Superiority of Ibutilide (A New Class III Agent) Over

568 Heart 1998;79:568–575 Superiority of ibutilide (a new class III agent) over

DL-sotalol in converting atrial ﬂutter and atrial Heart: first published as 10.1136/hrt.79.6.568 on 1 June 1998. Downloaded from ﬁbrillation

M A Vos, S R Golitsyn, K Stangl, M Y Ruda, L Van Wijk, J D Harry, K T Perry, P Touboul, G Steinbeck, HJJWellens, for the Ibutilide/Sotalol Comparator Study Group

Abstract III drug, under monitored conditions, is a Objective—To compare the eYcacy and potential alternative to currently available safety of a single dose of ibutilide, a new cardioversion options. class III antiarrhythmic drug, with that of (Heart 1998;79:568–575) DL-sotalol in terminating chronic atrial fibrillation or flutter in haemodynami- Keywords: atrial fibrillation; atrial flutter; cally stable patients. antiarrhythmic agents; ibutilide; sotalol Design—Double blind, randomised study. Setting—43 European hospitals. Atrial fibrillation and atrial flutter are the most Patients—308 patients (mean age 60 years, 70% men, 48% with heart disease) with frequently occurring tachycardias in man: sustained atrial fibrillation (n = 251) or prevalence is estimated to be 0.4% for atrial 1–3 atrial flutter (n = 57) (duration three fibrillation and 0.1% for atrial flutter, and hours to 45 days) were randomised to they may increase to 4% in people older than University Hospital, three groups to receive a 10 minute 60 years. Treatment for acute conversion of Maastricht, infusion of 1 mg ibutilide (n = 99), 2 mg these arrhythmias consists of antiarrhythmic Netherlands drugs or electrical cardioversion, or both. MAVos ibutilide (n = 106), or 1.5 mg/kg DL-sotalol HJJWellens (n = 103). Infusion was discontinued at The basic electrophysiological mechanism termination of the arrhythmia. thought to be responsible for atrial flutter and Cardiology Research Main outcome measure—Successful con- fibrillation is that of re-entry, with atrial fibril- Centre, Moscow, version of atrial fibrillation or flutter, lation being caused by multiple independent Russia defined as termination of arrhythmia re-entry wavelets, and atrial flutter by one large

S R Golitsyn http://heart.bmj.com/ 1–5 M Y Ruda within one hour of treatment. circuit often located within the right atrium. Results—Both drugs were more eVective In both instances prolongation of the Humholdt University, against atrial flutter than against atrial wavelength45 (the product of conduction Berlin, Germany fibrillation. Ibutilide was superior to DL- velocity of the impulse and the refractory K Stangl sotalol for treating atrial flutter (70% and period) may cause conversion from atrial St Chr Ziekenhuis 56% v 19%), while the high dose of arrhythmia to sinus rhythm. On the basis of this Refaja, Stadskanaal, ibutilide was more eVective for treating principle class III antiarrhythmic agents, which Netherlands atrial fibrillation than DL-sotalol (44% v increase duration of the action potential and L Van Wijk on September 27, 2021 by guest. Protected copyright. 11%) and the lower dose of ibutilide (44% v the refractory period of atrial muscle without 20%, p < 0.01). The mean (SD) time to Pharmacia & Upjohn, having much influence on conduction velocity, Crawley, West Sussex, arrhythmia termination was 13 (7) min- may help to restore sinus rhythm in patients UK utes with 2 mg ibutilide, 19 (15) minutes with atrial flutter and fibrillation.6–12 The J D Harry with 1 mg ibutilide, and 25 (17) minutes precise electrophysiological mechanism by with DL-sotalol. In all patients, the dura- which class III agents exert their beneficial Pharmacia & Upjohn, tion of arrhythmia before treatment was a Kalamazoo, Michigan, eVect remains speculative. USA predictor of arrhythmia termination, al- Ibutilide fumarate (U-70226E) is a new class though this was less obvious in the group KTPerry III agent for acute conversion of atrial flutter that received 2 mg ibutilide. This dose and fibrillation that has recently been intro- Hospitaux de Lyon, converted almost 48% of atrial fibrillation duced in the US.13–17 Introduction in Europe Lyon, France that was present for more than 30 days. P Touboul will take place throughout 1998. Preclinical Concomitant use of digitalis or nifedipine and prolongation of the QTc interval were animal studies have shown that ibutilide Klinikum Grosehadern prolongs duration of the action potential and of the University of not predictive of arrhythmia termination. Munich, Germany Bradycardia (6.5%) and hypotension the eVective refractory period of the atrium and G Steinbeck (3.7%) were more common side eVects ventricle, thereby preventing and suppressing with DL-sotalol. Of 211 patients given ibu- (the induction of) atrial and ventricular Correspondence to: arrhythmias.18–21 Ibutilide is available only as an Dr M A Vos, Department of tilide, two (0.9%) who received the higher Cardiology, Cardiovascular dose developed polymorphic ventricular intravenous preparation because of poor bio- Research Institute availability caused by a large first pass eVect Maastricht, University tachycardia, one of whom required direct Hospital Maastricht, PO Box current cardioversion. during oral administration. 5800, 6202 AZ Maastricht, Conclusion—Ibutilide (given in 1 or 2 mg DL-sotalol combines class III antiarrhythmic Netherlands. doses over 10 minutes) is highly eVective activity with â adrenoceptor blocking action Accepted for publication for rapidly terminating persistent atrial and is available in many countries as an 24 November 1997 fibrillation or atrial flutter. This new class intravenous formulation. Because it is widely EYcacy of ibutilide and sotalol in atrial arrhythmias 569

