1301 Effects of Electrophysiologic-Guided Therapy with Class JA Antiarrhythmic Drugs on the Long-Term Outcome of Patients with Idiopathic Ventricular Fibrillation with or without the Brugada Syndrome BERNARD BELHASSEN, M.D., SAMI VISKIN, M.D., ROMAN FISH, M.D., AHARON GLICK. M.D., ISRAEL SETBON, M.D.,* and MICHAEL ELDAR, M.D.^ From the'Departmeni of Cardiology. Tel-Aviv Sourasky Medical Center<'*Sapir Medical Center.and ""^Chaim Sheba Medical Center, and Tel-Aviv University, Sackler School of Medicine, Tel-Aviv,'Israel \ Electrophysiologic Drug Testing in Idiopathic VF. Introduction: Implantation of a iniplantabie cardioverter defibrillator (ICD) is viewed universally as the "gold standard" therapy for patients with idiopathic ventricular fihrillation (VF). We sought to sludy the long-term value of electrophysiologic (EP)-guided therapy with Class IA antiarrhythmic drugs in patients with idiopathic VF with or without the Brugada syndrome. Methods and Results: We performed EP studies in 34 consecutive patients who had idiopathic VF with (n = 5) or without (n = 29) the Brugada syndrome. All patients with inducihie sustained polymorphic ventricular tachycardia (SPVT) or VF underwent repeated EP evalua- tion after oral administration of a Class IA antiarrhythmic drug (mainly quinidine). Patients rendered noninducihie received this therapy on a long-term basis. SPVTA'F were induced in 27 (79.4%) patients at haseline studies. Class IA drugs effectively prevented induction of SPVTA'F in 26 (96%) patients. Of the 23 patients treated with these medications, no patient died or had a sustained ventricular arrhythmia during a mean follow-up period of 9.1 ± 5.6 years (7 to 20 years in 15 patients). Two deaths occurred in patients without inducible SPVTA'F at baseline studies who had been treated empirically. Conclusion: Our results suggest that EP-guided therapy with Class IA agents is a reasonable, safe, and effective approach for the long-term management of patients with idiopathic VF. A randomized prospective study of EP-guided Class IA therapy in patients with ICDs seems warranted. Ky Cardiovasc Electrophysiol. Vol. 10. pp. U01-13J2, October 1999} idiopathic ventricular fibrillation, Brugada syndrome, electrophysiologic study. Class IA antiarrhythmic drugs, quinidine Introduction In 5% to 10% of patients resuscitated from out-of-hospital cardiac arrest due to ventricular fibrillation (VF), no obvious heart disease can be found despite extensive investigation. Tbis ar- rhythmia is referred to as "idiopatbic VF."'^^ In Address for correspondence: Bernard Belhassen, M.D., Department of Cardiology, Tel-Aviv Sourasky Medical Center, Weiznian Streel 6. Tel-Aviv 64239, Israel. Fax: 972-3-697-4418; E-mail: [email protected] j Manuscript received 8 April 1999: Accepted for publication 14 June 1999. 1992, Brugada and Brugada^ identified a sub- group ot" patients with idiopathic VF who have a unique ECG pattern of right bundle branch block witb ST elevation in tbe right precordial leads. In tbese patients, evidence for a genetic basis that is related to mutations in the cardiac sodium chan- nel gene SCN5A were presented recently."^ Implantation of an implantable cardioverter defibrillator (ICD) is advocated by most investi- gators worldwide as first-line tberapy for patients witb idiopatbic VF. Tbis recommendation is based on several premises: (1) tbe relatively young age of tbe affected patients along with a normal life expectancy in addition to tbe arrbyth-
Transcript
1301
Effects of Electrophysiologic-Guided Therapy with ClassJA Antiarrhythmic Drugs on the Long-Term Outcome ofPatients with Idiopathic Ventricular Fibrillation with or
without the Brugada Syndrome
BERNARD BELHASSEN, M.D., SAMI VISKIN, M.D., ROMAN FISH, M.D.,AHARON GLICK. M.D., ISRAEL SETBON, M.D.,* and MICHAEL ELDAR, M.D.^
From the'Departmeni of Cardiology. Tel-Aviv Sourasky Medical Center<'*Sapir Medical Center.and"" Chaim Sheba Medical Center, and Tel-Aviv University, Sackler School of Medicine, Tel-Aviv,'Israel \
Electrophysiologic Drug Testing in Idiopathic VF. Introduction: Implantation of ainiplantabie cardioverter defibrillator (ICD) is viewed universally as the "gold standard"therapy for patients with idiopathic ventricular fihrillation (VF). We sought to sludy thelong-term value of electrophysiologic (EP)-guided therapy with Class IA antiarrhythmic drugsin patients with idiopathic VF with or without the Brugada syndrome.
