Clinical efficacy of amiodarone as an antiarrhythmic agent

Clinical Efficacy of Amiodarone as an Antiarrhythmic Agent

MAURICIO B. ROSENBAUM, MD, FACC PABLO A. CHIALE, MD M. SUSANA HALPERN, MD GERARD0 J. NAU, MD JULIO PRZYBYLSKI, MD RAirL J. LEVI, MD JULIO 0. LAZZARI, MD MARCEL0 V. ELIZARI, MD,

FACC

Buenos Aires, Argentina

Amiodarone, administered orally in doses of 200 to 600 mg/day, was remarkably effective in the treatment and prevention of a wide variety of atrial and ventricular arrhythmias. Total suppression and control was provided in 96 (92.4 percent) of 106 patients with supraventricular arrhythmias and in 119 (62 percent) of 145 patients with ventricular arrhythmias. The rates of total control of the arrhythmia were: 96.6 percent in 30 patients with recurrent atrial flutter or fibrillation, 96.6 percent in 59 patients with repetitive supraventricular tachycardia, 100 percent in 27 patients with Wolff-Parkinson-White syndrome and 77.2 percent in 44 patients with recurrent ventricular tachycardia unsuccessfully treated with other drugs. Excellent results were obtained in 6 of 6 patients with repetitive ventricular tachycardia and ventricular fibrillation related to postinfarction ventricular aneurysm and in 12 of 14 patients with ventricular extrasystoles and ventricular tachycardia related to Chagasic myocarditis. Amiodarone proved safe in patients with severe congestive heart failure and severe myocardial damage. Its clinical efficacy was related to its electrophysiologic properties and to two unique properties: its wide safety margin and its cumulative effect. The latter liberates patients from a rigid hourly schedule and provides for continuous antiarrhythmic control, days and even weeks after treatment is discontinued.

In a previous paper,l we reported the usefulness of amiodarone in controlling tachyarrhythmias associated with the Wolff-Parkinson-White syndrome. The drug was subsequently shown to have similar efficacy in a variety of atria1 and ventricular arrhythmias. In this paper we present results obtained in 252 patients, including several with disabling or life-threatening arrhythmias or arrhythmias resistant to other antiarrhythmic agents. The properties of the drug underlying its clinical efficacy as well as side effects and contraindications are emphasized. Material

and Methods

Two hundred fifty-two patients with persistent or recurrent supraventricular or ventricular arrhythmias were studied. They were classified into six groups according to their primary arrhythmia (Tables I to VI). Ninety-eight patients had previously been treated unsuccessfully with various antiarrhythmic agents

From the Service of Cardiology of Ramos Mejia Hospital, Urquiza 609, Buenos Aires, Argentina. This study was supported in part by the Comisi6n para et Estudio Integral de la Enfermedad de Chagas and by the Fundaci6n de lnvestigaciones Cardiok5gicasEinthoven, Buenos Aires, Argentina. Manuscript received March 26, 1976; revised manuscript received July 7. 1976, accepted July 7, 1976. Address for reprints: Mauricio B. Rosenbaum, MD, Rivadavia 3820 P.B. “A,” Buenos Aires, Argentina.

934

December 1976

(Tables I, II, V and VI); in 154 patients, amiodarone was the first antiarrhythmic drug given. Each episode of arrhythmia was studied with long electrocardiographic tracings and, when needed for diagnostic purposes, atria1 electrograms (22 cases), His bundle electrograms (6 cases), atria1 pacing (6 cases) and ventricular pacing (8 cases). Amiodarone* is a benzofuran derivative that shares some structural similarities with thyroxine (Fig. 1). The pharmacologic effects have been summarized in previous papers.2J Essentially, amiodarone increases coronary blood flow, reduces myocardial oxygen consumption without significantly affecting cardiac output, causes an atropine-resistant bradycardia and antagonizes the effects of catecholamines and sympathetic stimulation without causing competitive beta adrenergic receptor blockade.2 “Amiodarone (generic name) was kindly supplied by Laboratorios Roemmers, Buenos Aires, for this study, and was originally discovered and manufactured by Services de Recherche Labaz, Brussels.

The American Journal of CARDIOLOGY

Volume 38

ANTIARRHYTHMIC EFFICACY OF AMIODARONE-ROSENBAUM

TABLE

ET AL.

I

Repetitive

Atrial

Flutter

and Fibrillation:

Treatment

With Amiodarone

in 30 Cases Previous Treatment

Results With Amiodarone Diagnosis Wolff-Parkinson-White syndrome No heart disease Arterial hypertension Coronary insufficiency plus arterial hypertension Mitral insufficiency Chronic Chagasic myocarditis Pulmonary embolism Chronic hiatus hernia Chronic bronchitis Hypothyroidism Diabetes Undetermined Total

E

7 6 5 4

7 6 4 4

, , , , , , ,

1 , , , , ,

Q Cases ~ P (no.) G

G ..

...

.

6

, .

.. . . .

. .

1

4 5 ,

.

,

. . .

.

.

.

. . .

.

. . .

. . . . .

4

.

.

.

1 ,

‘;

D

@B

P

___ G

P

G

5

...

2

...

3 3

.

1

.

, .

. . .

,

,

.

-

, 3 ,

2

.

1

~ G

...

...

...

.

.

. ..

.

. .

. . .

..,

. .

.

. . .

. ..

. . .

. . .

. . .

.. . . ..

, , ,

.

..

. . .

.

. . .

.

.

.

1 2

A

PrcXZ ___ G P

L P 1

.

.

. . .

.

.

. . .

. .

.

. . .

.

.

.. , . .

,

..

1

.

...

.

. . .

~ G

P 1

.

..

.

.

. . .

. ..

... . . .

. . .

.. .

. . .

,..

.

...

. .

.

.

. . .

. . .

. . , ,

P

. . .

. . . .

.

DPH

~ G

.

. . .

.

. .

.

.

. .

. . .

.

.

2:

agents; D = digitalis;

DPH = diphenylhydantoin;

E = excellent;

G = good; L = lidocaine;

P = poor;Proc

=

II

Repetitive

Supraventricular

Tachycardia:

Treatment

With Amiodarone

in 59 Cases Previous Treatment

Results With Amiodarone

Q

Cases Diagnosis

(no.)

E

Wolff-Parkinson-White syndrome Lown-Ganong-Levine syndrome Cardiomyopathy Chronic Chagasic mvocarditis Coronary insufficiency Arterial hypertension Valvular heart disease No heart disease Undetermined Total

20 3 5 1 4 5 2 16 3 59

20 3 4 1 4 5

@B = beta blocking

Cases (no.)

P

G .. . ..

. . . 1 .

. . . . . . .

1,: 3 57

1

.

. . .

.

3” 1

G

P

G

1 1

9 1

1

3 1 1

1

TABLE

. .

1

.

4 2

. . .

1

::.

: 2

Treatment

With Amidarone

No heart disease Severe arterial hypertension Coronary insufficiency plus arterial hypertension Mild arterial hypertension plus chronic hiatus hernia Drabetes Coronary insufficiency Total E = excellent;

G = good; P = poor.

3 3 1

3 2 1

. .. .

