the antiarrhythmic effects of d-sotalol

The antiarrhythmic effects of d-sotalol

The antiarrhythmic properties of d-sotalol were studied in 38 patients undergoing electrophysiologic studies. Programmed electrical stimulatlon studies were performed in 28 men and in 10 women with a mean age of 67 years and a mean ejection fraction of 37 ? 3%. All patients had inducible ventricular tachycardia while they were off all antiarrhythmic therapy. D-sotalol was given as a 2 mg/kg infusion over 15 minutes and did not significantly change the PR, QRS, or QT, Intervals from baseline values in the group as a whole. In the group protected by d-sotalol, the percent change in the QT. interval as well as the percent change In refractoriness was significantly increased as compared to the group not protected. D-sotalol also significantly decreased heart rate. D-sotalol prevented the induction of ventricular tachycardia in 18 of the 38 patients, while significantly slowing the rate of the ventricular tachycardia in the group that could still have tachycardla provoked. Seventeen patients were tested on procainamide and only four were protected, while d-sotalol prevented the induction of ventricular tachycardia in 7 of these 17. Eleven patients were discharged on oral d-sotalol doses ranging from 100 to 400 mg twice daily. One patient died 1 month post discharge due to an acute myocardial infarction, and one patient had a cardiac arrest while on d-sotalol and survived and was switched to amiodarone therapy. The remaining nine patients are alive and well at 14 + 3 months. D-sotalol appears to be an effective antlarrhythmic drugs and appears to be well tolerated. (AM HEART J 1987;114:539.)

Joseph Schwartz, M.D., Kris Cracker, R.N., Jonathan Wynn, M.D., and John C. Somberg, M.D. Bronx, N. Y.

D-sotalol, the d-isomer of the racemic sotalol, is currently undergoing clinical investigation as an antiarrhythmic agent under the sponsorship of the Bristol-Myers/Mead Johnson Pharmaceutical Cor- poration. Among the beta-blocking drugs, sotalol has been shown to be unique by exhibiting class III activity, resulting in prolongation of repolarization in a variety of types of cardiac tissues.‘, 2 Early studies3m6 have demonstrated moderate antiarrhythmic efficacy of sotalol on a variety of supraventricu- lar and ventricular arrhythmias. These studies included groups with heterogeneous arrhythmias and only a few patients had ventricular tachycardia. More recently, Senges et a1.7 have demonstrated that sotalol can provide effective prophylaxis against sustained ventricular tachycardia in 12 of the 18 patients studied. Nademanee et al2 studied 33 patients and found sotalol effective acutely in 15

From the Cardiac Arrhythmia Service, Departments of Medicine and Pharmacology, Albert Einstein College of Medicine.

This study was supported in part by a grant from the Mead Johnson Bristol-Myers Corporation. Dr. Somberg is an Established Investigator of the American Heart Association.

Received for publication Nov. 3, 1986; accepted Apr. 3, 1987.

Reprint requests: John C. Somberg, M.D., Cardiac Arrhythmia Service, Albert Einstein College of Medicine, 1300 Morris Park Ave., F-208, Bronx, NY 10461.

patients (45% 1. Several studies performed on beta- blocking drugs8-l2 suggest antiarrhythmic action of the d-isomer as compared to the l-isomer, which solely possesses beta-blocking properties.

D,l-sotalol, a drug with beta-blocking properties, has been shown to increase the ventricular refractoriness, acting as an antiarrhythmic drug in an ische- mic canine heart.*3~*4 These investigators13 have shown that the d-isomer has an antifibrillatory action in a conscious canine model. The d-isomer (d-sotalol) produces a concentration-dependent lengthening of the action potential and the effective refractory periods in various cardiac tissue prepara- tions. Recently, Lynch et a1.13 have shown that d-sotalol suppressed the induction of ventricular tachycardia by programmed electrical stimulation in six of the nine conscious dogs tested, and slowed the rate of the ventricular tachycardia in two of the remaining three dogs. l4 D-sotalol also provided sig- nificant protection against the development of is- chemically induced ventricular fibrillation. These authors concluded that in this animal model incre- ments in ventricular refractoriness and repolarization as measured by the QT, suggest a class III electrophysiologic action of d-sotalol. They also found that d-sotalol has only minimal beta-adrenergic antagonistic action. This relatively greater beta-