Methods and Results: We performed EP studies in 34 consecutive patients who had idiopathicVF with (n = 5) or without (n = 29) the Brugada syndrome. All patients with inducihiesustained polymorphic ventricular tachycardia (SPVT) or VF underwent repeated EP evalua-tion after oral administration of a Class IA antiarrhythmic drug (mainly quinidine). Patientsrendered noninducihie received this therapy on a long-term basis. SPVTA'F were induced in 27(79.4%) patients at haseline studies. Class IA drugs effectively prevented induction of SPVTA'Fin 26 (96%) patients. Of the 23 patients treated with these medications, no patient died or hada sustained ventricular arrhythmia during a mean follow-up period of 9.1 ± 5.6 years (7 to 20years in 15 patients). Two deaths occurred in patients without inducible SPVTA'F at baselinestudies who had been treated empirically.
Conclusion: Our results suggest that EP-guided therapy with Class IA agents is a reasonable,safe, and effective approach for the long-term management of patients with idiopathic VF. Arandomized prospective study of EP-guided Class IA therapy in patients with ICDs seemswarranted. Ky Cardiovasc Electrophysiol. Vol. 10. pp. U01-13J2, October 1999}
In 5% to 10% of patients resuscitated fromout-of-hospital cardiac arrest due to ventricularfibrillation (VF), no obvious heart disease can befound despite extensive investigation. Tbis ar-rhythmia is referred to as "idiopatbic VF."'^^ In
Address for correspondence: Bernard Belhassen, M.D., Departmentof Cardiology, Tel-Aviv Sourasky Medical Center, Weiznian Streel6. Tel-Aviv 64239, Israel. Fax: 972-3-697-4418; E-mail:[email protected] j
Manuscript received 8 April 1999: Accepted for publication 14June 1999.
1992, Brugada and Brugada^ identified a sub-group ot" patients with idiopathic VF who have aunique ECG pattern of right bundle branch blockwitb ST elevation in tbe right precordial leads. Intbese patients, evidence for a genetic basis that isrelated to mutations in the cardiac sodium chan-nel gene SCN5A were presented recently."^
Implantation of an implantable cardioverterdefibrillator (ICD) is advocated by most investi-gators worldwide as first-line tberapy for patientswitb idiopatbic VF. Tbis recommendation isbased on several premises: (1) tbe relativelyyoung age of tbe affected patients along with anormal life expectancy in addition to tbe arrbyth-
1302 Journal of Cardiovascular Electrophysiology Vot. 10. Na. 10. October 1999
mic disorder'; (2) tbe relatively high recurrencerate of life-threatening arrbytbmic events in botbtreated and untreated patients'; (3) the low in-ducibility rate of sustained ventricular tacbyar-rbythmias at baseline electropbysiologic (EP)study (whicb prevents pbarmacologic drug test-ing)^; and (4) tbe uniform efficacy of ICD to ap-propriately diagnose and terminate VF, therebypreventing sudden cardiac death.
Twenty years ago. we observed our first pa-tient with recurrent idiopatbic VF.^ This patienthad multiple episodes of spontaneous VF, andthe same arrhythmia was easily inducible atbaseline EP study. However, following oralquinidine therapy, arrhythmias could no longerbe induced, nor did they recur during follow-up.Since tben, we have undertaken a systematicevaluation of the effects of Class IA antiarrbyth-mic drugs on arrbythmia induction in patientswitb idiopathic VF. A report including our firstfive patients treated according to tbis policy waspublisbed more tban 10 years ago.^ In the presentstudy, we report our experience with 34 consec-utive patients with idiopathic VF (including fivepatients eventually recognized as having tbe Bru-gada syndrome) in whom long-term therapy wasguided by EP drug testing with Class IA drugs.
Methods
Patient Selection
Following our initial publication,^ Israeli elec-trophysiology laboratories were invited to partic-ipate in a prospective study of patients with id-iopatbic VF. Criteria for inclusion in tbe studyincluded all tbe following: (I) aborted cardiacarrest with documented VF; (2) no recognizablebeart disease to account for the arrhythmic eventba,sed on normal findings during noninvasive(echocardiogram) and invasive (right and leftventriculography and coronary angiography)evaluation; (3) absence of triggering factors forcardiac arrest, sucb as drug toxicity, electrolyteor metabolic disturbances, or chest trauma: (4)normal QT interval on repeated ECGs; {5) per-formance of an EP study showing tbe absence ofaccessory patbway conduction and tbe inabilityto induce any supraventricular tachycardia; (6)EP testing with at least one Class IA antiarrhyth-mic agent in patients with inducible sustainedventricular tachyarrbythmias; and (7) long-termtberapy based on the results of EP testing. Pa-
tients were excluded from study if they had id-iopathic sustained monomorpbic VT or catechol-amine-sensitive polymorphic VT.**
Baseline EP Studies
EP studies were performed using a protocol ofprogrammed ventricular stimulation (PVS) thathad evolved over the years. From 1979 to 1982,PVS was performed only from tbe right ventric-ular apex, using tbree basic cycle lengths (600,500, and 400 msec) and a maximum of twoextrastimuli. In 1983, pacing from the right ven-tricular outflow tract was added, and the numberof basic cycle lengths was decreased to two (usu-ally 600 and 400 msec). The use of triple extra-stimulation was introduced in 1988. In addition,for tbe last 20 years our protocol has includedrepetition (lOX) of double extrastimulation atthe shortest coupling intervals.'' This was done ateach pacing site and for each of the cycle lengthstested. We previously found tbat tbis protocolincreases the sensitivity of PVS protocols with-out significantly affecting its specificity.^ In1988, repetition (5X) of triple extrastimulation atthe shortest coupling intervals was introduced, aswe found that it further increases sensitivity ofPVS protocols while keeping specificity in thesatisfactory range (> 90%) (unpublisbed data).The stimulus current intensity was set at 5Xdiastolic tbresbold (but never > 3 mA) in 29patients and at double diastolic threshold in fivepatients.