P

1

1

Undetermined Arterial hypertension Undetermined

1 1 7

:::

:::

Treatment

With Amiodarone

Results With Amiodarone

1

1 1 1 10

G

.

5 2

in

Diagnosis E

. .

IV

Cases (no.)

Results With Amiodarone Diagnosis

2 1

. . .. .

1 .

10 Cases

Cases (no.)

..

6 1 1

Q = quinidine.

Miscellaneous Arrhythmias: in Eight Cases

Extrasystoles:

2 . . .

P

G

32

G = good; P = poor; Proc = procainamide;

III

. . . . . . .

. .

P

.

. .

Proc

PB

P

. .

2 1 1

.

1

agents; D = digitalis; E = excellent;

13 2 2 .

D

G

TABLE

Atrial

P

.

.

. . .

,

3;

A = ajmaline; pB = beta blocking procainamide; Q = quinidine.

TABLE

Cases (no.)

2

Chronic Chagasic myocarditis Undetermined Total A-V

December 1876

Arrhythmia Chronic atrial flutter Chronic atrial tachycardia with A-V Wenckebach block Junctional rhythm with Wenckebach exit block Chronic atrial fibrillation with high ventricular response Sinus tachycardia

= atrioventricular;

E

G

1 1

. .

. . .

1

.

1

1

. .

1

1 1

.

4

. . .

:6 E = excellent;

P

11

G = good; P = poor.

The American Journal of CARDIOLOGY

Volume 38

938

ANTIARRHYTHMIC EFFICACY OF AMIODARONE-ROSENBAUM

ET AL

AMIODARONE

3-(4,

2-butyl,

diethylaminoethoxy,

benzoil)benzofuran

diiodo,

3

Treatment protocol: Amiodarone was administered orally in a dose of 200 (one tablet) to 800 mg/day, in a single or divided dose according to patient preference. The most common initial dose was 600 mg/day; when the desired antiarrhythmic effect was obtained, usually after 4 to 8 days of treatment, the dose was reduced to the minimum that would keep the patient free of arrhythmia, generally 200 to 400 mg/day. Treatment and follow-up periods ranged from 15 days to 3 years (average of 17 months). In 53 patients, administration of amiodarone was discontinued for 2 days every week or 1 week every month to assess whether this interruption of treatment was compatible with continuous control of the arrhythmia. In eight patients with daily episodes of supraventric&ar tachycardia, treatment was deliberately interrupted (and reinstituted) several times in order to evaluate the persistence of the an-

, 5’-

hydrochloride.

FIGURE 1. Structural formula of amiodarone.

TABLE

V

Persistent

Ventricular

Extrasystoles:

Treatment

With Amiodarone

in 101 Cases Previous Treatment

Results With Amiodarone Cases (no.1

Diagnosis Chronic Chagasic myocarditis No heart disease Cardiomyopathy Coronary insufficiency Acute myocardial infarction Postmyocardial infarction ventricular aneurysm Arterial hypertension Hyperthyroidism Chronic car pulmonale Diabetes Posterior mitral leaflet dysfunction Mitral-aortic disease Undetermined Thyroid adenoma with normal function Total pB = beta blocking quinidine.

TABLE

24 17 13 19 4 3

G

E

P

21 12 12 17 4 3

1 ..’ 1 2 ... ‘.’

2 5

7

... 1

1 1

8 3” 1 1 1 2 1 101

Q

3’

D

Cases ~ (no.) G

P

___ G

P

5

1

3 3

2 1 1 2

. .

1

P

1 1

1

DPH ___ G P 1

2

1 1 1

1

2

L ___ G

1

.

.

.

1

“’

1 1 1 85

“. “’

1

5

11

.

. .

1 22

agents; D = digitalis; DPH = diphenylhydantoin;

E = excellent;

1

G = good; L = lidocaine;

1

P = poor; Proc = procainamide;

Q =

VI

Repetitive

Ventricular

Tachycardia:

Treatment

With Amiodarone

in 44 Cases Previous Treatment

Results With Amiodarone Q

Cases Diagnosis

(no.)

Postmyocardial infarction ventricular aneurysm Chronic Chagasic myocarditis Cardiomyopathy Hypertensive heart disease Acute myocardial infarction Coronary insufficiency plus arterial hypertension Diabetes and gall bladder disease Chronic renal insufficiency Mitral-aortic disease with complete A-V block Hypothyroidism Undetermined Total

z*, 14 7 5 3 2 1 1 c:*r 1

E

G

&)

:::

12 6

2

; 1

34 (6”)

(&

6

1

6 3

2

1

. .

1 1 $*, 1

1 44 (7”)

P

Cases ~ (no.) G

1

December 1976

5

.

P6

1

2

. ..

..

P

~ G

P

1

.

1

2 1

1

1

. .

P

1

. .

..

D ~ G

:

Proc ~ G P

..

6 2

1

1

1

1

. .

1 1

2

,

.

1

DPH

L ___ G

P

. .

6

2 1

2 1

, 1

...

1 ..

1

,

1

~ G

P 4

“.

1

.. . 1

“’

. 1

1

1

.

,

,

.

1 5

23 &

*Patients with repetitive ventricular fibrillation. ,6B = beta blocking L = lidocaine; P = poor; Proc = procainamide; Q = quinidine.

936

P

.. ..

; .I

G

..

6 7

Proc ___ G P

P9 -

The American Journal of CARDIOLOGY

agents; D = digitalis: DPH = diphenylhydantoin;

Volume 36

E = excellent;

G = good;

ANTIARRHYTHMIC EFFICACY OF AMIODARONE-ROSENBAUM

tiarrhythmic effect. Findings in these patients were compared with data obtained from similar analysesin eight patients who discontinued treatment spontaneously. Forty-two patients presenting the most severe arrhythmias with or without atrioventricular (A-V) or intraventricular block were continuously monitored in the intensive care unit during the first days. The remaining patients were treated on an ambulatory basis. In 17 patients with advanced A-V or intraventricularblock, treatment with arniodaronewas started only after implantation of a temporary demand pacemaker. This served both to prevent possible complications and to permit study of the effects of the drug under such conditions. In 51 patients with isolated bundle branch block, the drug was administered without previous insertion of a pacemaker. In 25 patients with life-threatening arrhythmias, the treatment was started simultaneously with the administration of an antiarrhythmic drug of rapid action (Table VII); use of the latter was interrupted when the arrhythmia was controlled with amiodarone. In 47 patients an attempt was made to correlate at weekly intervals the antiarrhythmic action with the changes in ventricular repolarization caused by the drug, and with the presence of cornea1 microdeposits, observed through a slit-lamp microscope. Grading of therapeutic response: Response to the administration of amiodarone was classified as excellent, good or poor, according to whether the drug caused, respectively, total suppression of the arrhythmia, a reduction of 50 percent or more in frequency of occurrence of arrhythmia or a reduction of less than 50 percent. However, the evaluation varied according to whether the- patients had repetitive tachyarrhythmias or persistent extrasystoles. Since almost all episodes of paroxysmal tachyarrhythmia were clearly symptomatic, total suppression in these cases was judged present when the patient stated that the episodes had ended, and this judgment was verified in the group of patients treated and monitored in the intensive care unit. To quantitate the effect, the total number of tachyarrhythmic episodes occurring the month before and after administration of the drug were counted and compared. By contrast, because continuous electrocardiographic tape recording was unavailable, and because patients with persistentextrasystoleswere commonly unaware of the arrhythmia, these patients were accepted for entry into the study only when all tracings of 5 minutes’ duration recorded at weekly intervalsfor 4 weeks showed at least 10 extrasystoles/min. The effect of the drug was judged excellent when no extrasystole occurred in four similar weekly tracings recorded the month after initiation of treatment, good when the total number of extrasystoles similarly counted decreased by more than 50 percent and poor when the number was reduced by less than 50 percent. Results Supraventricular