Table 1 Number of evaluable patients disease, myocardial infarction or cardiac sur- gery within the previous 30 days, known sinus Ibutilide fumarate

node dysfunction, second or third degree Heart: first published as 10.1136/hrt.79.6.568 on 1 June 1998. Downloaded from Arrhythmia 1mg 2mg DL-Sotalol Total atrioventricular (AV) block, bundle branch block, WolV-Parkinson-White syndrome Atrial flutter 16 20 21 57 and/or torsade de pointes were not included. Atrial fibrillation 83 86 82 251 Concurrent treatment with verapamil, diltiazem, or drugs that prolong the QT inter- used for the treatment of atrial arrhythmias in val was not allowed. Treatment with class I or Europe,11 12 this drug was chosen as a compara- III antiarrhythmic agents or with â adrenoceptor. tor blocking agents was discontinued for more The European multicentre study reported than five half lives before enrolment. Antico- here compares the safety and eYcacy of agulation was the responsibility of the investi- intravenous ibutilide with that of intravenous gators. DL-sotalol in the acute termination of sustained The following information was collected to atrial flutter or fibrillation. identify eligible patients: medical history (including earlier episodes of atrial fibrillation or atrial flutter and treatment, and time of onset Methods of the current arrhythmic episode), physical STUDY DESIGN This multicentre trial was a prospective, double examination (including blood pressure), 12 blind, randomised, parallel group comparison lead ECG, and laboratory evaluation (includ- of two doses of ibutilide with a single dose of ing digitalis concentrations). DL-sotalol in haemodynamically stable patients who had recent onset sustained atrial flutter or STUDY MEDICATION fibrillation. Recent onset was defined as Patients were randomised to receive 1 mg ibu- continuous atrial flutter or fibrillation for tilide, 2 mg ibutilide, or 1.5 mg/kg DL-sotalol. longer than three hours but less than 45 days. Drugs were prepared in ampules of 25 ml of All centres obtained ethics committee approval which 20 ml was given as a single 10 minute and all patients gave informed consent—319 intravenous infusion using a similar infusion patients were treated at 40 diVerent sites. rate. Blinding was maintained by the drug The protocol intended to enrol 300 patients being prepared by an individual not responsi- equally distributed between the two arrhythmia ble for making assessments. Patients with atrial groups. This objective was not achieved, flutter and fibrillation were separately ran- however, because of the slow recruitment of domised to one of the treatment modes. patients with flutter. A total of 300 patients with both arrhythmias was estimated to detect http://heart.bmj.com/ adiVerence of 17% between both doses of ibu- OBSERVATIONS AND EVALUATIONS At least 15 minutes before administration of tilide combined and DL-sotalol, or 20% be- the drug, continuous ECG monitoring was tween one dose of ibutilide and DL-sotalol (p < 0.05, power 80%). started and continued until seven hours had passed after the start of drug infusion. A Holter recording was made during an additional 24 ELIGIBILITY CRITERIA hours if conversion to sinus rhythm occurred. Patients older than 18 years with recent onset ECGs were recorded at 30 minutes, and one on September 27, 2021 by guest. Protected copyright. sustained atrial flutter or fibrillation were eligi- and seven hours (for patients who were ble when they: were haemodynamically stable successfully treated) after the start of infusion. (systolic blood pressure > 90 mm Hg and The haemodynamic status of the patient was diastolic blood pressure < 105 mm Hg); had a regularly checked by measuring heart rate and normal serum potassium concentration blood pressure every five minutes for 15 (> 4 mEq/l); had a ventricular rate of > 60 minutes before the end of infusion, and at 10 beats/min; and had a rate corrected QT minute intervals for 50 minutes and then interval of no more than 440 ms in their 12 hourly for seven hours. Blood and urine were lead electrocardiogram (ECG). Patients with collected before drug infusion and seven hours hyperthyroidism, or with a history or evidence later for routine safety laboratory evaluations of of unstable angina pectoris, bronchospastic haematological and biochemical variables. Table 2 Demographic and baseline characteristics This seven hour observation period was selected arbitrarily on the basis that side effects Ibutilide have been reported to occur within this period, 1 mg (n = 102) 2 mg (n = 109) Sotalol (n = 108) and it was convenient in the daily logistics of the hospital. Mean age (years) 61.9 59.5 59.2 Range 21–83 22–89 24–85 Administration of the drug was stopped if: Mean weight (kg) 80.7 81.3 81.7 atrial flutter or fibrillation terminated; systolic Range 45–119 55–120 49–120 blood pressure decreased to < 90 mm Hg; Sex Female 31 (30.4%) 38 (34.9%) 27 (25%) haemodynamic instability occurred because of Male 71 (69.6%) 71 (65.1%) 81 (75%) rhythm changes; bundle branch block oc- Median duration of curred; QRS duration was prolonged by more arrhythmia (days) 16.0 5.4 7.2 Range 0.5–67.6 0.3–90.7 0.5–83.4 than 50%; the QTc interval exceeded 600 ms; Concomitant digoxin 39 (38.2%) 43 (39.4%) 33 (30.6%) new or repetitive forms of ventricular extrasys- Concomitant nifedipine 13 (12.7%) 4 (3.7%) 13 (12%) toles were noted; signs of bronchospasm History of heart disease 52 (51%) 46 (42.2%) 54 (50%) occurred; if any other adverse eVect was seen 570 Vos, Golitsyn, Stangl, et al

incidence of ventricular arrhythmias were 100 determined and conﬁrmed from the Holter Sotalol

tapes. Heart: first published as 10.1136/hrt.79.6.568 on 1 June 1998. Downloaded from Ibutilide 1 mg Medical events were listed in relation to Ibutilide 2 mg 80 * individual patients and study medication.