Drug Studies
In patients who had sustained polymorphicventricular tachycardia (SPVT)/VF induced atbaseline EP studies, PVS was repeated after theoral administration of a Class IA drug: quinidinebisulfate (1,000 to 2,000 mg/day), disopyramidephosphate (450 to 600 mg/day), or procainamidehydrochloride (3,750 mg/day). Quinidine wasthe first drug tested, and if sustained VT/VFremained inducible on the first dose tested, athird EP study was perfonned on a higber quin-idine dosage. In case of quinidine intolerance,disopyramide or procainamide was tested.
Tbe effects of intravenous administration ofdisopyramide (2 mg/kg per 5 min) or procain-amide (500 to 1,000 mg at 50 mg/min) on ar-rhythtTiia induction were tested at the completionof the baseline EP study in seven patients. How-ever, the results of this testing did not affect tbe
Belhassen, et at. Electrophysiologic Drug Testing in Idiopatliic VF 1303
evaluation of chronic oral therapy. Serum bloodlevels of antiarrhythmic drugs were determinedduring EP testing.
Definitions
SPVT/VF was defined as a ventricular tacby-arrbythmia manifesting a continuously varyingmorphology witb a mean cycle length < 200msec, wbicb required cardioversion for termina-tion or resulted in clinical cardiac arrest beforespontaneous termination. Nonsustained VT wasdefined as a VT of ^ 6 complexes that wasshorter tban 30 seconds in duration and not as-sociated witb loss of consciousness. Arrbytbmiaswere defined as "noninducible'" when < 6 repet-itive ventricular complexes were induced.
Follow-Up
Patients were discharged witb a drug regimentbat effectively prevented the induction of SPVT/VF, and they were followed as outpatients every6 to 12 months. Drug serum levels were moni-tored closely during follow-up, and drug dosagemodified to acbieve the serum levels found at EPtesting. Patients who became intolerant of theirmedications were advised to undergo EP testingon another antiarrhytbmic drug or to undergoimplantation of an ICD. In addition, wben tbenontboracotomy approach became available, theoption of drug discontinuation and ICD implan-tation was discussed witb each patient at leastonce yearly. Patients in whom SPVT/VF couldnot be induced at baseline EP studies or couldnot be prevented by antiarrhythmic drugs wereadvised to undergo implantation of an ICD whennontboracotomy devices became available. How-ever, patients evaluated before the era of nontbo-racotomy devices received empiric therapy witbquinidine.
Patient compliance with medications was es-timated during each follow-up visit. Drug com-pliance was defined as "excellent" when a patientregularly took tbe prescribed dosage and his orher serum drug levels were consistently in thetherapeutic range; "moderate" when a patienttook the medication irregularly, albeit > 50% oftime, or decreased tbe dose by less than half, andbis or ber serum drug levels were occasionallybelow tbe therapeutic range; and "poor" wben apatient took tbe medications < 50% of the timeor at less than bait of tbe prescribed dose, or bisor her serum drug levels were occasionally un-
detectable. Notes about estimated drug compli-ance were noted prospectively in the patients'charts.
Patients with ICDs were followed at 2- to4-montb intervals. At each visit, they were ques-tioned about the presence of syncope or devicediscbarges, and tbeir ICDs were inteirogated. Allpatients underwent repeat echocardiogram every5 years. For patients lost to follow-up, the regis-try of the Ministry of Interior was examined byMay 1, 1999 to ascertain if the patients were stillalive.
Statistical Analysis.
All values are expressed as mean ± SD orpercentages (as appropriate). Univariate analysiswas performed by Chi-square test for discretevariables. P < 0.05 was considered statisticallysignificant.
Results
Patient Characteristics
Tbe study cobort consisted of 34 patients (19males and 15 females; age range 14 to 69 years.40.6 ± 14.5). Patient characteristics are listed inTable 1. The first five patients were included inour previous publication.^ Most patients (n = 26)underwent EP studies in our hospital. Twenty-nine patients (14 males and 15 females) had anormal baseline ECG. Five patients (no. 3, 23,24, 25, 33), all males, had tbe Brugada sign (Fig.I).'' Of tbe 34 patients, one patient (no. 26)underwent EP study 6 years before cardiac arrest,due to an bistory of asymptomatic higb-gradeventricular arrhythmias. In this patient, no sus-tained ventricular arrbytbmias were induced us-ing up to two extrastimuli and repetition of dou-ble extrastimulation.^
Baseline EP ResuUs
Tbe interval between the first documented VFand tbe baseline EP study ranged from a fewdays lo 3 years, lasting ^ 4 weeks in 21 (62%)patients. Baseline EP results are listed in Table 1.Baseline studies were performed in 27 (79%)patients in the absence of antiarrbythmic therapy.Tbe remaining seven patients (no. I, 3. 4. 8, 12,16, 22) were on amiodarone therapy tbat wasstarted following the cardiac arrest.