Arrhythmias

Supraventricular arrhythmias showed the greatest sensitivity to the drug. Thus, these arrhythmias were totally suppressed in 98 of 106 patients (92.4 percent), only 5 patients (4.7 percent) showing a poor response to amiodarone. The drug’s efficacy was even more remarkable in the following subgroups. Recurrent paroxysmal atria1 flutter or fibrillation was totally suppressed in 29 of 30 patients (96.6 percent) (Table I). During the month preceding treatment, 24 of these 30 patients had 720 episodes of tachyarrhythmia (average 30 episodes, range 2 to 140), and the other 6 had continuously recurring short and uncounted episodes. In

ET AL.

the 29 successful cases, the total incidence was reduced to 0 during the month after the initial 4 to 8 day period of treatment. Total suppression occurred also in 57 of 59 patients with repetitive supraventricular tachycardia (Table II). In the month before treatment, 54 of these 59 patients had 965 episodes of tachyarrhythmia (average 17.8 episodes, range 1 to SO), and the other 5 had continuously recurring and uncounted episodes. Total suppression occurred in all 27 patients (100 percent) with tachyarrhythmias related to the Wolff-Parkinson-white syndrome (Tables I and II). In the month before treatment, 25 of these 27 patients had 351 episodes (average 14, range 1 to 60), and the other 2 had continuously recurring episodes. In 19 of these 27 cases, amiodarone blocked anterograde conduction in the anomalous bundle, causing normalization of the QRS complex. The 89 patients in these three groups had had paroxysmal arrhythmia for 1 to 53 years (average 12 years); 13 patients had had the arrhythmia for at least 5 years, and 34 for at least 10 years. However, complete control of the arrhythmia was maintained during the entire follow-up period (1 to 36 months, average 16 months), provided that the correct dosage of the drug was also maintained. Amiodarone was less effective in treatment of simple atria1 extrasystoles (Table III). Ventricular

Arrhythmias

Amiodarone produced excellent results in 119 of 145 patients (82.0 percent) with ventricular arrhythmias and poor results in only 16 (11.0 percent) (Tables V and VI). It was in this group that the drug proved most valuable, because it included the sickest patients with the most dangerous arrhythmias. Thus, amiodarone caused total suppression and control of recurrent ventricular tachycardia in 34 of 44 patients (77.2 percent) who had responded poorly to previous treatment with other drugs at usual therapeutic doses (Table VI). Of these 44 patients, 32 had continuously recurring episodes of ventricular tachycardia during the week before treatment, and the other 12 had 274 episodes (average 22.8, range 4 to 30) during the month before administration of amiodarone. Special mention must be made of the excellent results obtained in six of eight patients with repetitive ventricular tachycardia related to a postmyocardial infarction ventricular aneurysm and in six cases associated with recurrent ventricular fibrillation. Despite the administration of lidocaine and other drugs (Cases 1 to 7, Table VII), seven of the eight patients required repeated electric cardioversion to permit survival until amiodarone could provide total control of the arrhythmia. Two of these eight patients (Cases 1 and 5, Table VII) underwent surgical resection of the aneurysm but had no reduction in episodes of ventricular tachycardia or fibrillation postoperatively. Of the six survivors at the time of discharge, 1 died suddenly 2 months later, 15 days after abandoning treatment; another died 18 months later of mediastinal carcinoma. The other four are free of arrhythmia and doing well after 18 to 26 months (average 23 months) of follow-up study.

December 1976

The American

Journal

of CARDIOLOGY

Volume

38

937

ANTIARRHYTHMIC EFFICACY OF AMIODARONE-ROSENBAUM

TABLE

ET AL

VII

Combined

Treatment

in Dangerous

Arrhythmias

in 25 Cases Drugs Initially Used With Amiodarone

Case no.

Clinical Status and Diagnosis

Arrhythmia

1

Repetitive VT and VF

Cardiogenic shock*; postinfarction

2

Repetitive

c ,vFeny;;;i+&~;~;;~*;

3 4

VT

Repetitive VT and VF

6

Repetitive VT and VF

7

VT, VFI, VF

8

Repetitive

9

VT, VE

Cardiogenic shock*; postinfarction ventricular aneurysm Cardiogenic shock*; postinfarction ventricular aneurysm Postinfarction ventricular aneurysm; diabetic acidosis; septic shock Cardiomegaly +++; old posterior infarction; AH

VT

10

Repetitive VT; multifocal VE

11

Multifocal

12

Multifocal VE; repetitive PAT, PAFI, PAF

13

Multifocal

14 15 16

Repetitive Multifocal

VE

VE VT VE

VT; multifocal

VE

Old anterior and posterior myocardial infarction; postinfarction angina AH; old anterolateral myocardial infarction; repetitive pulmonary and systemic embolism CHF; cardiomegaly ++++; cardiomyopathy Cardiomegaly ++; CHF; cardiomyopathy

VT; multifocal

VE

18

VT; multifocal

VE

CHF; cardiomegaly +++; hepatic and renal insufficiency; Ch.Myo

19

VT; multifocal

VE

CHF; cardiomegaly ++++; hepatic and renal insufficiency; Ch.Myo

20

VT; multifocal

VE

21

Repetitive VT and VF Multifocal VE

CHF; cardiomegaly ++; Ch.Myo Complete A-V block; mitral valvulopathy; AH Severe chronic car pulmonale Severe chronic car pulmonale Cardiogenic shock*; WPW syndrome CHF; mitral insufficiency

23 24 25

Proc

DPH

pB

_

Multifocal VE, PAF PAF I, PAF, VF PAFI

D

Cardioversion

OD

-

+fin50 instances)

+-

+ (in 15 instances)

_

+ (in6 instances) + (in 5 instances)

..

4

18 months,

-

3

+ (in 21 instances)

-

18 months 9 (mediastinal carcinoma) §(I day after aneu rysmectomy)

+ (in 3 instances)

3

2 years, alive

+(in8 instances)

7

4

2 months5 (SCD 15 days after discontinuing treatmentl 15 days5 (SCD 8 days after discontinuing treatment) 14 months, alive

5

2 years, alive

4

1 year, alive

4+

_ .

.

+

..

-

+

f

4

.

...

.

