Use of disopyramide by arrhythmia specialists after Cardiac Arrhythmia Suppression Trial: Patient selection and initial outcome

CRITICAL DECISIONS IN ARRHYTHMIA Proceedings Montreal, October Supported

MANAGEMENT

of a symposium

Quebec, 19,199O

Canada

by an educational

grant

from

Searle

Use of disopyramide by arrhythmia specialists after Cardiac Arrhythmia Suppression Trial: Patient selection and initial outcome Eric N. Prystowsky, MD,a Albert L. Waldo, MD,b and John D. Fisher, MD.” Indianapolis, Ind., Cleveland, Ohio, and Bronx, N.Y.

The Cardiac Arrhythmia Suppression Trial (CAST) results1 heralded a reevaluation of traditional thinking on the use of certain antiarrhythmic agents. The preliminary results of the study revealed that surprisingly, patients treated after an acute myocardial infarction (AMI) with either of two class IC antiarrhythmic agents (encainide or flecainide) had a higher death rate than placebo-treated patients during a mean of 10 months after initiation of therapy. The increased sudden death rate in patients receiving encainide or flecainide compared with placebo was interpreted as possibly the result of a proarrhythmic propensity of the drugs tested in the recent post-AM1 population. Also, the findings were even more remarkable because both encainide and flecainide successfully suppressed asymptomatic or mildly symptomatic high-grade ventricular arrhythmias in patients after AM1 entered into the study. The implications of the CAST study results with regard to extrapolation to other antiarrhythmic From St. Vincent Hospital,’ Case Western Reserve University/University Hospitals of Cleveland,b and Montefiore Medical Center.C Reprint requests: Eric N. Prystowsky, MD, physiology Laboratory, Northside Cardiology, Indianapolis, IN 46260.

4/O/27501

Director of Clinical Electro8402 Harcourt Rd., Suite 300,

agents used in a similar clinical setting, that is, in patients with coronary artery disease and a recent myocardial infarction, have been considered by a number of authors.2-6 Many doubts and uncertainties concerning the use of antiarrhythmic agents remain as a result of the CAST data. Indeed, in a recently conducted survey of physicians treating patients with arrhythmias, including general practitioners, family practitioners, internists, and cardiologists, it was noted that after CAST, drug use for ventricular arrhythmias had declined when compared with use before CASTS7 In particular, cardiologists more than other physicians appeared to have decreased drug treatment of patients with ventricular arrhythmias after myocardial infarction, apparently as a result of the CAST findings. In contrast, physicians surveyed indicated that their prescribing of antiarrhythmic drugs during the past year for atria1 arrhythmias had not changed significantly (Table I). However, there were changes in the antiarrhythmic agents selected for the treatment of these arrhythmias, since the use of more traditional class IA drugs, such as disopyramide and quinidine, increased (Table II). To substantiate this trend and learn more about the use of a particular class IA agent, disopyramide, after CAST, additional data were obtained from a

1571

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et al.

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Table I. Post-CAST antiarrhythmic terns for cardiologists

drug prescribing

pat-

Net change in prescriptions (before and after CAST)

Type of arrhythmia Atria1 Ventricular From

Market

Table

Measures

Inc. Arrhythmia

II. Antiarrhythmic

Drug

Market

Study

IX. May

1990.

agent use: 1989 versus 1990 % Cardiologists using products on a regular basis

Agent

(trade)

Quinidine (Quinidex) Quinidine (Quinaglute) Procainamide (Procan SR) Mexiletine (Mexitil) Disopyramide (Norpace) From

Market

Measures

1989

1990

% Change, 1989-1990

50

55

+10

54

65

+20

61

62

+2

27

36

i-33

16

33

+106

Inc. Arrhythmia

Drug

Market

Study

IX. May

1990.