539

540 Schwartz et al. September 1987

American Heart Journal

Table I. Characteristics of the patient population

Cardiac diagnosis Atherosclerotic heart disease Cardiomyopathy Hypertensive heart disease

Presenting problem

Cardiac arrest Sustained ventricular tachycardia

Mean ejection fraction Age

21 9 2

15 23

37 + 3%

62 + 7 years

blocker activity of the l-isomer and ant&rhythmic properties of the d-isomer have been reported for other beta blockers.8-12

It is therefore the purpose of this study to exam- ine the electrophysiologic and antiarrhythmic effects of d-sotalol, when given by the intravenous route, to patients undergoing invasive electrophysiologic study for malignant ventricular arrhythmias. Additionally, we were interested in determining the extent of its beta-adrenergic blockade and the drug’s effect on electrophysiologic parameters in patients with heart disease and life-threatening arrhythmias.

METHODS

Patient population. Thirty-eight patients (28 men and 10 women) were studied (Table I). Their ages ranged from 39 to 86 years, with a mean age of 62 + 7 years. They were referred to our laboratory for selection of antiarrhythmic therapy. Fifteen patients were referred after resuscitation following a cardiac arrest. Twenty-three patients had documented sustained ventricular tachycardia (37 to 172 beats) on Holter monitoring or coronary care monitoring, with symptoms of hemodynamic compromise. The under-

(. lying cardiac diagnosis for the patient population was coronary artery disease in 27 patients (71% 0) and cardiomyopathy of 11 (29%).

Protocol design. Informed consent was obtained in each case. The study protocol and consent form were approved by the Committee on Clinical Investigation of the Albert Einstein College of Medicine. All antiarrhythmic agents were discontinued 5 half-lives prior to study initiation. No patient had previously received amiodarone. Nitrates, digitalis, and diuretics used for the control of angina and congestive heart failure were continued during the study and subsequently as clinically indicated. All patients underwent programmed electrical stimulation prior to drug infusion. Only those patients with provokable ventricular tachycardia (VT) were entered into this study. Fifteen-minute baseline monitoring was obtained prior to infusion of d-sotalol. D-sotalol was infused at a concentration of 2.0 mg/kg over 10 minutes in 33 of the patients, while the first five patients received the drug at a concentration of 1.0 mg/kg. A blood specimen for sotalol was obtained 20 minutes after the infusion from a site

different from the one used for the infusion. After comple- tion of drug infusion and a waiting period of 20 minutes, all patients underwent repeat programmed electrical stimulation. Fifteen-minute monitoring was obtained in each case after infusion of d-sotalol. Trending data obtained over 15 minutes were evaluated by hand counting of three simultaneous ECG lead recordings for an increase or decrease in ventricular premature depolarizations. An increase in ventricular premature depolarization frequency was defined as a 5-times or greater increase if baseline ventricular premature depolariations were 51 to 100 ventricular premature depolarizations/hr and a lo-times increase if baseline ventricular premature depolarizations were 1 to 50 ventricular premature depolarizations/hr. A decrease in ventricular premature depolarization frequency was defined as a 5-times or greater decrease from baseline if ventricular premature depolarizations were 51 to lOO/hr and a lo-times decrease if baseline ventricular premature depolarization’s were 1 to 50 ventricular premature depolarization&r. To determine the degree of ventricular premature contraction (VPC) variability between trending periods, two 15-minute studies were performed 5 minutes apart in patients off antiarrhythmic therapy. Minimal variability was noted in VPC frequency, with only a 9.7% variation between studies.

Seventeen patients were also evaluated by programmed electrical stimulation after an infusion of 1000 mg procainamide over 50 minutes, with monitoring of ECG and blood pressure response. Procainamide was administered either at least 5 half-lives before or after sotalol administration. Twenty-one patients were not tested on procainamide due to a history of clinical ineffectiveness or adverse side effects on procainamide.

Programmed electrical stimulation. Programmed electrical stimulation was performed with a hexapolar pacing catheter inserted via the right internal jugular vein to the apex of the right ventricle. In patients in whom ventricular tachycardia could not be induced from the right ventricular apex, the catheter was repositioned to the right ventricular outflow tract. A digital stimulator (Bloom Associates, Nanbeth, Pa.) was used to deliver square-wave electrical impulses of 2.0 msec duration with the amplitude set at twice the diastolic threshold. The right ventricle was driven with a pacing train of 6 beats at a cycle length of 500 msec, with an intertrain interval of 8 seconds.