* STATISTICS 60 The statistical package used was release 6.08 of * † SAS (Statistical Analysis Software). All statistical tests were two sided, p < 0.05 was consid- 40 Success rate (%) ered significant. Chi squared tests were applied for group comparisons of the main end point. Relations among response (conversion v 20 non-conversion), ibutilide dose, and selected predictor variables (duration of arrhythmia, use of digitalis or calcium channel blockers during 0 21 16 20 82 83 86 the 24 hour period before infusion) were inves- Flutter Fibrillation tigated separately for each predictor variable Figure 1 Comparison of conversion rates induced by the two doses of ibutilide and sotalol using a logistic regression analysis with a in patients with atrial flutter and fibrillation. Numbers are total number of patients entered response variable of conversion (yes/no), ex- into each group.*p < 0.05 compared with sotalol; †p < 0.05 compared with 1 mg ibutilide. planatory variables of dose and each individual and regarded by the investigator as detrimental predictor variable, and an interaction term to the patient’s health. dose by predictor variable. The test for interaction was significant if it generated p 0.10. If Patients in whom the arrhythmia stopped < the test for interaction was non-significant and no new arrhythmias developed were (p > 0.10), the interaction term was eliminated discharged from hospital seven hours after the from the model and a logistic regression analy- start of drug treatment with a Holter device. sis was used to analyse the relation between a Patients in whom arrhythmias recurred or new response variable of conversion and explana- ones developed after treatment were kept in tory variables dose and individual predictor hospital. variable. If the arrhythmia was not stopped within the Comparison between results obtained from one hour observation period the patient could reported conversions and those on Holter tapes be treated as desired by the investigator, with was made by Pearson’s contingency coefficient. the suggestion that no other antiarrhythmic Medical events were compared between treat- agents be given until at least four hours after ment groups using a ÷2 test for homogenicity of http://heart.bmj.com/ infusion. proportions. Demographic and pretreatment Medical events were recorded while patients characteristics were compared in each group by were in hospital. They were contacted by analysis of variance (ANOVA) for age, height, and telephone 72 hours after the start of infusion to weight, and ÷2 tests for race, sex, and variables record any additional medical events. from medical histories. QTc prolongation was compared in patients who converted and those who did not in the diVerent treatment groups

DATA ANALYSIS by one way ANOVA. on September 27, 2021 by guest. Protected copyright. The main end point was termination of the atrial arrhythmia for any period of time up to one hour after the start of infusion. This was assessed on the basis of the judgment of the Results Eleven of 319 patients who enrolled in the investigator, while separate analysis from the study were excluded: nine had arrhythmia for ECG (Holter) was used for confirmation. To more than 45 days and two received incorrect obtain an estimate of clinical usefulness, time dosage of the study medication because of a to arrhythmia termination and time without misinterpretation by an investigator. Holter atrial flutter or fibrillation were also recorded tapes were obtained in 281 of the 319 patients. during the 31 hour observation period. QTc Therefore, 308 patients were evaluated for eY- measurements were made from 12 lead ECGs. cacy: 99 patients received 1 mg ibutilide, 106 During ECG monitoring (for seven hours patients 2 mg ibutilide, and 103 patients after the start of infusion) the occurrence and 1.5 mg/kg DL-sotalol (table 1). The three treatment groups (considering all Table 3 Logistic regression analysis for duration of arrhythmias in evaluable patients (n = patients) were similar in age and weight. Thirty 308) per cent of patients were women and 96% were white (table 2). They were similar with respect Variable CoeYcient SE coeYcient p value to medical history, physical examination vari- With interaction term included ables, concomitant medication, duration of Medication 0.7382 0.2186 0.0007 Duration −0.0612 0.0232 0.0082 arrhythmia, and heart disease (table 2). There Medication by duration 0.0233 0.0142 0.1017 was no evidence for toxic concentrations of Without interaction term included digitalis. Medication 0.9765 0.1741 0.0001 The screening ECG was taken on the same Duration −0.0281 0.0093 0.0024 day as the infusion in 279 patients. A mixed SE, standard error. fibrillation/flutter was diagnosed in 12 patients. EYcacy of ibutilide and sotalol in atrial arrhythmias 571

75 eVective than 1 mg and reverses the trend that longer duration of atrial ﬁbrillation decreases

the success rate of drugs. Heart: first published as 10.1136/hrt.79.6.568 on 1 June 1998. Downloaded from 0–3 days QTc prolongation occurred with all drugs 30 4–30 days minutes, and one and seven hours after 31–45 days infusion. Comparison of the magnitude of QTc 50 prolongation in patients in whom treatment was either successful or failed showed no signiﬁcant diVerences between the groups. Successful conversion rates in the two ibutilide groups were not associated with the use of dig-

Success rate (%) 25 oxin or nifedipine.