clinical survey initiated in May 1990. To enhance the validity of the results, the parameters of this clinical survey were in keeping with guidelines usually used for phase IV (postmarketing surveillance) studies. Participating physicians were specialists in arrhythmia treatment, individuals who frequently initiate antiarrhythmic therapy and who often influence treatment patterns by general practitioners. Participating physicians were asked to fill out a form (“enroll”) for all patients given disopyramide without requiring that it be for a particular “type” of arrhythmia or patient. Thus data collected were relevant to the clinical practice of medicine. The sample size of both physicians and patients was sufficiently large to allow meaningful analyses of the data collected. The limits of the data collection method and analyses were determined, and statistical methods used were appropriate for the type of data collected. Results were formatted so that comparison with results of existing literature and practical implications of the results of the study would be clear and relevant. DESCRIPTION

OF DISOPYRAMIDE

Disopyramidephosphate, cu-[2-(diisopropylamino) ethyl]-a-phenyl-2-pyridineacetamide phosphate, was

May 1991 Heart Journal

approved by the Food and Drug Administration for antiarrhythmic use in 1977. The chemical structure for the compound is shown in Fig. 1.8 Mechanism of action. Although disopyramide is chemically distinct from quinidine and procainamide, it has electrophysiologic actions similar to these class IA antiarrhythmic agents. For instance, their effect on the ECG is to prolong the QT interval (because it prolongs repolarization, i.e., phase 3, of the transmembrane action potential).g On a more basic level, disopyramide also shares with other class IA agents actions mediated through a reduction in the fast inward sodium current. This includes the ability to produce a depression of maximum velocity (Vm,,) of phase 0 of the cardiac transmembrane action potential and also to depress the slope of phase 4 depolarization in Purkinje fibers. In addition, these agents prolong the refractory periods of the atria and ventricles to a greater degree than the transmembrane action potential duration.‘O Furthermore, disopyramide has weak anticholinergic activity, which is estimated at 1000 times less than that of atropine. lo In general, this anticholinergic activity is not regarded as contributory to the antiarrhythmic effect of disopyramide,ll, ‘? and antisympathetic effects have not been shown with this agent.‘:’ There is a direct correlation of plasma levels of disopyramide with electrophysiologic activity-the greater the absolute plasma level, the more the activity. 14sl5 Particularly after large intravenous or oral loading doses of disopyramide, an elevation in peripheral vascular resistance associated with a reduction in cardiac contractility may be observed.1° Pharmacologic properties. The clinically important pharmacologic properties of disopyramide and controlled-release disopyramide are summarized in Table III. In essence, disopyramide is quite soluble in water, with approximately 80 % bioavailable after oral administration. Onset of action usually occurs within 2 hours of oral administration, and the mean plasma elimination half-life for the immediate-release preparation is 7 hours and 11 hours for the sustained-release preparation.‘” Therapeutic plasma levels are usually seen in the range of 2 to 6 pg/ml, with toxicity generally observed at plasma levels is excreted primarily above 7 pg/ml. lo Disopyramide by the kidneys (80%, with approximately 50% unchanged), and 10% is excreted in the feces. Therefore renal insufficiency requires a reduction in dosage proportional to the extent of the renal impairment. The electrophysiologic action of disopyramide correlates closely with free drug concentration. Although the agent is bound to an al-acid glycoprotein,

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Use of disopyramide

the binding sites of this protein are saturated in the therapeutic plasma level range, with a free disopyramide concentration of 22 % at a plasma level of 2 pg/ ml and a 54 % concentration at a level of 5 pg/ml.i6, l7 Clinical activity. The results of numerous published reports during the past 20 years document the clinical efficacy of disopyramide for the treatment of ventricular and supraventricular arrhythmias. An evaluation of 17 uncontrolled studies of the effectiveness of oral disopyramide in suppressing ventricular premature depolarizations revealed an excellent or good response in approximately 65% of 369 patients. I8 In a controlled trial of 124 outpatients with ventricular and/or supraventricular arrhythmias documented by ambulatory ECG recordings, treatment with oral disopyramide (150 mg every 6 hours) was as highly effective and equal to quinidine (325 mg every 6 hours) in reducing ectopic complexes, multifocal ectopy, and nonsustained paroxysmal ventricular tachycardia (VT-NS).r’ In an additional controlled study of oral disopyramide (400 mg/day) compared with another class IA agent, procainamide (2400 mg/day), disopyramide produced a greater long-term ventricular antiarrhythmic response (79.4% reduction of premature ventricular contractions [PVCs]) with disopyramide compared with 55.8% with procainamide).2” Also, disopyramide was found equally as effective as quinidine in preventing a recurrence of atria1 fibrillation after successful cardioversion in 42 patients studied in a double-blind fashion.21 Special