1304 Journal of Cardiovascular Electrophysiology Vol. 10. No. 10. October 1999
IV PRO 500 (3.1)QND 1500(2.1)IV PRO 1000(12.7)QND 1000(1,0)QND 1500(3.7)
IV PRO 500 (5.3)QND 1.500(6.2)IV PRO 500 (3.0)IV PRO 1000 (8.9)QND 1500(3.1)SOT 480IV PRO 500 (2,7)QND 15(X)(3.7)QND 2250 (4,4)
InducedArrhylhmiii
NoNoNoNo
NSVT (7)VFNoNo
NSVT (18)NoNo
NSVT (16)NoNo
NSVT (8)
VFNoNo
NoVF
NSVT (10)
NoNSVT (16)
No
NoNSVT (9)
VFVFNo
NSVT (15)
NoNoNoVFNo
NSVT (10)NoVFVFNoVFVF
NSVT (48)No
Follow-Up(months)
241218
209170160
144143
137136132.5
12296
119
113488785
74.57069
6760,55757
41403833
32
292117
15
11
BL = blood serum level (mg/L): DIS = disopyramide: I = immediate trial of extraslimulation: IV = intravenous: Max HS = maximal numberof exiraslimuli delivered; NSVT = nonsu,slained ventrieular tachycardia (number of beats): PRO = procainamide: QND = Ljuinidine: R =repetition of extrasiimulaiion; RVA = right ventricular apex: RVO = right ventricular outllow tract (basic cycle iengih in msec): SOT =sotalol: VF = ventricular fibrillation.
SPVT/VF was itiduced in 27 (79.4%) patients,in a reproducible fashion in all five patients (no.28, 29, 32, 33, 34) in whom reproducibility oftachyarrhythmia induction was examined. Non-sustained PVT (9 to 13 complexes) was induced
in 3 (8.8%) patients. No significant ventriculararrhythmias could be induced in 4 (1 1.8%) pa-tients. SPVT/VF was induced in all five (100%)patients with the Brugada syndrome and in 22(76%) patients with normal baseline ECG (P =
Belhassen. et al. Electrophysiologic Drug Testing in Idiopathic VE 130.5
aVI V4I
«VL—N
Figure 1. Patient.?. Twetve-tead ECG during sinus rtiyttimon no antiarrtiythmic medication stiowing a typicat "Bru-gada sign."
NS).The inducibility rate of SPVTA^F was sim-ilar in patients who received amiodarone at base-line study (6 of 7 [86%]) and in those who didnot (21 of 27 [78%1) (P = NS). SPVT/VF wasinduced in 10 (83%) of 12 patients studied withprotocols using two extrastimuli and in 17 (77%)of 22 patients studied with X 3 extrastimuli (P =NS). SPVT/VF was induced with single, double,and triple ventricular extrastimulation in 1, 15,and 11 patients, respectively (Fig. 2A). Inductionof SPVT/VF occurred during repetition of dou-ble and triple extrastimulation in five and twopatients, respectively.
EP Drug Testing
All 27 patients who had induction ofSPVT/VF at baseline EP studies underwent drugtesting (Table 1). Oral quinidine, disopyramide,and procainamide were evaluated in 2.5, 4. and 1patient, respectively. Oral treatment with a ClassIA antiarrhythmic agent effectively preventedthe induction of SPVT/VF in 26 (96%) of 27patients, including 4 (80%) of 5 patients with the
RVA
Figure 2. Patient 3. Data from the initial etectropttysiotogic (EP) studies (November 18. 1981). Shown are ECG leads I, U,III. and V,. as wett as etectrograms from the right ventricular apex (RVA). (A) During basetine EP study performed afier 10days of amiodarone therapy, a sustained potymorphic ventricutar tachycardia/ventricutar fibrittation is induced at an"immediate triat" of doubte e.xtnisttmtitatlon. (B) After addition of quinidine, onty a few repetitive ventricutar beats areinduced using a protocot that inctuded up to tno extrastlrnuti ami repetition (n = 10) of doubte extrastimutation detivered fromttie RVA at ttiree basic cycte lengths (60, 500, and 400 msec).