TIME TO TERMINATION AND DURATION OF THE ARRHYTHMIA FREE PERIOD The mean time to termination of the arrhyth- 0 Ibutilide 1 mg Ibutilide 2 mg Sotalol mia was shortest after treatment with 2 mg ibutilide (table 4). This finding seemed to be Figure 2 Successful conversion rates of atrial flutter and fibrillation for the two doses of ibutilide and sotalol in relation to duration of the arrhythmia. independent of the type of arrhythmia, but reached significance only for the overall group. EFFICACY However, both doses of ibutilide achieved Figure 1 shows overall success rates in faster termination of the arrhythmia than evaluated patients. The higher dose of ibutilide DL-sotalol (p < 0.05) in the atrial fibrillation (2 mg) was superior to DL-sotalol in both atrial group. flutter and fibrillation, and 2 mg ibutilide was The arrhythmia terminated within 20 min- statistically more eVective than 1 mg ibutilide utes after the start of infusion in 83% (65/78) in atrial fibrillation (p < 0.01) but not in atrial of patients who were successfully treated with flutter (p < 0.4). The lower dose of ibutilide ibutilide. was superior to DL-sotalol in terminating atrial From the Holter recordings (about 31 flutter (p < 0.05) but not atrial fibrillation. hours) it was noted that most patients (66 of Both doses of ibutilide were more eVective 76) remained free from their arrhythmia during against atrial flutter (56% for 1 mg ibutilide follow up. There was no diVerence in success and 70% for 2 mg) than atrial fibrillation (20% among the three treatment groups at the end of and 44%, respectively). the 31 hour observation period.

Interpretation of overall eYcacy rates as http://heart.bmj.com/ assessed by the investigators from 12 lead and monitoring ECGs versus Holter analysis PROARRHYTHMIC ACTIVITY Ventricular extrasystoles were reported by showed good agreement (94%). investigators in 6% of patients who received Logistic regression analysis indicated that 1 mg ibutilide, 9% in those given 2 mg there was a significant relation between dura- ibutilide, and 2% in those given DL-sotalol tion of the arrhythmia and success of drug (table 5). These findings did not reach signifi- treatment (table 3). The mean duration of the cance in a group comparison (p = 0.065). arrhythmia was 11 days for patients who were on September 27, 2021 by guest. Protected copyright. Drug related ventricular tachycardias (VTs) successfully treated compared with 17 days for were reported during treatment in 19 of 319 patients in whom treatment failed. The pres- patients. Table 5 shows the incidence of ence of marginally significant interaction ef- non-sustained or sustained, monomorphic or fects, however, suggests the possible differential polymorphic VTs as indicated by the investiga- degrees of association between duration and tors. Four VTs are listed as a serious medical conversion for the three treatment groups. event. One patient with reported sustained There is also the suggestion that patients with polymorphic VT needed treatment with car- longer lasting atrial flutter or fibrillation, or dioversion. Figure 3 shows the onset of both (31–45 days), may require higher doses of polymorphic VT in this patient, VT clearly ibutilide for conversion (fig 2). For such occurred during atrial fibrillation and not after patients the 2 mg ibutilide dose becomes more conversion to sinus rhythm. In the ibutilide Table 4 Mean time (in minutes) to successful termination of atrial arrhythmia group, all these proarrhythmic responses occurred within the one hour observation period. Ibutilide As shown in fig 3 the occurrence of arrhythmias was not restricted to patients who were Arrhythmia 1mg 2mg Sotalol p value successfully converted. Atrial flutter (n = 27) Eighteen of the 19 arrhythmias were con- Mean (SD) 23 (11) 15 (8) 19 (4) 0.0833 firmed on the Holter tapes but only three of the Median 21 14 19 Atrial fibrillation (n = 64) 16 reviewed were considered by four independ- Mean (SD) 17 (17)† 12 (7)† 27 (20) 0.0049 ent cardiologists to be true VTs after assess- Median 11 12 20 All (n = 91) ment of the tapes, the other episodes were Mean (SD) 19 (15) 13 (7)*† 25 (17) 0.0017 interpreted as being very suggestive of aberrant Median 13 12 20 conduction of a supraventricular rhythm. The *Significantly diVerent from 1 mg ibutilide (p < 0.05); †significantly diVerent from sotalol magnitude of QTc changes was not predictive (p < 0.05); ANOVA. of torsade de pointes arrhythmias. 572 Vos, Golitsyn, Stangl, et al Heart: first published as 10.1136/hrt.79.6.568 on 1 June 1998. Downloaded from

Figure 3 Onset of the single sustained polymorphic ventricular tachycardia that required electrocardioversion from the Holter recording occurring 11 minutes after the start of 2 mg ibutilide infusion. Note that a longer RR interval and a prolonged QT interval precede the ventricular arrhythmia.