_

+ ..,

+*

Follow-up 2 years, alive

56 days3 (cardiogenie shock)

5

+ (in 4 instances)

Cardiomegaly +++; CHF; cardiomyopathy Complete A-V block; cardiogenic shock* Cardiomegaly ++++; complete A-V block; Ch.Myo CHF; cardiomegaly ++; Ch.Myo Cardiomegaly +++; Ch.Myo

17

22

Q

postinfarction ventricular aneurysm CHF; postinfarction ventricular aneurysm Postinfarction ventricular aneurysm

Repetitive VT and VF Repetitive VT and VF

5

L

Other Procedures

Days Required for Total Control of Arrhythmia

alive

.........

_

3

15 days5 (massive pulmonary emboiism) without arrhythmias 1 month, unknown

.........

_

7

2 months,

_

2

1 year, alive

2

1 year, alive

.

. _

.

..

.

,.. .

...

10 (good); 45 (excel lent) 4

,..

+

,..

......... ...

......

...

...

6

.. .. . . ...

. *

-

...

......... _

-

17 months, alive

12 days 9 (hepatic and renal insufficiency) without arrhythmias 20 days5 (hepatic and renal insufficiency) without arrhythmias 18 months, alive 18 months, 2 months,

,..

unknown

15 months,

alive unknown alive

+

_

3 years, alive

+

_

6 months,

alive

*Excellent result for ventricular extrasystoles only; +Excellent result for all the arrhythmias; *Cardiogenic shock was related to the arrhythmia; §Died; + = excellent result; - = poor result; ++ = moderate; +++ = severe; t+++ = extreme. AH = arterial hypertension; A-V = atrioventricular; pB = beta blocking agents; CHF = congestive heart failure; Ch.Myo = chronic Chagasic myocarditis; D = digitalis; DPH = diphenylhydantoin; L = lidocaine; OD = overdrive pacing; PAF = paroxysmal atrial fibrillation; PAFI = paroxysmal atrial flutter; PAT = paroxysmal atrial tachycardia; Proc = procainamide; Q = quinidine; SCD = sudden cardiac death; VE = ventricular extrasystoles; VF = ventricular fibrillation; VFI = ventricular flutter; VT = ventricular tachycardia; WPW = Wolff-Parkinson-White.

938

December 1978

The American Journal of CARDIOLOGY

Volume 38

ANTIARRHYTHMIC EFFICACY OF AMIODARONE-ROSENBAUM

ET AL.

The results were also excellent in 12 of 14 patients with ventricular tachycardia related to Chagasic myocarditis, and in 6 of 7 patients with ventricular tachycardia related to chronic nonspecific cardiomyopathy (Table VI). Excellent results were obtained in the control of premature ventricular contractions in 21 of 24 patients with Chagasic myocarditis, in 24 of 26 cases of ischemic heart disease and in 85 of a total of 101 patients (84.1 percent) with ventricular extrasystoles (Table V). The efficacy was slightly less for ventricular extrasystoles occurring in patients with no detectable heart disease. Serious life-threatening arrhythmias: Table VII summarizes the findings in a subset of 25 critically ill patients with serious arrhythmias who were given amiodarone together with other antiarrhythmic drugs of rapid action, particularly lidocaine, and who were treated with cardioversion and overdrive pacing to permit survival until amiodarone became effective in controlling the arrhythmia. Since in all such cases the arrhythmias were of recent onset or had been documented only at the time of admission, it is difficult to be certain that the excellent results were due to amiodarone and not to the other antiarrhythmic drugs and maneuvers, or to the natural course of the disease. However, previous experience with similar patients in our coronary care unit before the introduction of amiodarone, as well as the experience of others,P17 suggests that amiodarone played an important if not an essehtial role in providing total control of the arrhythmias after the first few days of treatment.

were never a cause for discontinuing treatment. Only 2 of the 252 patients required interruption of treatment, one because of nausea and vomiting and one because of the occurrence of erythema nodosum. Cornea1 microdeposits: These deposits were documented in all 47 patients who were examined for this condition. -Although the magnitude and time of appearance were in general dose-dependent, in some patients the microdeposits were initially detected after 14 days and in others only after 4 months of treatment. Like other iodine compounds,18 amiodarone is excreted through the lacrimal gland and is deposited directly or

Persistence of Amiodarone Effect

Atrial extrasystoles

In 53 patients with repetitive supraventricular arrhythmias (29 cases) or persistent extrasystoles (24 cases), discontinuation of administration of amiodarone for 2 days every week (47 cases) or 1 week every month (6 cases) revealed no evidence of recurrence of the arrhythmia. To assess with greater precision the persistence of the antiarrhythmic effect, treatment with amiodarone was deliberately interrupted several times and for variable periods in eight patients with daily episodes of supraventricular tachycardia. These patients were evaluated together with eight similar patients who had abandoned the treatment spontaneously and returned for consultation when the arrhythmia reappeared. Four of the 16 patients had taken 400 mglday of amiodarone for 30 to 45 days. In this group the repetitive arrhythmias reappeared 10 to 20 days after interruption of treatment. In the other 12, who had been taking a similar dose for several months, the therapeutic effect was maintained for up to 30 days (9 cases) and even 45 days (3 cases) after discontinuation of amiodarone. When the tachyarrhythmias reappeared, the frequency of the episodes was initially much less, and it generally took an additional 10 to 15 days to reach the daily frequency documented before amiodarone was first administered. Side Effects Constipation and light skin rashes (photodermatosis) occurred in approximately 10 percent of the patients but

TABLE

VIII

Conduction 67 Cases

Disturbances:

Type of Arrhythmia

Cases (no.)

Paroxysmal atrial flutter and fibrillation

i

Paroxysmal supraventricular tachvcardia

2

2

Miscellaneous

Ventricular extrasystoles

Treatment

Preexistent Conduction Disturbances

Effects on Conduction During Amiodarone Treatment

Intermittent LPH I RBBB RBBB LAH Intermittent Intermittent LAH

RBBB-

LBBB LBBB-

RBBB

Higher degree of RBBB (1)

2’ A-V block with Wenckebach periods 3 1

1” A-V block High degree A-V block Complete A-V block RBBB-LAH I RBBB-LAH I RBBB RBBB RBBB

4

LAH I LBBB-LAH I LBBB

2

Complete A-V block High degree A-V block 1” A-V block 1” A-V block-LAH Intermittent RBBBLAH RBBB-LAH RBBB LAH I LBBB Intermittent RBBB

2

8 2 3 1

. . RBBB (1); 2”A-V block, Mobitz II (1) lo A-V block, permanent RBBB-LAH (I)

. Permanent LAH

RBBB-

Permanent

RBBB

..

Figures in parentheses indicate number of cases. A-V = atrioventricular; I = incomplete; LAH = left anterior block; LB88 = left bundle branch block; LPH = left posterior block; RBBB = right bundle branch block.