Single premature ventricular stimuli (S,) were delivered in late diastole starting at 500 msec from the end of the pacing train and progressively introduced earlier by 20 msec decrements immediately after the pacing train every 8 seconds. The shortest interval at which S, fails to evoke a depolarization is termed the effective refractory period, and the stimulus is brought out 10 msec further from the end of the pacing train and a second extrastimulus is introduced at the sum of the S,-S, and S,-S, intervals and is introduced at 20 msec decrements. This programmed introduction of premature stimuli is performed until nonsustained VT (at least 10 beats) is obtained or until three extrastimuli are introduced. We use nonsustained

Volume 114 Number 3 Antiarrhythmic properties of d-sotalol 541

Table II. Electrophysiologic and electrocardiographic effects of d-sotalol

HR PR QRS QTc (bpm) (msec) (msec) (msec)

ERP S, AH (msec) (msec)

HV (msec)

Drug-free d-Sotalol Significance

72 * 2 64 f 3

p < 0.05

222 f 3 98 f 2 438 k 13 239 k 5 95 rt 5 50 _t 4 193 + 4 105 k 1 486 k 7 283 r 4 90 f 5 45 IL 6

NS NS p < 0.01 p < 0.001 NS NS

HR = heart rate; ERP = effective refractory period.

ventricular tachycardia as a marker of electrical instabili- ty and do not introduce additional stimuli trying to provoke sustained VT when the patient is off antiarrhythmic therapy. When the patient has received an antiarrhythmic agent, we introduced three extrastimuli obtain- ing sustained VT or complete protection (less than six repetitive beats). Statistical analysis. The mean f the standard error of the mean are reported. Differences between means were determined by a Student’s t test. A two-tailed test was used to determine the level of significance. The percentage change was determined as the quotient of the initial and final value after drug infusion divided by the initial value. The difference in means was determined by Student’s t test. Analysis of correlation of arrhythmia frequency and inducibility at programmed electrical stimulation is performed by chi square analysis. McNemar’s test for paired sampling of nominal scale data was used to determine significance.

RESULTS

VT was provoked in all 38 patients off antiarrhythmic therapy. Thirty-two patients had VT provoked with stimulation at the right ventricular apex, while six patients required stimulation at the right ventricular outflow tract. At a cycle length of 500 msec, VT was induced by one extrastimulus in five patients, by two extrastimuli in 20 patients, and by three extrastimuli in 13 patients. Nonsustained VT was induced in 17 patients and sustained VT was induced in 21 patients. If nonsustained VT was induced (range 15 to 28 beats), we did not try to provoke sustained VT at baseline. The mean VT rate was 246 + 8 bpm. Sustained VT was termi- nated by pacing in 17 patients and by direct current countershock in four patients.

Effects of d-sotalol. Thirty-eight patients received d-sotalol intravenously. Mean arterial blood pressure changed minimally from an average of 102 + 4 to an average of 100 f 6 mm Hg. Heart rate decreased from a control value of 72 * 2 to 64 2 3 bpm. Infusion of d-sotalol failed to significantly change either the AH or the HV intervals (AH = 95 -+ 5 to 90 +- 5 msec; HV = 50 + 4 to 45 f 6 msec). At electrophysiologic testing after antiarrhythmic drug infusion, we introduced extrastimuli

Table Ill. Percent change in QT, interval and refractoriness in patients protected and not protected at electrophysiologic testing

% change QTc*

Protected 13 * 3

Not protected 4k2

Significance p < 0.05

ERP = effective refractory period.

% change ERP S,*

24 + 3 16 +- 3

p < 0.05

*Percent change in QT, and ERP determined as the quotient of the interval after d-sotalol infusion minus baseline interval divided by the baseline interval.

until sustained VT was provoked or until 3 extrastimuli were introduced, even if VT was provoked off the drug by a lesser number of stimuli. After d-sotalol infusion, VT was no longer inducible in 18 of the 38 patients (47% efficacy). Of the 20 patients who could still have VT inducible after the infusion of d-sotalol, VT was inducible by the first extrastimulus in two patients, by the second extrastimulus in 10 patients, and by the third stimulus in eight patients. Two patients showed a reduction in the number of stimuli required to induce VT. D-sotalol slowed the VT rate from the baseline VT rate of 220 f 12 to 160 5 10 bpm.