1306 Journal of Cardiovascular Electrophysiology Vol. 10, No. 10. October 1999
Brugada syndrome and al! 22 (100%) patientswith nonnal ECG (P = NS). Quinidine therapywas effective in 24 (96%) of 25 patients tested(Fig. 2B). In 16 of these 24 patients, only repet-itive ventricular beats (mean 2 ± 2) were in-duced, whereas asymptomatic nonsustained PVT(7 to 18 heats, mean 13 ± 4) was induced in theremaining 8 patients. In 20 (83%) of the 24quinidine responders., the drug was effective atthe first dose tested (mean daily dosage 1.510 ±133 mg), whereas in the remaining 4 (17%)patients, a higher dose (mean 2,250 ±612 mg)was required. The effective quinidine serumblood levels ranged from 1.0 to 7.5 mg/L (mean3.4 ± 1.6). Oral disopyramide (450 to 600 mg/day) and oral procainamide (3,750 mg/day) wereeffective at the first dose tested in four and onepatient, respectively.
Three patients who were rendered noninduc-ible by quinidine but developed intolerance tothat medication subsequently were tested on oraldisopyramide. In all instances, no significantventricular arrhythmias could be induced. In con-trast, oral sotalol (320 to 480 mg/day) did notprevent induction of VF in one patient who re-sponded to quinidine and in one patient with theBrugada syndrome in whom quinidine also wasineffective.
Class IA drugs were less effective duringacute intravenous testing than after oral therapy.Of the 5 patients tested on intravenous procain-amide, 2 had inducible SPVT/VF, yet all 5 wererendered noninducible following oral quinidinetherapy. Similarly, 1 of 2 patients tested withintravenous disopyramide had inducible SPVT/VF, yet both were noninducible on oral quinidineor disopyramide.
The ventricular effective refractory periods atthe right ventricular apex (during pacing a basiccycle length of 600 msec) were 228 ± 14 msecbefore and 263.5 ± 15 msec after administrationof Class IA antiarrhythmic agents (P < 0.0001).
Follow-Up
As of May I, 1999, 32 patients are alive andundergoing regular follow-up. Two patients (no.12, 15) were lost to follow-up 1 and 2 years afterpresentation, respectively. Both patients wereregistered as dead 4 and 7 years after diagnosis,respectively (see later).
EP-guided therapy
All 26 patients who had inducible SPVT/VFprevented by Class IA drugs were discharged onthese effective medications. All are alive anddoing well after 11 to 241 months (mean 102 ±65) of follow-up. This includes six patients whohad a positive baseline EP study on amiodaroneand who were rendered noninducible on a ClassIA drug and amiodarone combination. Three ofthese patients (no. 1. 3, 22) were discharged onthis combination: amiodarone was discontinuedin the retnaining three patients. Two patients (no.22, 33) developed intolerance to quinidine anddisopyramide within 1 month of therapy andunderwent implantation of an ICD. One of thesepatients (no. 22) decided to continue taking ami-odarone. In these two patients, device interroga-tion did not reveal ventricular tachyarrhyihmiasduring a 14- and 60'month follow-up period,respectively. Nevertheless, one of the patients(no. 33) experienced several inappropriate dis-charges due to rapid atrial tachyairhythmias ofunclear mechanism. Another patient (no. 10) be-came intolerant of disopyramide utter a fewmonths and was treated with oral sotalol for anadditional 8 years. She then opted for implanta-tion of an ICD, which has not discharged sinceimplantation.
All 23 patients who received long-term ther-apy with Class IA drugs found to be effective atEP studies have remained free of sustained ven-tricular arrhythmias over a mean follow-up pe-riod of 109 ± 67 months (range 11 to 241).Moreover, all but 2 of these 23 patients haveremained entirely symptom-free during fol-low-up periods ranging from II to 241 months(mean 110 ± 69) and lasting > 7 years in 15patients. Two patients had recurrent symptoms.Patient 1 I had syncopal episodes due to nonsus-tained polymorphic (with a normal QT interval)after 8 months of procainamide therapy at a timewhen she had severe laxative-induced hypokale-mia. Following correction of the hypokalemia,she remained free of symptoms and arrhythmiason the same procainamide regimen for the sub-sequent 114 months. Patient 16 had recurrentpresyncope after 4 years of therapy with 1,500mg of quinidine. He underwent a new EP .studyon this medication. Nonsustained PVT was in-duced, and the dose of quinidine was increased to2,000 mg. This patient has remained asymptom-atic for an additional 39 months.
Compliance with therapy was excellent or
Belhassen. et al. Eiectrophysiologic Drug Testing in Idiopathic VF 1307
moderate in 16 and 3 patients, respectively.Compliance was poor in the remaining four pa-tients (no. 3, 6.. 17, 19). Patient 3 took amioda-rone and quinidine regularly for 5 years beforediscontinuing all medications for the next 6 yearsand accepting amiodarone for the last 6 years.The other three patients (no. 6, 17, 19) discon-tinued their medications or dramatically reducedtheir doses for period.s ranging from 1 to 5 years.
Repeat EP study was perfonned in two pa-tients 8 years (no. 8) and 11 years (no. 3) afterinitial studies. In patient 8, the study was per-formed on quinidine and showed no induciblearrhythmias with triple extrastimulation. In pa-tient 3, a baseline study performed on no antiar-rhythmic medication showed VF induction withrepetition of double ventricular extrastimulation(Fig. 3). After addition of quinidine, no arrhyth-mias could be induced using triple extrastimula-tion (Fig. 4).