OTHER MEDICAL EVENTS AFTER TREATMENT Discussion Reported medical events that were judged by Ibutilide and DL-sotalol are methanesulphoni- investigators to be related to the study drug lides with class III electrophysiological and 12–21 were primarily from the cardiovascular system. antiarrhythmic eVects. Unlike DL-sotalol, These were equally distributed across the ibutilide does not have â blocking activity at the treatment groups. Adverse eVects of DL-sotalol doses used in this study. In canine studies, ibu- specifically related to its â adrenergic blocking tilide was eVective against atrial flutter activities and included bradycardia (6.5% of (0.006 mg/kg),19–21 atrial fibrillation patients) and hypotension (3.7%). Ibutilide (0.150 mg/kg),20 and the subacute phase of had no adverse eVects on heart rate or blood ventricular tachycardias (0.030 mg/kg) after pressure, or on routine haematological or myocardial infarction.18 The exact mode of biochemical tests. action of ibutilide is a matter of discussion.16 Serious medical events were listed in a total Activation of a slow (Na+) inward current,13 14 15 of 10 patients treated with ibutilide and in five blockade of Ikr, and/or additional or com- 15 treated with DL-sotalol. Four ibutilide events bined eVects may explain the class III eVect. http://heart.bmj.com/ were proarrhythmic responses (see earlier). In contrast, activation of an outward potassium Infusion of study medication was stopped current at higher dosages may explain self limi- prematurely in five patients: in three patients it tation in prolongation of the cardiac action was listed as a serious medical event because of potential.13 Ibutilide has not been shown to complete AV block (sotalol), bundle branch produce important haemodynamic changes at block (1 mg ibutilide), or serious ECG abnor- doses of less than 3 mg/kg. Comparative stud- malities (heart rate > 200 beats/min caused by ies in animals involving single cell preparations and models of ischaemia have shown that ibu- a more rapid AV nodal conduction) with severe on September 27, 2021 by guest. Protected copyright. hypotension (1 mg ibutilide); QTc in the other tilide is about 100 times more eVective than two patients who received 2 mg ibutilide DL-sotalol in prolonging action potential dura- exceeded 600 ms but no proarrhythmic events tion. Therefore dosages of the two compounds developed. Further serious medical events, all used in this study are considered comparable in witnessed once, were seen in four patients who terms of their electrophysiological activities. received 2 mg ibutilide, namely junctional The dosage of DL-sotalol used here is com- bradycardia and a vasovagal reaction with monly advised in Europe for the treatment of 11 12 severe hypotension, and in four who received supraventricular arrhythmias, because it DL-sotalol, namely bradycardia with hypo- gives optimal success rates, while higher tension. dosages are associated with adverse haemody- The events judged not to be related to treat- namic eVects and increase the risk of proar- ment were endocarditis and dyspnoea in rhythmic reactions. patients given 2 mg ibutilide, and left heart In phase I studies, up to 0.030 mg/kg failure and ventricular fibrillation in those ibutilide was given by a 10 minute intravenous given DL-sotalol. infusion. A dose dependent eVect was seen, with a maximum near the end of the infusion Table 5 Incidence and type of drug related ventricular arrhythmia in all patients time with a mean rate corrected QT interval prolongation of 18% (0.01 mg/kg) to 43% Ibutilide (0.03 mg/kg). QTc returned to baseline after a Ventricular arrhythmia 1mg(n=102) 2mg(n=109) Sotalol (n = 108) maximum of four hours, depending on the dose. Before the present study, 375 patients Ventricular extrasystoles* 5.9% 9.2% 1.9% Non-sustained monomorphic VT 4.9% 7.3% 3.7% were treated with ibutilide for conversion of Non-sustained polymorphic VT – 0.9% – atrial flutter or fibrillation with a duration of up Sustained polymorphic VT – 0.9% – to a maximum of 90 days (placebo controlled *Includes isolated ventricular extrasystoles, couplets, and triplets. studies and one comparative study with VT, ventricular tachycardia. procainamide).22–25 Ellenbogen et al,24 in a study EYcacy of ibutilide and sotalol in atrial arrhythmias 573

with 200 patients reported an overall success tered over a 10 minute period. If this dose fails rate of 47.5% at a dose of 0.025 mg/kg, as to convert the arrhythmia within 10 minutes

compared with 2.4% in the placebo group. after the end of infusion, then a second 10 Heart: first published as 10.1136/hrt.79.6.568 on 1 June 1998. Downloaded from Success was higher in the atrial flutter group minute infusion of equal strength may be (58% v 40%). The median time to conversion administered.25 was 10–23 minutes, while in 70% of success- Another new class III agent (dofetilide) fully treated patients, termination occurred showed an overall eYcacy rate of 53% for con- within 20 minutes. In a second study,25 266 verting atrial fibrillation to sinus rhythm, patients were randomised to receive up to two whereas the conversion rate for atrial flutter 10 minute infusions of ibutilide (1 and 0.5 mg was 80%.9 In more recent studies similar or 1 and 1 mg) or placebo. Ibutilide was supe- results have been reported for atrial flutter rior to placebo in converting both atrial (75% and 54%, respectively) but much less arrhythmias and more eVective for atrial flutter eYcacy was shown for atrial fibrillation (22% (56% after two infusions) than for atrial fibril- and 15%) using 0.008 mg/kg dofetilide.28 29 lation (31%). Two dosages of ibutilide were The higher conversion rates of the newer chosen in this study to evaluate further the class III drugs (ibutilide and dofetilide) in the optimal dose. Ibutilide was administered as a treatment of atrial flutter compared with those fixed dose rather than corrected for body in the treatment of atrial fibrillation can be weight to accommodate the physician in daily explained by the wavelength theory. Atrial flut- practice. Body weight was similar in the groups ter is a stable re-entrant process in which (> 80 kg, table 2) so that the dosages of ibuti- lengthening of the refractory period leads to lide amounted to 0.0125 mg/kg for the 1 mg prolongation of the wavelength. Whether the dose and to 0.025 mg/kg for the 2 mg dose. wavelength concept is also useful to explain The outcome of our study is in accordance drug eYcacy in atrial fibrillation has recently with the findings that 2 mg ibutilide is more been questioned. In a goat study by WijVels eVective against atrial flutter (70%) than atrial and coworkers30 termination of atrial fibrilla- fibrillation (44%), and when eVective, ibutilide tion by drugs could not be predicted by their rapidly converts the arrhythmia (in 83% of eVect on the wavelength. Rather, they showed patients within 20 minutes). EYcacy seems to that all drugs (classes I and III) progressively be dose dependent, especially with regard to widen the excitable gap during atrial fibrilla- atrial fibrillation. Interestingly, the reported tion. A diVerent eVect on this variable may decreased eYcacy of antiarrhythmic drugs to explain the higher eYcacy of ibutilide over convert long standing atrial arrhythmias was DL-sotalol in terminating this arrhythmia. not seen in patients given 2 mg ibutilide. Class I drugs are also used intravenously to Almost 48% of the total number of arrhythmias treat atrial fibrillation or flutter. In a series of