December 1976

in

1” A-V block I RBBB I RBBB-LAH Intermittent RBBB

Intermittent

Ventricular tachycardia

With Amiodarone

The American Journal of CARDIOLOGY

Volume 38

hemihemi-

939

ANTIARRHYTHMIC

EFFICACY

OF AMIODARONE-ROSENBAUM

ET AL.

one.1,3,30Although in many patients the three variables were dose-dependent and related to each other, the general correlation was poor. Thus, although some patients with overt changes in ventricular repolarization and dense microdeposits had a poor therapeutic response, others had an excellent antiarrhythmic effect accompanied by an insignificant amount of microdeposits and practically no change in ventricular repolarization. Effects on conduction and automaticity: Amiodarone caused further deterioration of conduction in 6 (8.8 percent) of 68 patients with intraventricular or A-V block, or both (Table VIII). In general, this consisted of an increment in the degree of block in a previously damaged fascicle. However, no case of complete A-V block was provoked by the drug. In three patients with such A-V block, amiodarone did not change the rate of the spontaneous idioventricular rhythm; this finding is consistent with previous data31 indicating that the drug does not significantly affect ventricular automaticity. Right bundle branch block developed in 2 (1.09 percent) of the 184 patients without conduction defects. However, both patients had shown right bundle

as a metabolite in the most superficial layers of the comea.1s-24 A mechanical factor plays a role, because the deposits occur initially and predominantly in the lower third of the cornea, along the line where the upper border of the inferior eyelid makes contact with the eye. Accordingly, they less frequently invade the pupillary area and seldom cause subjective phenomena. Only 6 of our 252 patients complained spontaneously of visual problems: blurred vision in 4 and colored vision in 2. It is well established that the cornea1 microdeposits are reversible1gJ-23 although complete disappearance may take several months. Microdeposits did not occur in any of 13 children, aged 8 months to 15 years, receiving amiodarone,25 probably because of the greater secretion and faster circulation of the lacrimal fluid in children compared with adults. The microdeposits suggest that the drug may also be deposited in other body tissues.23,26-2g In 47 patients, the cornea1 microdeposits were correlated with therapeutic efficacy and with changes in ventricular repolarization (bifid or bimodal T waves, prominent U waves, prolonged Q-T interval) that commonly accompany the administration of amiodar-

A Control

“r&

Amiodarons

. . *

300

P 4 ;

+;‘+ . -+ \‘++ . . ‘+ .+

150 :

g

loo

Y B

1 60 Mcmbr~na

940

December

,

I

70

90

potential

1976

r&

z

50 250 i

: ++

Control

200

. . * -t L I 40

50

:’ + . + t ’ ++

Amiodarone

I

I

60

70

1

90

J

90

Membranepotential(mv)

The American Journal of CARDIOLOGY

Volume 38

FIGURE 2. Electrophysiologic study of ventricular and Purkinje fibers of a rabbit heart, pretreated for 4 weeks with amiodarone, 100 mg/kg per day orally. A, left, transmembrane action potential and dV/dt recorded from a ventricular fiber from a control animal and from another one receiving amiodarone. Action potential duration is 57 and 60 percent greater at 50 percent and 90 percent repolarization, respectively, in the fiber of the animal pretreated with amiodarone. No significant difference occurs in the resting potential or in the amplitude of the action potential. Right, Purkinje fibers of the right bundle branch in the same two animals. A slight prolongation of the action potential duration (14 percent at 50 percent repolarization) is the only difference between the two fibers. B, left, depression of membrane responsiveness caused by amiodarone in a ventricular fiber. The curves were obtained by premature stimulation at different coupling intervals, delivered every 10 regular beats at a basic cycle length. of 800 msec. Right, the depression of membrane responsiveness is similar but quantitatively less important in a Purkinje fiber explored at a basic cycle length of 1,000 msec. Data in A and B are representative of results obtained in 54 ventricular and 48 Purkinje fibers from 16 rabbit hearts, 8 pretreated with the same dose of amiodarone. Since amiodarone has no direct effect when added to the superfusant (standard Tyrode solution), the drug was administered in vivo, as indicated, and the control tissues were from tissue of nontreated animals. The control and pretreated tissues showed results similar to those illustrated when both were studied in the same bath preparation

ANTIARRHYTHMIC EFFICACY OF AMIODARONE-ROSENBAUM ET AL.

under way in our laboratory: (1) amiodarone prolongs the action potential duration of atria1 and ventricular fibers and to a lesser degree of Purkinje fibers of rabbit and canine hearts, without changing the resting potential (Fig. 2A). (2) It diminishes the maximal rate of rise of the action potential (Fig. 2A) and slows conduction velocity. (3) It depresses membrane responsiveness (Fig. 2B). (4) It does not significantly depress the spontaneous diastolic depolarization of Purkinje fibers. (5) It has a strong antifibrillatory action. After ligation of the anterior descending coronary artery at its origin, amiodarone prevented the occurrence of ventricular fibrillation in all 10 pretreated dogs receiving orally 10 to 40 mg/kg daily for 1 to 4 weeks, whereas ventricular fibrillation occurred in 7 of 8 untreated animals. Five of the pretreated animals had no ventricular extrasystoles after ligation; four had isolated and transient ventricular extrasystoles 2.5 to 40 minutes after ligation, and brief episodes of transient ventricular tachycasdia developed in one dog. By contrast, seven of the eight control dogs manifested multiple ventricular extrasystoles that rapidly degenerated into ventricular tachycardia and ventricular fibrillation 5 to 11 minutes after ligation.

branch block spontaneously 5 to 12 months before, thus indicating that amiodarone only uncovered a latent conduction disturbance.32 Practically all the patients under prolonged treatment manifested sinoatrial slowing, which was dosedependent and proportional to the spontaneous heart rate.3,30J3 In most patients, the sinus rate was maintained at 55 to 75 beatslmin. In 3 of the 252 patients amiodarone caused pronounced but still asymptomatic bradycardia (37 to 40 beats/min). The bradycardic action was useful in the treatment of sinus tachycardia. In four patients with pronounced and symptomatic sinus tachycardia (120 to 160 beatslmin), the heart rate was slowed and stabilized below 80 beatslmin after 6 to 10 days of treatment (Table IV). The drug was equally effective in 10 other patients with pronounced sinus tachycardia associated with other arrhythmias. Thyroid function: A molecule of amiodarone contains 2 atoms of iodine,1,3*26,34,35 and the administration of 400 mg (a common daily dose) is equivalent to 148.8 mg of iodine or 24 drops of Lug01 solution. Because of this, amiodarone may uncover the existence of subclinical forms of both hypothyroidism and hyperthyroidism.36-38 Symptomatic hypothyroidism developed in 2 of our 252 patients and symptomatic hyperthyroidism in 2 others.

Discussion Antiarrhythmic Effects

Electrophysiologic Studies

Our results confirm previous data25,31,41-43 indicating that amiodarone effectively controls, with minimal toxicity, atria1 and ventricular arrhythmias in a variety of clinical conditions, including severe congestive heart failure and complicated forms of acute myocardial infarction. This efficacy was more readily demonstrated in a large series of patients with symptomatic repetitive tachyarrhythmias, who themselves clearly and uniformly reported total suppression of the episodes. Most such patients had had a long history of repetitive tachyarrhythmia which apparently concluded after treatment with amiodarone. Furthermore, in 16 patients with daily episodes of tachyarrhythmia, interruption

Singh and Vaughan Williams34 reported that amiodarone, administered intraperitoneally to rabbits in a dose of 20 mg/kg body weight daily for 6 weeks, caused a significant prolongation of the action potential duration in atria1 and ventricular muscle without changes in the resting membrane potential and with a slight depressing effect on the maximal rate of depolarization. They therefore classified amiodarone as having a class III antidysrhythmic action,3gy40which they attributed to prolongation of the action potential. Because no other electrophysiologic studies have been reported, we give here the following preliminary data from studies now

q fgm

57

a5 80%

E

G P

34

6 7

60%

FIGURE 3. Comparative effects of amiodarone on different types of arrhythmias. Percent of results is indicated at left; numbers over bars indicate number of cases. White bars (E) = excellent results; hatched bars (G) = good results; solid bars (P) = poor results. AE = atrial extrasystoles; M = miscellaneous; PAF = paroxysmal atrial fibrillation; PAFI = paroxysmal atrial flutter; PAT = paroxysmal atrial tachycardia; VE = ventricular extrasystoles; VT = ventricular tachycardia.