During our yearly discussions of alternativetherapeutic options, two patients (no. 20, 26)opted for drug discontinuation and ICD implan-tation after 59 and 44 months of antiarrhythmictherapy, respectively, during which they wereasymptomatic. After discontinuation of antiar-rhythmic therapy, no discharge from the ICDoccurred in these patients during a 10- and8-month follow-up period, respectively.
Non-EP-guided therapy
Of the 7 patients with noninducible sustainedtachyarrhythmias at baseline EP study, 5 arealive after follow-up periods ranging from 21 to74.5 months (mean 46 ± 24) and 2 died (4 and 8years, respectively), after the baseline study. Ofthe 5 patients alive, one patient (no. 18) hasremained asymptomatic for 74.5 months whilebeing treated with quinidine and refuses ICDimplantation. Four patients (no. 21, 27, 30, 31)had an ICD implanted. Three of the 4 patientswith an ICD have remained free of ICD dis-charges for 21 to 67 months while on no antiar-rhythmic medication. One patient (no. 30) expe-rienced an inappropriate discharge from thedevice. One of the ICD patients (no. 27) hadfrequent symptomatic nonsustained VTs thateventually were controlled with empiric quini-dine therapy.
The two deaths involved two patients who hadno sustained ventricular tachyarrhythmias atbaseline EP studies with a maximum of twoventricular extrastimuli. These patients were not
followed at our institution, and the circumstancesof the deaths are unknown. Patient 12 with noinducible arrhythmias was empirically treatedwith quinidine but, against our advice, was givenmexiletine for 1 year. This patient was lost tofollow-up. He was 77 years old when he died.Patient 15 with inducible nonsustained PVT (12beats) also was empirically given quinidine andthen disopyramide for 1.5 years, but subse-quently discontinued her medications for 6months before being lost to follow-up. She died2 years later at the age of 41 years.
The only patient in whom quinidine failed toprevent the induction of SPVT/VF at EP studywas a 22-year-old man with the Brugada syn-drome (no. 24). Sotalol also was ineffective, andthe patient received an ICD without drug ther-apy. The latter successfully terminated multipleepisodes of VF beginning 24 months after im-plantation. Empiric therapy with quinidine wasstarted, and no arrhythmias recurred.
Discussion
Main Findings
This is the largest series of patients with idio-pathic VF who have been treated according tothe results of EP testing. The relatively longfollow-up period of the present series allowsadequate appraisal of this form of therapy. Ourresults suggest that an EP-guided managementwith Class IA agents is possible, safe, and effec-tive in most instances. In contrast, an unaccept-able mortality rate was observed among patientswho had no sustained ventricular tachyarrhyth-mias inducible at baseline study and did notreceive an ICD.
Baseline EP Features
The high inducibility rate of SPVT/VF ob-served in our study (79.4%) is in agreement withthat observed in small series of patients withidiopathic VF with or without the Brugada syn-drome.'"'- However, lower (22% to 50%) induc-ibility rates have been reported by most investi-gators,'^ " including preliminary results from alarge European registry.'^ These differences ininducibility rates may be partly related to thecharacteristics of the patients studied. For exam-pie, patients with catecholamine-sensitive poly-morphic or monomorphic VT (arrhythmias that
1308 Journal of Cardiovascular Electrophysiology Vol. 10. No. 10, October 1999
B
RVO
n
, l liliyLlllijJij.
rr
Figure 3. Patient 3. Data from the elecrrophysiologic .ttudies, peiformed U years after the initial studies, on no antiarrhythmicmedication (July 7, 1992). (A) Repetition (n = 5) of douhle right ventricular apex (RVA) extrastimulation at the same couplingintervals (600/250/200) induces only a single repetitive ventricular re.spon.'te. (B) At the si.xth trial using the same couplinginterval, sustained polymorphic ventricular tachycardia/ventricular fibrillation /.v induced.
Belhassen. et al. Electrophysiologic Drug Testing in Idiopathic VF 1309
Quinidine
RVA
RVO
Figure 4. Patient 3. After administration of quinidine (1.500 mg/day). ventricular fihrillation can no longer be induced u.singrepetition (iOX) of double e.xtrastimutalion and repetition (5X) of triple extra.mnmlation at the shortest coupling interyals.Note a persistent Brugada sign in lead V,.
generally are not inducible with PVS) were in-eluded in one series.'-'' Such patients were ex-cluded from our study. In addition, the higherrate of VF induction in our study may be relatedto our stimulation protocol, wbich used a stimu-lus current intensity that is higher than the oneused in most laboratories'' as well as repetition ofextrastimulation.^ In this regard, one should em-phasize that although the induction of SPVT/VFwith PVS is often a nonspecific response In pa-tients without spontaneous arrhythmias,'^ the in-duction of VF in patients witb a history of car-diac arrest generally is considered to be clinicallyrelevant.-^" Moreover, tbe spontaneous arrhyth-mias in idiopathic VF are polymorphic at theirinitiation and are triggered by spontaneous extra-systoles with very short coupling intervals.-' Ac-cordingly, we believe that the induction of VFwitb PVS is a valid endpoint. and using shortcoupling intervals is rea.sonable whenever idio-pathic VF is diagnosed."!" jhe controversial sig-nificance of VF induction should support ourefforts to induce VF with the minimal number ofextrastimuli possible. In our study, induction ofSPVT/VF was achieved with single or doubleventricular extrastimulation in most patients (16of 27 [59%]) and during repetition of doubleextrastimulation in 5 (33%) of the L*) patientswho had arrhythmias induced with two extra-stimuli.