present for 31–45 days were converted with studies (patient numbers ranging from 10 to http://heart.bmj.com/ 2 mg ibutilide. This important finding needs to 52), the overall eYcacy of flecainide (up to be confirmed by additional studies. 2 mg/kg/10 min) for restoring sinus rhythm In addition, the present study provides was between 65% and 90% in patients with evidence that ibutilide is more eVective than paroxysmal atrial fibrillation.6–8 10 The overall DL-sotalol in converting these atrial arrhyth- conversion rate in patients with atrial flutter 610 mias. In other clinical studies, DL-sotalol (0.4– varies between 0% and 40%. In a study 1.5 mg/kg) converted 47 of 106 (46%) epi- similar to the present one Stambler et al sodes of supraventricular tachycardias or recently showed that ibutilide is superior to on September 27, 2021 by guest. Protected copyright. paroxysmal atrial fibrillation in seven open procainamide.22 trials.11 12 The exact values from these studies Duration of the arrhythmia seems to be a were between 25% and 60% and seemed to major determinant for successful termination. depend on the dose of sotalol (higher doses When paroxysmal atrial fibrillation was present producing greater eVects with a maximum at for more than 24 hours then success rates with approximately 1.5 mg/kg) and perhaps infu- administration of flecainide dropped dramati- sion time.11 12 It was decided therefore that the cally from 86% to 40%.6 Recent animal and recommended dose of 1.5 mg/kg sotalol should human data may explain this finding and our be used in the present study (approximating to observations on the basis of altered electro- a unit dose of 100 mg), while infusion should physiological behaviour caused by chronic be preferred to a single bolus dose. In contrast atrial fibrillation.30–32 These observations have to the treatment of atrial fibrillation, DL-sotalol changed the treatment of atrial fibrillation. seems to be rather ineVective against atrial Many electrophysiologists no longer consider flutter.61112 In our study, the eYcacy of this condition to be a relatively benign disease DL-sotalol to convert atrial fibrillation was low and now elect to treat this arrhythmia more (11%) compared with that reported in the aggressively. literature, however a study by Sung et al Several proarrhythmic events have been reported similar values.26 reported in previous studies using class III As a placebo group was not used here we are antiarrhythmic drugs,12 33 34 ranging from con- unable to account for spontaneous termination duction disturbances and extrasystoles to the of atrial fibrillation or flutter. This has been most important one the occurrence of torsade reported to be as high as 40% in patients with de pointes. Several comparative studies in a atrial fibrillation of less than 48 hours rabbit model of torsade de pointes have been duration.27 performed to assess the proarrhythmic poten- For future applications, we suggest that a tial of this class of drugs.35 36 DiVerent results first dose of 1 mg ibutilide should be adminis- have been reported, but the important message 574 Vos, Golitsyn, Stangl, et al

is that each drug tested can have proarrhythmic This study was supported in part by a grant from the Upjohn eVects. The incidence of these events with Company (Pharmacia & Upjohn), Europe. 12