Monomorphic VT was provoked in 28 patients and polymorphic VT was provoked in 10 patients. Six patients were documented to have polymorphic VT clinically. D-sotalol was effective in 14 patients in whom monomorphic VT was provoked and in four patients with polymorphic VT.

In the group as a whole, the refractory period was prolonged for the first extrastimulus after infusion of d-sotalol. Also, the sinus cycle length slowed and the QT, interval prolonged significantly, while the PR and QRS intervals did not change significantly from baseline values (Table II). In the group protected by d-sotalol, the percentage increase in the refractoriness of the first extrastimulus on the drug compared to the baseline value as well as the percent change in the QT, interval were significantly increased as compared to the group not protected on



Table IV. Evaluation of VPC frequency and ventricular tachycardia inducibility at programmed electrical stimulation testing

VPC frequency

Increase * Decrease * No change

d-sotalol (n = 38) PES inducibility Protected 8

Not protected 5 9 5 5 6

x2 = 0.02 p=NS

Procainamide (n = 17) PES inducibility Protected

Not protected 2 2

2 0 9 2

x2 = 0.4 p=NS

PES = programmed electrical stimulation; VPC = ventricular premature contraction. *Definitions: An increase in ventricular premature depolarization frequency ~88 defined as a 5-times or greater increase if baseline ventricular premature depolarizations were 51 to 100 ventricular premature depolarizations/hour and a lo-times increase if baseline ventricular premature depolarizations were 1 to 50 ventricular premature depolarizations/hour. A decrease in ventricular premature depolarization frequency was defined as a 54imes or greater decrease from baseline if ventricular premature depolarizations were 51 to NO/hour and a lo-times decrease if baseline ventricular premature depolarizations were 1 to 50 ventricular premature depolarizations/hour.

Table V. The effectiveness of d-sotalol at electrophysiologic testing evaluated by presenting arrhythmia

Protected Not protected

Sustained VT 14 9 Cardiac arrest 4 11

Total 18 20

VT = ventricular tacbycardia.

d-sotalol (Table III). We also evaluated the percentage change in the JT, and the effective refractory period in those patients protected and in those not protected. In the protected group a 17 * 4% increase in JT, and a 25 + 4% increase in the effective refractory period were observed, compared to a 6 + 3% increase in JT, and a 15 + 2% increase in the effective refractory period in the unprotected group 03 < 0.05). The ratio of the effective refractory period to delta QT, in the group with inducible VT was 562 +- 44 msec compared to 620 ? 21 msec in the protected group (p < 0.01).

Seventeen patients were tested on both d-sotalol as well as procainamide. Four patients not protected on procainamide were successfully protected by d-sotalol, while only one patient not protected by d-sotalol was successfully protected by procainamide. Of these 17 patients, only four were protected by procainamide, while a total of seven patients in this drug-resistant group were protected by d-sotalol. In the group who could still have VT inducible on procainamide, seven patients required

additional extrastimuli for the induction of VT. Four patients required the same number of extrastimuli as was required in the baseline study. Two patients had the induction of VT facilitated by procainamide. Twenty-one patients were not tested on procainamide due to a history that procainamide was ineffective clinically; 11 of these patients were successfully protected by d-sotalol.

Antiarrhythmic drug levels were obtained from patients after electrophysiologic testing. The serum concentration of d-sotalol was 2.4 f 0.3 pg/ml in those patients in whom VT could no longer be provoked and 2.9 + 0.3 pg/ml in those not protected. The procainamide concentration was 6.1 + 0.6 &ml in the protected group and 7.2 f 0.5 pg/ml in the group in whom ventricular tachycardia was still provokable.

The results of the trending data are presented in Table IV. There was no correlation between the effects of antiarrhythmic drug action on ventricular premature depolarixation frequency and protection against VT induction at programmed electrical stimulation. This was true both for d-sotalol and procainamide.

Subgroup analysis by presenting diagnosis reveals that d-sotalol was effective in 4 out of 15 patients who presented with a previous cardiac arrest and 14 out of 23 patients with sustained VT were protected (Table V).

Chronic therapy. Due to lack of supplies of oral d-sotalol early in the study as well as effectiveness of other antiarrhythmic drugs in some patients, only 11

Volume 114 Number 3 Antiarrhythmic properties of d-sotatol 543

patients were discharged on oral d-sotalol doses ranging from 100 to 400 mg twice daily. One patient suffered a fatal myocardial infarction 4 weeks post discharge, and one patient had a breakthrough sustained VT 8 weeks following hospital discharge (doses were 100 mg twice daily). The remaining patients have had no adverse side effects from chronic oral d-sotalol therapy and are alive and well (nine patients), with 14 it 3 months of follow-up.