EP Drug Testing
The high success rate (96%) of oral Class IAdrugs, especially quinidine, in preventing the in-duction of SPVT/VF in our patients is consistentwith the results obtained by other investigators ina few isolated cases.' -' - - ^ This exceptionallyhigb suppression rate markedly differs from therelatively low suppression rate reported for pa-tients with various cardiac diseases and inducibleVT/VF,--* suggesting a role of cardiac functionstatus in tbe beneficial response of Class I drugs.In addition, our results observed with Class Idrugs contrast with the inability of amiodarone toprevent tbe induction of SPVT/VF in 6 of our 7patients.
It is important to note that in 17%- of patientstested with quinidine, VF that was inducible atthe first dose tested became noninducible at ahigher dose, suggesting that bigher doses of an-tiaiThythmic drug sbould be tested in the event asustained ventricular tacby arrhythmia is inducedat the first drug dose. Also, effective serum bloodlevels of quinidine varied greatly (range 1.0 to7.5 mg/L), suggesting that they could not be usedreliably to predict drug efficacy. In addition, thepoor correlation between the efficacy of intrave-nous and oral Class IA drugs in this population isinteresting and requires confirmation. Finally,that the response to quinidine therapy predictedtbe response to oral disopyramide suggests a
1310 Journal of Cardiovascular Electrophysiology Vol. 10, No. 10. October 1999
class effect. Therefore, disopyramide should beevaluated in patients intolerant of quinidine, be-cause it can be a valuable alternative.
Mechanism of Action of Class IA AntiarrhythmicAgents
Induction of SPVTA'F in all five of our patientswith the Brugada syndrome and in most patientsreported with this entityi2.25^6 suggests that a reen-trant mechanism is operative. It has been suggestedrecently that the mechanism of the arrhythmias inBrugada syndrome is due to electrical inhomoge-neity and phase 2 reentry related to a prominenttransient outward I,,, current. •'• ** Such a mecha-nism is supported by the fact tbat quinidine pre-vented the induction of VF in 4 of 5 of our patientsas well as in the patient reported recently by Garget al.2^ Quinidine has been shown to strongly in-hibit T,,.. thus restoring electrical homogeneity andabolishing phase 2 reentrant activity. ^ Unlike quin-idine, other Class I agents, such as flecainide, pro-cainamide, and ajmaline, which strongly depressI jj, but affect only mildly I, ,, are well known toexacerbate the Brugada syndrome. ^
The mechanism of idiopathic VF appears to bemore obscure. Several recent observations ' •*' aswell as tbe higb inducibility rate of SPVT/VFfound in our study suggest the existence of asubstrate for a reentrant mechanism. It is tempt-ing to speculate tbat anomalies related to thecardiac sodium channel are involved in idio-pathic VF not associated with the Brugada syn-drome. Further studies, including molecular ge-netic studies, are necessary to study the possiblerelationship between idiopathic VF with normalECG and the Brugada syndrome.
Long-Term Outcome
EP-guided therapy
There have been only few reports on the long-term outcome of patients with idiopathic VF treatedwitb Class IA dmgs effective at EP testing.'"'^.^a i^our study, 23 patients were treated with Class IAantiarrhythmic medications found effective at EPtesting. All are alive and have remained free ofsustained ventricular arrhythmias after 9.1 ± 5.6years of follow-up. However, these results deserveseveral comments. (I) A very poor compliance tomedications was observed in four of our patients.Tbis could have resulted in a fatal outcome, which.
in tum, could have been interpreted as a failure ofClass IA drugs to prevent arrhythmia recurrence.(2) Considering tliat patienis with idiopathic VFmay enjoy long asymptomatic periods even on noantiarrbythmic therapy, as found in some of ourpatients and in a previous study,'-* one should becareful before attributing the excellent chnica! out-come of our patients to drug efficacy alone. (3) Onthe other hand, the relatively high recurrence rate ofanhythmic events or sudden death (30% within 5years in UCARE-""), as well as the high frequencyof electrical discharges from ICDs in large series ofpatients witb idiopathic VF or Biugada syn-drome'- '*'^ left on no inedications. strongly sup-port the idea that Class IA antiaiThythmic therapyplayed a favorable role in our patients. (4) Finally,proarrhythmic effects were not ob.served in any ofour patients treated with Class IA drugs. In the onlypatient who developed PVT on procainamide ther-apy, the QT remained nonnal and the arrhythmiaresolved after correction of the coexisting hypoka-lemia without discontinuation of procainamidetherapy.