DL-sotalol is 1–5%. Of a total of 586 patients Heart: first published as 10.1136/hrt.79.6.568 on 1 June 1998. Downloaded from 1 Kulbertus HE, Wellens HJJ, Bourgeois IMGP, et al,eds. treated with ibutilide (including this study), the Atrial fibrillation. Facts from yesterday—ideas for tomorrow. incidence of sustained polymorphic VT requir- Armonk, New York: Futura, 1994. 2 Olsson SB, Allessie MA, Campbell RWF, eds. Atrial fibrilla- ing electrical cardioversion was 1.7% and of tion. Mechanisms and therapeutic strategies. Armonk, New York: Futura, 1994. non-sustained polymorphic VT 2.7% (a com- 3 Waldo AL. Atrial flutter: mechanisms, clinical features, and bined total of 4.3%). These episodes occurred management. In: Zipes DP, Jalife J, eds. Cardiac electrophysi- ology. From cell to bedside. Philadelphia: WB Saunders, within 30 minutes after the start of infusion. In 1995:666–81. addition, non-sustained monomorphic VT was 4 Allessie MA, Lammers WJEP, Rensma PL, et al. Flutter and fibrillation in experimental models: what can be learned seen in 4.9% of patients. Most proarrhythmic that can be applied to humans. In: Brugada P, Wellens HJJ, events in this study occurred when the atrial eds. Cardiac arrhythmias: where to go from here. Mount arrhythmia was still present and not directly Kisco, New York: Futura, 1987:67–82. 5 Rensma PL, Allessie MA, Lammers JEP, et al. The length of after successful pharmacological cardioversion the excitation wave as an index for the susceptibility to reentrant atrial arrhythmias. Circ Res 1988;62:395–410. to sinus rhythm (as shown in fig 3). 6 Suttorp MJ, Jessurun ER, Kingma JH. Pharmacological It can be concluded that ibutilide is more cardioversion of paroxysmal atrial fibrillation or flutter to sinus rhythm. In: Kingma JH, van Hemel NM, Lie KI, eds. eVective than DL-sotalol in rapidly terminating Atrial fibrillation, a treatable disease? Dortrecht: Kluwer atrial fibrillation and atrial flutter with a similar Academic Publishers, 1992: 87–103. 7 Crijns HJGM, Wijk van LM, Gilst van WH, et al. Acute safety profile. Our observation that long stand- conversion of atrial fibrillation to sinus rhythm: clinical eY- ing atrial fibrillation can be converted by ibuti- cacy of flecainide acetate. Comparison of two regimens. lide merits further study. Eur Heart J 1988;9:634–8. 8 Crozier IG, Ikram H, Kenealy M, et al. Flecainide acetate for conversion of acute supraventricular tachycardia to Appendix sinus rhythm. Am J Cardiol 1987:59:607–9. 9 Suttorp MJ, Pollack PE, van het Hof A, et al.EYcacy and Participants in the Ibutilide/Sotalol Comparator Group— safety of a new selective class III agent dofetilide in parox- P L M Bernink (Martini Ziekenhuis Lokatie van ysmal atrial fibrillation or flutter. Am J Cardiol 1992;69: Ketwich, Groningen, Netherlands); P Blomström (Uni- 417–19. versity Hospital, Uppsala, Sweden); P Bloomfield and H 10 Suttorp MJ, Kingma JH, Jessurun ER, et al. The value of class IC anti-arrhythmic drugs for acute conversion of par- Oxenham (Royal Infirmary, Edinburgh, United King- oxysmal atrial fibrillation or flutter to sinus rhythm. JAm dom); J Brachmann (Medical University-Klinik Innere, Coll Cardiol 1990;16:1722–7. Heidelberg, Germany); Brembilla-Perrot (Cardiologie 11 Camm AJ, Paul V. Sotalol for paroxysmal supraventricular tachycardias. Am J Cardiol 1990;65:67A–73A. A Hôpital d’adultes, Vandoeuvre les Nancy, France); C 12 Hohnloser SH, Woosley RL. Sotalol. N Engl J Med Brohet (Hospital Saint-Luc Bruxelles, Bruxelles, Bel- 1994;331:31–8. gium); Brugada Terradellas (José, Hospital Clinico I 13 Lee KS. Ibutilide, a new compound with potent class III + Provincial de Barcelona, Barcelona, Spain); Chauvin anti-arrhythmic activity, activates a slow inward Na current in guinea pigs ventricular cells. J Pharmacol Exp (Centre Médico Chirurgical et Obstétrical, Strasbourg, Ther 1992;262:99–108. France); HJGMCrijns (University Hospital, Gronin- 14 Yang T, Snyders DJ, Roden DM. Ibutilide, a methane- sulfonanilide antiarrhythmic, is a potent blocker of the rap- gen, Netherlands); H J Dargie (Western Infirmary, + idly activating delayed rectifier K current, (IKr)inAT-1