considerations

For all class IA agents, the risk of proarrhythmia (potential for producing new arrhythmias or aggravating an existing arrhythmia) is increased for patients with sustained ventricular tachycardia (VT-S) or ventricular fibrillation. Other conditions increasing the risk of proarrhythmia are poor ventricular function (particularly in patients with concomitant heart failure), preexisting repolarization abnormalities, such as a prolonged QT interval, and electrolyte imbalance, such as potassium or magnesium.22-‘T Variations in use can alter the risk of proarrhythmia. Antiarrhythmic agents titrated upward rapidly to a high dose pose a greater proarrhythmic threat than when gradually increased.28 Comparative data of aggravation of arrhythmia by class IA agents provided by Podrid showed relative frequencies of 15 % for quinidine, 9 % for procainamide, and 6 % for disopyramide. Negative inotropic action. Published data indicate a greater negative inotropic effect for disopyramide than for quinidine or procainamide.2g*30 In the setting of moderate to severe left ventricular dysfuncProarrhythmia.

‘I \ (CH 3k“I” 3 il-CH,CH,-6

-

post-CAST

1573

CONH2-H,PO,

Fig. 1. Structural formula for disopyramide free base. (From ANGIOLOGY, the Journal of Vascular Diseases, Fig. 1, Vol. 26: 67-84,1975. Reproduced with permission of the copyright owner: WESTMINSTER PUBLICATIONS, INC., Roslyn, New York [U.S.A.], all rights reserved.)

tion using therapy with higher doses of disopyramide, infrequent but serious decrements in cardiac performance have been reported with this agent.31-s3 However, a study by Podrid et a1.33 demonstrates the importance of preexisting heart failure as a risk factor for this problem, and it appears that adverse inotropic effects of disopyramide are dose related and much more likely to be found in patients with a preexisting history of congestive heart failure (CHF).3” Also, it has been shown that if an effect of disopyramide on left ventricular function occurs, it does so most commonly during the first week of use.33 In fact, later or progressive side effects of disopyramide affecting ventricular function are extremely uncommon. Therefore the safety of disopyramide is increased by avoiding: (1) loading doses34; (2) rapid titration to higher doses; (3) higher than necessary maintenance doses with respect to renal clearance; and (4) treatment of patients with a history of CHF or important left ventricular dysfunction.35 Other adverse reactions. Disopyramide, like other antiarrhythmic agents, has the potential to depress infranodal conduction and can precipitate complete heart block.36 Therefore disopyramide must be used with caution in patients with intraventricular conduction delays, particularly if there is associated atrioventricular block. Similar to the other membrane-active antiarrhythmic agents, disopyramide is contraindicated in patients who have ventricular arrhythmia associated with a prolonged QT syndrome.37 The anticholinergic side effects of disopyramide, such as dry mouth, constipation, and urinary hesitancy, may be disturbing to elderly persons, particularly men with prostatic enlargement, who are more susceptible to urinary-retentive symptoms. Also, because of anticholinergic side effects, disopyramide should be used with caution in patients with glaucoma. Of note, concurrent use of an anticholinest-

May 1574

Prystowsky

et al.

Table III. Pharmacokinetics disopyramide

American

and long-term

oral use characteristics

of disopyramide

and controlled-release

Disopyramide immediate-release

Usual doses Dose range Onset of action Elimination half-life Hepatic metabolism Renal excretion Concentration-dependent Metabolite Modified from DiRianco recent advances. Fort

R. Dismvramide for the treatment ._ Lee: Health Communications, Inc.,

of cardiac 1989:129-47.

arrhvthmia.