:I IIi:l 2

P

A FL P A F

PAT

December 1976

1 :::* ::: ::: :::

1 ::: ::: ::: ::: :::

A E

M

1

5 5 ii. ::: ii .. V T

The American Journal of CARDIOLOGY

Volume 36

941

ANTIARRHYTHMIC EFFICACY OF AMIODARONE-ROSENBAUM

ET AL.

of treatment was followed by recurrence of the arrhythmia after various periods of time, and reinstitution of treatment was again followed by total control of the arrhythmia. Becase continuous electrocardiographic tape recording was not utilized, it was more difficult to evaluate the effect of amiodarone in patients with persistent ventricular extrasystoles. Although we documented a remarkable reduction in the frequency of premature beats, we cannot be certain that total suppression was attained. However, our similar results in patients with both repetitive tachyarrhythmias and persistent extrasystoles (Fig. 3) suggest that the suppressive effect of the drug in patients with ventricular extrasystoles was at least highly significant. Comparison with other antiarrhythmic drugs: It is difficult to establish valid comparisons of the efficacy of different antiarrhythmic drugs because criteria for selection of patients and evaluation of drug effects may vary according to the reported series. Nevertheless, the high percentage of excellent results shown in Figure 3 suggests that amiodarone compares favorably in therapeutic efficacy with quinidine,5,44-4s procainamide,5,44.-%49,50 lidocaine,5,44,51-54 propranolo15,44,55-57 and diphenylhydantoin5,44p58-60 and appears to be superior to all of them in versatility, tolerance and simplicity of dose scheduling. A more direct comparison made among our own patients revealed that amiodarone provided total control and protection in 93 of 98 patients with recurrent disabling or dangerous supraventrieular arrhythmias (53 cases) and ventricular arrhythmias (45 cases), whereas the other drugs mentioned, used singly or in different combinations, yielded only a poor response. Ventricular arrhythmias related to postinfarction ventricular aneurysm: Postinfarction ventricular aneurysm may be accompanied by recurrent episodes of ventricular tachycardia and fibrillation, implying a bad or ominous prognosis. These episodes are extremely resistant to antiarrhythmic drugs,iO-l7 and surgical resection of the aneurysm has been performed with various degrees of success.10-17 Table VI shows that amiodarone provided total control in six of eight patients with such arrhythmias. Although there was no control group, the well known poor prognosis in similar casesi indicates that the drug played an important role in treatment. We have since learned that the initial administration of 1,000 to 1,500 mg/day of amiodarone may increase effectiveness of the drug and reduce to only 48 hours the time needed to develop its antiarrhythmic action. Ventricular arrhythmias in chronic Chagasic myocarditis: Chagasic myocarditis causes frequent and multifocal ventricular premature beats4 which may degenerate into ventricular tachycardia or ventricular fibrillation, precipitating the sudden death commonly reported in this disease. Since these arrhythmias occur often in the presence of extensive intraventricular block, severe congestive heart failure and a greatly dilated heart, most antiarrhythmic drugs are ineffective and even dangerous. Therefore, it was surprising to us that amiodarone could be so effective and safe in treating ventricular extrasystoles and preventing the recurrence

S42

December 1976

The American Journal of CARDIOLOGY

of ventricular tachycardia in patients with Chagasic myocarditis (Tables V and VI). Chagasic myocarditis can be taken as a clinical model providing possibly the most demanding conditions under which an antiarrhythmic drug can be tested. Two reasons may account for the unexpected efficacy and safeness of amiodarone under such unfavorable conditions: the lack of a significant negative inotropic effect and the potent antifibrillatory action. Tachyarrhythmias associated with the WolffParkinson-White syndrome: In a previous report,i we have shown the usefulness of amiodarone in controlling the tachyarrhythmias associated with the Wolff-Parkinson-white syndrome in 11 patients, and compared its effect with that of other drugs. Our experience has now been extended to 27 such patients and has again shown a 100 percent rate of efficacy (Tables I and II). No matter how favorable the surgical results may be,6-g our results show that surgery is unnecessary when amiodarone can be administered to patients with this condition,

Properties of Amiodarone Three main properties appear to determine the usefulness of amiodarone as an antiarrhythmic agent: (1) electrophysiologic properties; (2) the drug’s capacity for storage in the body and its cumulative effect; and (3) the lack of significant toxicity, which allows a wide margin of therapeutic dosage. Which electrophysiologic property is mainly responsible for the antiarrhythmic effect will probably be open to debate for some time. However, because many other drugs with comparable, different or even opposite electrophysiologic properties are also potent antiarrhythmic agents but less successful clinically, we believe that the electrophysiologic properties may be less decisive for the clinical effectiveness of amiodarone than the other properties to be discussed. The cumulative effect: Amiodarone is variably absorbed from the intestinal tract and is well retained by the body, with a very slow rate of elimination.26 Except for digitalis, most antiarrhythmic drugs now used are rapidly metabolized and excreted, have a short half-life, have a brief or ephemeral effect and must be administered at regular brief intervals. None of this is true of amiodarone. Although the half-life of the drug is still undetermined, it has been estimated that 30 days after its administration is discontinued the body concentration has diminished by only 16 to 34 percent.26 In 67 of our patients who had daily arrhythmias, amiodarone, at a dose of 400 to 600 mglday, took 4 to 8 days to attain its therapeutic effect. When in 16 of these patients the administration of the drug was interrupted, it took a much longer time for the effect to disappear, and this interval was dose-dependent and related to the total time of previous treatment. Persistence of the antiarrhythmic effect for 10 to 20 days and even up to 30 and 45 days was not uncommon, and this long-term effect coincided with a similarly prolonged persistence of the electrocardiographic changes caused by the drug,3 and with a prolonged persistence of the cornea1 microdeposits. Whatever the mechanism, this property con-

Volume 38

ANTIARRHYTHMIC EFFICACY OF AMIODARONE-ROSENBAUM ET AL.