Glasgow, United Kingdom); F Dateling (Johannesburg cells. Concentration-, time-, voltage-, and use-dependent http://heart.bmj.com/ Hospital, Parktown, South Africa); N Edvardsson eVects. Circulation 1995;91:1799–806. (Sahlgrens Hospital, Gothenbürg, Sweden); Fauchier 15 Lynch JL, Baskin EP, Nutt EM, et al. Comparison of bind- ing to rapidly activating delayed rectifier K+ channel, I , (Hôpital Trousseau, Tours Cedex, France); S P Kr and eVects on myocardial refractoriness for class III Golitsyn (Cardiology Research Centre, Moscow, Rus- antiarrhythmic agents. J Cardiovasc Pharmacol 1995;25: sia); R Gomes (Seabra, Hospital de Santa Cruz, Linda- 336–40. a-Velha, Portugal); A K Gruzdev (Central Clinical Hos- 16 Lee KS, Gibson JK. Unique ionic mechanism of action of ibutilide on freshly isolated heart cells [letter]. Circulation pital of the Medical Centre of the Russian Federation 1995;92:2755–6. Government, Moscow, Russia); R Haberl (Klinikum 17 Roden DM. Ibutilide and the treatment of atrial arrhyth- Grosehadern der University of Munich, Munich, mias. A new drug—almost unheralded—is now available to US physicians [editorial]. 1996;94:1499–502. Germany); R Henâge (Medical Academy Carl Gustav Circulation on September 27, 2021 by guest. Protected copyright. 18 Buchanan LV, Kabell G, Turcotte UM, et al.EVects of ibu- Carus, Dresden, Germany); G Jackson, Guy’s Hospital, tilide on spontaneous and induced ventricular arrhythmias London, United Kingdom; P Jordaan (University O F in 24 hour canine myocardial infarction: a comparative S, Bloemfontein, South Africa); L Jordaens (University study with sotalol and encainide. J Cardiovasc Pharmacol 1992;19:256–63. Hospital, Ghent, Belgium); V Kühlkamp (Med-Uni- 19 Buchanan LV, Kabell G, Gibson JK. Acute intravenous con- Kinik u polikl, Tübingen, Germany); H Kulbertus version of canine atrial flutter: comparison of anti- (Universitaire CIIR Surt Tilman, Liege, Belgium); arrhythmic agents. J Cardiovasc Pharmacol 1995;25:539– Mehmel Staedt (Klinikum Karlsruhe, Karlsruhe, Ger- 44. 20 Nabih MA, Prcevski P, Fromm BS, et al.EVect of ibutilide, many); A Moya Mitjan (Hospital Vall Hebron, Barce- a new class III agent, on sustained atrial fibrillation in a lona, Spain); M J Nagelsmit (Scheperziekenhuis, canine model of acute ischemia and myocardial dysfunc- Emmen, Netherlands); H Queiâer (Städt Krankenhaus tion induced by microembolisation. PACE 1993;16:1975– 83. Neustadt, Dresden-Neustadt, Germany); Reichenmiller 21 Buchanan LV, LeMay RJ, Walters RR, et al. Anti-arrhythmic (Marienhospital, Stuttgart, Germany); Richter (Klini- and electrophysiologic eVects of intravenous ibutilide and kum Nord, Nürnberg, Germany); M Y Ruda (Cardiol- sotalol in the canine sterile pericarditis model. J Cardiovasc ogy Research Centre, Moscow, Russia); M J Schalij Electrophysiol 1996;7:113–19. 22 Stambler BS, Wood MA, Ellenbogen KE. Antiarrhythmic (University Hospital Leiden, Leiden, Netherlands); A actions of intravenous ibutilide compared with procaina- Schmidt (Karl Olga Krankenhaus, Stuttgart, Ger- mide during human atrial flutter and fibrillation. Circula- many); P Smith (Dr Are Normann Medicinsk Avd tion 1997;96:4298–306. 23 Volgman AS, Stambler BS, Kappagoda C, et al. Comparison Baerum SjukhusBaerum, Norway); C Sonnhag (Uni- of intravenous ibutilide versus procainamide for the rapid versity Hospital, Linkoping, Sweden); K Stangl termination of atrial fibrillation or flutter [abstract]. PACE (Humholdt-Uni, Berlin, Germany); J Stephens (Old- 1996;19:169. church Hospital, Romford, United Kingdom); M R van 24 Ellenbogen KA, Stambler BS, Wood MA, et al.EYcacy of intravenous ibutilide for rapid termination of atrial fibrilla- der Linde (Protestant Ziekenhuis, Drachten, Nether- tion and flutter: a dose response study. J Am Coll Cardiol lands); J S van Os (Ziekenhuis de Tjongerschans, Heer- 1996;28:130–6. enveen, Netherlands); L M van Wijk (St Chr Ziekenhuis 25 Stambler BS, Wood MA, Ellenbogen KA, et al, and the Ibu- tilide Repeat Dose Study Investigators. EYcacy of Refaja, Stadskanaal, Netherlands); JHJWeich (R S repeated, intravenous doses of ibutilide, for rapid conver- Blake, Tygerberg Hospital University Stellenbosh, sion of atrial flutter or fibrillation. Circulation 1996;94: South Africa); HJJWellens (Academic Hospital, 1613–21. Maastricht, Netherlands); E Wunderlich (Städt Klini- 26 Sung RJ, Tan HL, Karagormis L, et al, and the Sotalol Mul- ticentre Study Group. Intravenous sotalol for the termina- kum, Dresden Freidrichstadt, Germany); and S Yuan tion of supraventricular tachycardia and atrial fibrillation and B Olsson (University Hospital, Lund, Sweden). and flutter. Am Heart J 1995;129:739–48. EYcacy of ibutilide and sotalol in atrial arrhythmias 575

27 Falk RH, Knowlton AA, Bernard SA, et al. Digoxin for con- 32 Zipes DP. Electrophysiological remodeling of the heart verting recent-onset atrial ﬁbrillation to sinus rhythm: a owing to rate [editorial]. Circulation 1997;95:1745–8. randomized, double blinded trial. Ann Intern Med 1987; 33 Singh BN, Wellens HJJ, Hiraoka M, eds. Electropharmaco- 106:503–6.

logical control of cardiac arrhythmias: to delay conduction or to Heart: first published as 10.1136/hrt.79.6.568 on 1 June 1998. Downloaded from 28 Bianconi L, Dinelli M, Pappalardo A, et al. Comparison of prolong refractoriness. Mount Kisco, New York: Futura, intravenously administered dofetilide versus amiodarone in 1994. the acute conversion of atrial fibrillation and flutter. A mul- 34 Colatsky TJ, Follmer CH, Starmer CF. Channel specificity ticenter, randomized, double-blind, placebo controlled in anti-arrhythmic drug action. Mechanism of potassium study [abstract]. 1995; :774. Circulation 92 channel block and its role in suppressing and aggravating 29 Falk RH, Pollack A, Singh SN, et al. Intravenous dofelitide, a class III anti-arrhythmic agent, for the termination of sus- cardiac arrhythmias. Circulation 1990;82:2235–42. tained atrial fibrillation or flutter. J Am Coll Cardiol 35 Carlsson L, Almgren O, Duker G. QTU-prolongation and 1997;29:385–90. Torsade de Pointes induced by putative class III anti- 30 WijVels MCEF. Atrial fibrillation begets atrial fibrillation. arrhythmic agents in the rabbit: etiology and interventions. An experimental study in chronically instrumented goats J Cardiovasc Pharmacol 1990;16:276–85. [thesis]. Maastricht: University of Maastricht, 1996. 36 Buchanan LV, Kabell G, Brunden MN, et al. Comparative 31 WijVels MCEF, Kirchhof CJHJ, Dorland R, et al. Atrial fibril- assessment of ibutilide, d-sotalol, clofilium, E-4031, and lation begets atrial fibrillation. A study in awake chronically UK-68798 in a rabbit model of pro-arrhythmia. J instrumented goats. Circulation 1995;92:1954–68. Cardiovasc Pharmacol 1993;22:540–9. http://heart.bmj.com/ on September 27, 2021 by guest. Protected copyright.