DISCUSSION

Previous studies79 l5 have demonstrated that d- sotalol prolongs the action potential duration and increases the refractory period. D-sotalol has also been shown to be effective in suppressing the induction of VT in a canine model in which the animals had a previous myocardial infarction 3 to 5 days before study.13014 The findings of our study demon- strate the effectiveness of d-sotalol in preventing the induction of VT in 47% of patients as well as in considerably slowing the rate of the induced tachycardia. In the majority of the 20 subjects who still had VT inducible after the infusion of d-sotalol, extra premature stimuli were required to induce the arrhythmia as contrasted to the baseline determina- tion. No patients developed spontaneous VT after receiving d-sotalol.

Studies by Edvardsson et a1.,15 as well as the study by Senges et al., 7 have demonstrated an increase in ventricular refractoriness as well as an increase in the QT, interval in patients tested with sotalol. These authors7j l5 also demonstrated the effectiveness of sotalol in 67% of patients tested. Our results may support the previously reported findings in animal models13+14 that the effectiveness of d-sotalol seems to be due to class III electrophysiologic actions, as evidence by the increases in the myocardial ventricular refractoriness as well as the prolongation in the QT, interval. The somewhat lower effectiveness of d-sotalol as compared to the 6’7% effectiveness of sotalol reported by Senges et al.’ may be due to the less aggressive stimulation protocol used in that study or to the differences in the type of patients studied, cardiac arrest, and sustained VT in this protocol. Our results with d-sotalol are similar to those reported with sotalol by Nade- manee et al.’

Prolongation of the QT interval has been felt to be proarrhythmic,16, l7 increasing myocardial vulnera- bility. Experience with class III antiarrhythmic drugs and the elucidation of their electrophysiologic properties have led investigators to question the concept that QT prolongation is always proarrhythmic.ls Recent studies of the antiarrhythmic proper-

ties of bepridiPg have found that patients protected from arrhythmia induction had a correlation between the percent prolongation of the QT interval and the percent increase in the effective refractory period. Those patients not protected by bepridil had no correlation between the percent QT increase and the percent effective refractory period prolongation. These studieslg suggest that a uniform increase in repolarization and refractoriness may be necessary for the effectiveness of a class III drug in preventing VT induction. This relationship has also been observed with N-acetylprocainamide (NAPA),20~21 an agent with reported class III effects. Our study is consistent with these findings by demonstrating positive correlation between the percent increase in QT, and the percent increase in refractoriness in the group of patients protected by d-sotalol. The group not protected by d-sotalol did not show a correlation between the QT, prolongation and increase in refractoriness as measured by the extrastimulus technique. These observations support the hypothesis that a combined increase in QT, as well as an increase in refractoriness may be a factor in the effectiveness of VT suppression by d-sotalol. Regional myocardial changes not reflected in the gross measurement of repolarization as measured by the QT interval or refractoriness measured at only one myocardial site may be limiting in precisely defining this relationship. Unfortunately, clinical electrophysiologic studies do not permit more spe- cific measurements of regional changes in repolarization and refractoriness. Still, even with these imprecise measurements, the majority of patients respond in a predictable manner, those with an increase in repolarization and refractoriness being protected against VT induction. The ratio of the effective refractory period to delta QT, was longer in the protected group, emphasizing the importance of repolarization effects in the action of type III agents. These findings support the hypothesis that class III antiarrhythmic agents like d-sotalol are effective when refractoriness and repolarization are both significantly increased.

This study demonstrates the effectiveness of intravenous d-sotalol against the induction of VT by programmed electrical stimulation in a surprisingly high percentage of patients. These results are similar to previous clinical studies performed with sota- 101 in man.2p7 We believe that the effectiveness of the drug is related to the homogeneous increase in repolarization as well as to ventricular refractoriness. Additional studies with this drug as well as with others with class III electrophysiologic properties need to be performed. In patients started on



d-sotalol, the drug appears to be chronically effective and well tolerated, although the number of patients is few for a critical evaluation.

We also note a low incidence of drug facilitation of arrhythmias (proarrhythmic action), with no patient developing spontaneous VT following intravenous administration of d-sotalol. Although the d-isomer is reported to have minimal beta-blocking action, heart rate was reduced following d-sotalol infusion. It is possible that the beta-blocking action may play a role in the antiarrhythmic action of d-sotalol.

