by DM, et al. twice Maffucci Suppression daily dosing RJ, Vesper of resistant of flecainide. BS, Conard ventricular Am J 1981; ii . Long term use of flecainide in patients wih supraven- Effects dial Effects 1991; on Am Matayer P. le traitement de 98 patients. Arch S. Flecamnide supraventricular 83:345-49 of its profile. Eur J Heart HK, JJ, Lee NC, heart Verma infarction. of Flecainide Eur Eur and Propafenone J J Heart GIC, 1984; Cardiol CIC, J Hussain in 1984; flecainide Hemo- flecainide 1983; acute (R- 51:422-26 M, Taylor myocardial 5:289 Hussain M, acetate Taylor 5K. in myocar- 5(B):113 on Systolic Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21669/ on 05/13/2017 HE. agent, flecainide of infused Heart meas- P. Kulbertus B, Nelson of Nelson effects of M-mode ofechocardiographic Am SP, Silke SP, A. The Committee on Society of Echocar- antiarrhythmic disease. [abstract]. 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