tributes greatly to the clinicial usefulness of amiodarone because it liberates patients from submission to a rigid hourly schedule and provides them with an apparently more continuous and sustained antiarrhythmic protection than is afforded by other drugs. It is worth mentioning that the electrophysiologic properties can be studied for many hours even though the Tyrode solution bathing the tissue (of pretreated animals) contains no drug, thus suggesting that amiodarone may be firmly bound to some receptor in the myocardial cells from which it dissociates only at a very slow rate. This may preclude the wide fluctuations in the tissue levels of the drug that characterize other antiarrhythmic drugs. 5118,52,59 The wide safety margin: Most antiarrhythmic drugs have a rather narrow therapeutic ratio (relation between the lethal [LD5e] and therapeutic dose)18; and classic drugs like quinidine and procainamide may kill by provoking ventricular fibrillation, even at therapeutic doses, if administered to patients with a severely damaged heart. Whereas the LDsa of quinidine and procainamide is approximately 2.5 times the therapeutic dose,61@ the LD5c of amiodarone is more than 10 times the therapeutic dose when the drug is given intravenously,63 and there is practically no lethal dose when it is administered orally.63 In practical terms, this means that it is impossible to kill an animal with an acute dose of orally administered amiodarone. In addition, the absence of other significant toxic effects explains the great safety with which amiodarone can be given to patients in large doses for long periods of time. This wide safety margin is at least partially related to the antifibrillatory action of the drug. From our clinical and experimental experience, it appears that ventricular

fibrillation is unlikely to occur in the presence of sufficient premeditation with amiodarone. From experimental studies on the canine heart, it appears that amiodarone has little negative inotropic effect.64 In this respect, our clinical study was even more reassuring. The response of patients with severe congestive heart failure clearly indicated that amiodarone lacked any significant negative inotropic effect. Side Effects and Contraindications The most important undesirable effect of amiodarone is the occurrence of corneal microdeposits. However, these deposits seldom cause ocular symptoms, are totally reversible and can be diminished or prevented by the use of eyedrops containing metilcelulose37 or sodium-iodine heparinate.1gv37 The most relevant question concerning them is whether they can cause irreversible damage although this has never been reported. The widespread European use of amiodarone as an antianginal agent for 10 years1g,21,26,30,35,65and the absence of reported late ill effects on the eye allow us to be optimistic, but every effort should be made to settle this point conclusively. The most important contraindication is the presence of intraventricular or A-V block, a contraindication shared with other antiarrhythmic drugs such as quinidine 44-4s procainamide44,4sv50 and even lidocaine.szJi Because amiodarone does not appear to depress ventricular automaticity as do the other drugs, its use is apparently safer. However, any one of these drugs, when greatly needed, can be given to patients with conduction disturbances, provided a temporary artificial pacemaker is inserted.

References 1. Rosenbaum MB, Chiale PA, Ryba D, et al: Control of tachyarrhythmias associated with Wolff-Parkinson-White syndrome by amiodarone hydrochloride. Am J Cardiol 34:215-223, 1974 2. Charlier R: Cardiac actions in the dog of a new antagonist of adrenergic excitation which does not produce competitive blockade of adrenoceptors. Br J Pharmacol 39:668-679, 1970 3. Pritchard DA, Singh BN, Hurley PJ: Effects of amiodarone on thyroid function in patients with ischaemic heart disease. Br Heart J 37:856-860, 1975 4. Rosenbaum MB: Chagasic myocardiopathy. Prog Cardiovasc Dis 7:199-225, 1964 5. Lown B, Wolf M: Approaches to sudden death from coronary heart disease. Circulation 44:130-142, 1971 6. Burchell HB: Management of tachycardias associated with Wolff-Parkinson-White syndrome. In, Cardiac Arrhythmias. The Twenty-Fifth Hahnemann Symposium (Dreifus LS, Likoff W, ed). New York and London, Grune & Stratton, 1973, p 475-478 7. Dreifus LS, Nichols H, Morse D, et al: Control of recurrent tachycardia of Wolff-Parkinson-White syndrome by surgical ligature of the A-V bundle. Circulation 38:1030-1036, 1968 8. Cobb FR, Blumenschein SD, Sealy WC, et al: Successful surgical interruption of the bundle of Kent in a patient with Wolff-Parkinson-white syndrome. Circulation 38:1018-1029, 1968 9. Lindsay AE, Nelson RM, Abildskov JA, et al: Attempted surgical division of the preexcitation pathway in the Wolff-Parkinson-White syndrome. Am J Cardiol 28581-585, 1971 10. Warembourg H, Ducloux G, Pauchant M, et al: Les anevrysmes ventriculaires post-infarctus. Coeur Med lnterne 12:385-396, 1973

11. Hunt D, Sloman G, Westlake G: Ventricular aneurysmectomy for recurrent tachycardia. Br Heart J 31:264-266, 1969 12. Kenaan G, Mendez M, Zubiate P, et al: Surgery for ventricular tachycardia unresponsive to medical treatment. Chest 64574-578, 1973 13. Magidson 0: Resection of postmyocardial infarction ventricular aneurysms for cardiac arrhythmias. Chest 56:211-218, 1969 14. Ritter ER: Intractable ventricular tachycardia due to ventricular aneurysm with surgical cure. Ann Intern Med 71:1155-l 157, 1969 15. Schlesinger 2, Lieberman Y, Neufeld HN: Ventricular aneurysmectomy for severe rhythm disturbances. J Thorac Cardiovasc Surg 61:602-604, 1971 16. Wardekar A, Son B, Gosaynie CD, et al: Recurrent ventricular tachycardia successfully treated by excision of ventricular aneurysm. Chest 62:505-508, 1972 17. Bouvrain Y, Slama R, Motte G, et al: Les tachycardies ventriculaires. Etiologie et evolution, a propos de 161 malades. Arch Mal Coeur 61:909-920, 1968 18. Goodman L, Gilman A: The Pharmacological Basis of Therapeutics. New York, Macmillan, 1955, p 10 19. Verin Ph, Gendre Ph, Barchewitz G, et al: Thosaurismose cor&enne par amiodarone. Donn&ss mcentes. Arch Ophtalmol (Paris) 31:581-596, 1971 20. Berkman N: Le soecialiste vous reoond. Vie Medicale 2:12131214, 1971 21. Babel J, Stangos N: L’action de I’amiodarone sur les tissues oculaires. Schweiz Med Wochenschr 102:220-223, 1973 22. Babel J, Stangos N, Ferrer0 C: Thesaurismose corneenne due a

December 1976

The American Journal of CARDIOLOGY

Volume 36

943

ANTIARRHYTHMIC

EFFICACY

OF AMIODARONE-ROSENBAUM

ET AL.