Non-EP-guided therapy
Non-EP-guided therapy of idiopathic VF mayseem obsolete nowadays. However, it is worthremembering tbe patient reported by Moe^- in1949. Following multiple syncopal attacks dur-ing wbich a prolonged episode of self-terminat-ing VF was documented, this 38-year-old manwas treated with quinidine for 43 years until hedied of noncardiac illness at the age of 81.^^ Inour study, a poor outcome was observed in 2 ofthe 3 patients who did not receive an ICD. Thatboth patients were first studied before the adventof nonthoracotomy ICDs, were not followed reg-ularly, and at least one of them was poorly com-pliant witb medications probably played a majorrole in the fatal outcome.
Study Limitations
The number of patients included in tbe presentstudy (n = 34) was relatively small. However,this is the largest series of patients with idio-pathic VF who had inducible sustained ventric-ular tachyarrhythmias at baseline EP studies, al-lowing pharmacologic drug testing. This also isthe largest series of patients in whom a system-atic evaluation of tbe effects of Class IA antiar-rhytbmic drugs on arrhythmia induction wasdone. Finally, the duration of the follow-up pe-
Beihassen, et al. E lec trophys io log ic D r u g Tes t ing in Idiopathic V F 1311
riod (ranging from 7 to 20 years in 15 patients),is the longest reported for idiopathic VF. allow-ing appropriate evaluation of tberapy.
Our study spanned over 2 decades, and changesin the .stimulation protocol occuiTed during thisperiod. It is noteworthy, however, that the induc-ibility rate of SPVTA' F was not significantly dif-ferent during the periods when we used eitber dou-ble or triple extrastimulation. Nevertheless, onecould wonder whether the use of triple extrastimu-lation in patients in whom only double extrastimu-lation was performed to test drug efficacy wouldhave revealed drug failure among some of the pa-tients. Three observations suggest that this was notthe case. (1) Two patients (no. 3. 8) in whom drugefficacy was first tested with double extrastimula-tion bad identical results when tested with tripleextrastimulation several years later. (2) All fivepatients (no. 17, 22, 23, 25, 28) who underwentPVS using up to triple extrastimulation but had VFinduction using double extrastimulation at baselinestudy had no sustained arrhythmias inducible ondrugs using up to triple extrastimulation. (3) Fi-nally, nine patients (no. 1 to 9) who remained freeof arrhythmias during long-term follow-up hadtheir drug regimen selected based on noninducibil-ity results with double extrastimulation.
Our study did not include a randomized controlgroup: therefore, one may argue that the reason theoutcome was .so favorable in our patients is becausethe .study population had an inherently low recur-rent VF. However, as stated eiirlier, data fromUCARE ' showed a 30% recurrence rate of ar-rhythmic event or sudden death within 5 years inpatients left on no medications, which contrastsmarkedly with the results of our study, therebysupporting a true beneficial role of Class IA anfi-arrhythmic tberapy in our patients.
implantation and replacements of ICD over theyears will make impossible the ICD option.Otber potential candidates for EP-guided ClassIA tberapy are patients in wboni ICD needs to beexplanted due to complications (recurrent infec-tions for example). Finally, our results suggestthat Class IA drugs could be the drugs of choicein ICD patients when medications are necessaryto prevent multiple device discharges resultingfrom recurrent ventricular tachyarrhythmias.
To our best knowledge, tbere are no availabledata from randomized studies comparing ICD andantiarrhythmic therapy for patients with idiopathicVF. Based on the results of the present .study, arandomized prospective study comparing EP-guided Class IA therapy with ICD appears to beethically jusfifiable and of great clinical impor-tance. From a practical point of view, however, itseems tbat most electrophysiologists will be reluc-tant to leave young survivors of cardiac arrest non-protected with ICD. '* Therefore, the value of ClassIA antiarrhythmic drugs in patients with idiopathicVF could be best tested in a population of survivorsof cardiac arrest who carry an ICD and who will begiven Class IA therapy in a randomized manner.Finally, for patients with the Brugada syndrome,confirmation of the high efficacy of quinidine,shown in this study for a small number of patients,would have major implications. Because of thegenetic transmission of this disease,^ many asymp-tomatic relafives of affected patients may be dis-covered.'^ Brugada and Brugada'^ recently recom-mended ICD implantation for these asymptomaticpatients because they are at high risk for fatalarrhythmias. EP-guided therapy with quinidinecould prove to be a valuable alternative to ICDimplantation for this large group of asymptomatichigb-risk patients.
Clinical Implications
The results of our study suggest that EP-guided therapy witb Class IA agents may be areasonable therapeutic alternative for patientswith idiopathic VF, provided several conditionsare fulfilled: (1) the patients bave inducibleSPVT/VF at baseline EP study; (2) Class IAagents prevent tbe reinduction of SPVT/VF; (3)the patients exhibit a good tolerance to medica-tions: and (4) the patients are willing to committhemselves to a life-long regimen of medications.Such a therapeutic option can be proposed topatients who refuse implantation of an ICD or topatients for whom cost constraints resulting from
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