REFERENCES

1.

2.

3.

4.

5.

6.

7.

8.

Carmeliet E. An electrophysiologic and voltage clamp analysis of sotalol effects on cardiac muscle and Purkinje fibers. Circulation 1983;68:111-297. Nademanee K, Feld G, Hendrickson J, Singh P, Singh B. Electrophysiologic and antiarrhythmic effects of tachyar- rhythmias. Circulation 1985;72:5, 555-564. Prakash R, Parmley WW, Allen HN, Matloff JM. Effect of sotalol on clinical arrhythmias. Am J Cardiol 1972;29:397. Fogelman F, Lightman SL, Sillett RW, McNicol MW. The treatment of cardiac arrhythmias with sotalol. Eur J Clin Pharmacol 1972;5:72. Simon A, Berman E. Long term sotalol therapy in patients with arrhythmias. J Clin Pharmacol 1979;19:547. Myburgh DP, Goldman AP, Cartoon J, Schamroth JM. The efficacy of sotalol in suppressing ventricular ectopic beats. S Afr Med J 1979;56:295. Senges J, Lengfelder W, Jauernig R, Czygan E, Brachmann J, Rizos I, Cobbe S, Kubler W. Electrophysiologic testing in assessment of therapy with sotalol for sustained ventricular tachycardia. Circulation 1984;69:577-584. Dure B, Garberg L, Johansson B. The effect of propranolol and the dextro and levo isomers of H 56/28 upon ouabain- induced ventricular tachycardia in unanesthetized dogs. Acta Pharmacol Toxic01 1967;25:2, 41-49.

9.

10.

11.

12.

13.

14.

15.

16.

17.

Whitshitt LS, Lucchesi BR. The cardiac beta-adrenergic receptor blocking actions of propranolol and its stereoiso- mers. Life Sci 1967;6:939-950. Howitt G, Husaini M, Rowlands D, Logan W, Shanks R, Evans M. The effect of the dextro isomer of propranolol on sinus rate and cardiac arrhythmias. AM HEART J 1968;76:6, 736-745. Levy J, Richards V. Inotropic and chronotropic effects of a series of beta adrenergic blocking drugs: Some structure- activity relationships. Proc Sot Exp Biol Med 1966;122:373- 379. - Fitzgerald JD. Perspectives in adrenergic beta-receptor blockade. Clin Pharmacol Ther 1969:10:292-306. Lynch JJ, Coskey LA, Montgomery ‘DG, Lucchesi BR. Pre- vention of ventricular fibrillation by dextrorotatory sotalol in a conscious canine model of sudden coronary death. AM HEARTJ 1985;109:949-958. Patterson E, Lynch JJ, Lucchesi BR. Antiarrhythmic and fibrillatory actions of the beta adrenegic receptor antagonist, dl-sotalol. J Pharmacol Exp Ther 1984;230:519-526. Edvardsson N, Hirsch I, Emanuelsson H, Ponten J, Olsson SB. Sotalol-induced delayed ventricular repolarization in man. Eur Heart J 1980;1:335. Seizer A, Wray WH. Quinidine syncope: Paroxysmal ventricular fibrillation occurring during treatment of chronic atria1 arrhythmias. Circulation 1964;30:17. Reynolds EW, Vander Ark CR. Quinidine syncope and delayed repolarization syndromes. Mod Concepts Cardiovasc Dis 1976;55:117.

18. Vaughan Williams EM. QT and action potential duration. Br Heart J 1982;47:513.

19. Somberg J, Torres V, Flowers D, Miura D, Butler B, Gottlieb S. Prolongation of QT interval and antiarrhythmic action of bepridil. AM HEART J 1985;109:19-27.

20. Oates JA, Woosley RL. Antiarrhythmic efficacy, pharmacoki- netics and safety of n-acetylprocainamide in human subjects: Comparison with procainamide. Am J Cardiol 1980;46:463.

21. Wynn J, Miura D, Torres V, Flowers D, Keefe D, Williams S, Somberg J. Electrophysiologic evaluation of the antiarrhythmic effects of n-acetylprocainamide for ventricular tachycardia secondary to coronary artery disease. Am J Cardiol 1985;56:877-881.

the antiarrhythmic effects of d-sotalol

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