la Cordarone. Therapie 25:331-334, 1970 23. Miller MHA: Keratopathie consecutive au traitement par Cordarone (clorhidrate d’amiodarone). Bull Sot Ophtalmol Fr 69:1059-1065, 1969 24. Cornand G, Biard L: Problemes ophtalmologiques poses par I’utilisation therapeutique de I’amiodarone. Lyon Medical 4: 333-336, 1971 25. Kreutzer EA, Roman MI, Elissetche M, et al: Amiodarone en arritmias pediatricas. XV Congreso de la Cardiologia Argentina, Mar del Plata, 26-31 Octubre, 1975 26. Broekhuysen J. Laruel R, Sion R: Recherches dans la serie des benzofurannes. XXXVII. Etude comparee du transit et du metabolisme de I’amiodarone chez diverses especes animales et chez I’homme. Arch Int Pharmacodyn Ther 177:340-359, 1969 27. Morand P, Benatre J, Viau G, et al: Etude clinique et histologique (ultraestructure) de la pigmentation par le chlorhydrate d’amiodarone. Sem Hop Paris 48553-563, 1972 28. Geerts ML: Amiodarone pigmentation. An electron microscopic study. Arch Belg Dermatol Syphil 27:339-349, 1971 29. Wanet J, Achten G, Barchewitr G, et al: Amiodarone et depots cutanes. Etude clinique et histologique. Ann Dermatol Syphiligr (Paris) 98:131-140, 1971 30. Facquet J, Nlvet M, Groegogeat Y, et al: L’influence de I’amiodarone sur rythme cardiaque et l’electrowdiogramme. Therapie 251335-340, 1970 31. Coumel P, Bouvraln Y: Etude clinique des effets pharmacodynamiques et antiarythmiques de I’amiodarone. J Agreges 6:69-81, 1973 32. Chlale PA, Levi RJ, Halpern MS, et al: Efecto de diferentes drogas antiarrkmicas sobre un case de bloqueo de rama intermitente. Medicina (B Aires) 35:1-13, 1975 33. Friart J, Rasson G: Etude des modifications de I’electrocardiogramme provoquees par I’amiodarone. Arzneim Forsch 10: 1535-1541.1971 34. Slngh BN, Vaughan Williams EM: The effect of amiodarone, a new antianginal drug, on cardiac muscle. Br J Pharmacol 39:657-667, 1970 35. Zelvelder WG: Investigation of the therapeutic activity of amiodarone (Cordarone) in the treatment of angina pectoris. Eur J Clin Pharmacol3:158-162, 1971 36. Barrillon A, Himbert J: Amiodarone et thyr&de. Presse Med 79: 1498-1499, 1971 37. Soussi A, Colonna D: Troubles du rythme auriculaire et amiodarone. J Agreges 7~43-55, 1974 38. Hazard J, Perlemuter L, Bernhelm R, et al: lnsuffisances thyro’tdiennes secondaires a un traitement par I’amiodarone. Presse Med 2:691-696, 1973 39. Vaughan Williams EM: Classification of anti-arrhythmic drugs. In, Symposium on Cardiac Arrhythmias (Sandee E, Flensted-Jensen E, Olesen KH. ed). Sodertalje, Sweden, AB Astra, 1970, p 449 40. Olsson SB, Brorson L, Varnauskas E: Class 3 ant&rhythmic action in man. Observations from monophasic action potential recordings and amiodarone treatment. Br Heart J 35: 1255-126 1, 1973 41. Charlier R, Delaunois G, Bauthier J, et al: Recherches dans la s&ie des benzofurannes. XL. Proprietes antiarrhythmiques de I’amiodarone. Cardiologia 54:82-90, 1969 42. Van Schepdael J, Solvay H: Etude clinique de I’amiodarone dans les troubles du rythme cardiaque. Presse Med 78:1849-1850, 1970 43. Vastesaeger M, Guillot P, Van Der Straeten P: L’effet antiarythmique de I’amiodarone. Brux Med 51:99-104, 1971 44. Scherf D, Schott A: Extrasystoles and Allied Arrhythmias. London,

944

December

i976

The American Journal of CARDIOLOGY

45

46.

47.

48.

49. 50.

51.

52. 53

54

55

56

57

58.

William Heinemann, 1973, p 612-670 Hoffman BF, Rosen MR, Wit AL: Electrophysiology and pharmacology of cardiac arrhythmias. VII. Cardiac effects of quinidine and procainamide. A. Am. Heart J 89:804-808, 1975 Hoffman BF, Rosen MR, Wit AL: Electrophysiology and pharmacology of cardiac arrhythmias. VII. Cardiac effects of quinidine and procainamide. B. Am Heart J 90:117-122, 1975 Kalmansohn RW, Sampson JJ: Studies of plasma quinidine content. Relation to toxic manifestations and therapeutic effect. Circulation 1:569-575, 1950 Sokolow M, Edgar AL: Blood quinidine concentrations as a guide in the treatment of cardiac arrhythmias. Circulation 1:576-592, 1950 Kayden HJ, Steele JM, Mark LC, et al: The use of procaine amide in cardiac arrhythmias. Circulation 4:13-22, 1951 Mark LC, Berlin J, Kayden HJ, et al: The action of procaine amide on ventricular arrhythmias. J Pharmacol Exp Ther 98:21-27, 1950 Gianelly R, Von der Groeben JO, Splvak AP, et al: Effect of lidoCaine on ventricular arrhythmias in patients with coronary heart disease. N Engl J Med 277:1215-1219, 1967 Grossman JI, Lubow LA, Frleden J, et al: Lidocaine in cardiac arrhythmias. Arch Intern Med 121:396-401, 1968 Rosen MR, Hoffman BF, Wlt AL: Electrophysiology and pharmacology of cardiac arrhythmias. V. Cardiac antiarrhythmic effects of lidocaine. Am Heart J 89:526-536, 1975 Sobella G: Erfahrungen mit Xylocaine bei Rhythmusstoerungen des Herzens auf einer internen Wachstation. Herz/Kreisl 7: 363-371, 1969 Luria MH, Adelson El, Miller AJ: Acute and chronic effects of an adrenergic beta-receptor blocking agent (propranolol) in treatment of cardiac arrhythmias. Circulation 34:767-773, 1966 Stock JPP: Beta adrenergic blocking drugs in the clinical management of cardiac arrhythmias. Am J Cardiol 18:444-449, 1966 Wit AL, Hoffman BF, Rosen MR: Electrophysiology and pharmacology of cardiac arrhythmias. IX. Cardiac electrophysiologic effects of beta-adrenergic receptor stimulation and blockade. Part 6. Am Heart J 90:665-675, 1975 Stone N, Klein MD, Lown B: Diphenylhydantoin in the prevention of recurring ventricular tachycardia. Circulation 43:420-427, 1971

59. Wit AL, Rosen MR, Hoffman BF: Electrophysiology and pharmacology of cardiac arrhythmias. VIII. Cardiac effects of diphenylhydantoin. A. Am Heart J 90:265-272, 1975 60. kit AL, Rosen MR, Hoffman BF: Electrophysiology and pharmacology of cardiac arrhythmias. VIII. Cardiac effect of diphenylhydantoin. B. Am Heart J 90:397-404, 1975 61. Kirchmann LL: Detoxification of quinidine by synephrine. Arch Exp Path Pharmakol 205:129-136, 1948 62. Manchetti G: Pharmacology of procaine amide hydrochloride (abstr). Arch ltal Sci Farmacol 2:134, 1952 63. Charlier R, Deltour G, Tondeur R, et al: Recherches dans la serie des benzofurannes. VII. Etude pharmacologique preliminaire du butyl-2 (diiodo-3’,5’beta-N-diethylaminoethoxy 4’benzoyl)-3 benzofuranne. Arch Int Pharmacodyn Ther 139:255-264, 1962 64. Charlier R, Deltour G, Baudine A, et al: Pharmacology of amiodarone: an antianginal drug with a new biological profile. Arzneim Forsch 11:1408-1417, 1968 65. Vastesaeger M, Glllot P, Rasson G: Etude clinique dune nouvelle medication antianooreuse. Acta Cardiol (Brux) 22:483-500, 1967

Volume 38