erase agent can reduce the anticholinergic side effects of disopyramide. In fact, without inhibiting the antiarrhythmic properties of disopyramide, a sustained-release form of pyridostigmine has been shown to prevent the anticholinergic side effects of disopyramide.‘l, l2 Combination with other antiarrhythmic drugs. A combination of antiarrhythmic agents may be useful for situations complicated by inadequate antiarrhythmic effects at the highest tolerated dose for single agents and for added benefits in the treatment of life-threatening arrhythmias.38-40 However, when disopyramide is used with other drugs, careful monitoring of electrophysiologic parameters and use of lower doses of disopyramide as well as other agent(s) are generally regarded as prudent, because interactions of these antiarrhythmic drugs may be difficult to predict in an individual patient.6 Compliance. Improved compliance with presented therapy is found when drugs need be taken only once to twice daily. 41 Convenience is the most obvious reason for improving compliance with a once- to twice-daily dose compared with the more traditional three to four times daily administration. Therefore the controlled-release formulation of disopyramide given on a 12-hour schedule that can provide comparable plasma levels and antiarrhythmic effects to equivalent dosages of the standard immediate-release drug given every 6 hours enhances compliance. 42-45 Another benefit of controlled-release disopyramide comes from slower drug delivery, and a decrease in early side effects that occur at the time of peak absorption (and therefore highest plasma level) is limited.46 METHODS

FOR CURRENT

Disopyramide. controlled-release

150 mg every 6 hr 400-800 mg/day Within 2 hr Mean: 7 hr Range: 4-70 hr 3O’t TO“, 15r, -65”; Mono-N-dealkyl-disopyramide

plasma protein binding

INVESTIGATION

Beginning May 1990 and concluding September 1990, patients were enrolled in an open-label, non-

In: Ciles

T, Garbus

1991 Journal

Heart

S, eds. Use of longer-acting

300 mg ever” 12 hr 400-800 mg/day Within 2 hr Mean: 11.6 hr Range: 7-15 hr 30’; 70°C 15’; -65”,, Same agents

in cardiac

therapy:

blinded, noncomparative study by 47 U.S. physicians representing 24 different states (see Appendix). In addition, retrospective, noncomparative patient data were provided by a number of these physicians. All participating physicians were identified by the use of a list of physicians board certified in cardiology with special expertise in clinical electrophysiology and/or arrhythmia management and were invited to participate in the program by us. The participating physicians were representative of electrophysiologists in private practice as well as those involved only in university-based practice; 27 (57 % ) were primarily university based, and 20 (43 % ) were primarily in private practice. inclusion and exclusion criteria. Male and female patients were eligible for prospective enrollment provided they had an arrhythmia that was deemed appropriate for treatment with disopyramide. Retrospective data were collected on patients treated with disopyramide for an arrhythmia only if therapy with disopyramide was initiated after publication of the CAST preliminary report in August 1989.l Determination of eligibility for inclusion of patients prospectively or retrospectively in the survey was based entirely on the assessment by the enrolling physician. There were no specific exclusion criteria other than contraindications for the use of disopyramide, that is, presence of cardiogenic shock, pre-existing second- or third-degree atrioventricular block (if no pacemaker is present), congenital QT prolongation, or known hypersensitivity to the drug. Patient evaluation. Participating physicians documented the enrollment and participation of each patient by completing a standardized Clinical Survey Form (CSF) developed by us. Patient data included date of enrollment, age, gender, history of CHF, type of heart disease, reasons(s) for antiarrhythmic therapy, arrhythmia symptoms, previous antiarrhythmic

Volume Number

121 5

therapy, concomitant cardiovascular medication, and current antiarrhythmic therapy. Patients were monitored clinically and assessed during initial therapy at intervals determined by the participating physician. The enrolling physician assessed the initial response to therapy as an “all or none” phenomenon, that is, disopyramide did or did not control the arrhythmia. The enrolling physician also commented for each patient enrolled about whether a medical problem related to the use of disopyramide occurred during the initial evaluation. In all instances when the answer to this question was positive, adequate follow-up information was obtained from the participating physician to determine the problem and its relationship to disopyramide therapy. Data assessment. Collection of the CSFs, data entry, and analyses was coordinated by Health Care Communications, Inc., Fort Lee, NJ. The statistical analyses were descriptive and were tabulated exactly from the CSFs. Data from prospective patients were analyzed both separately and together with data from retrospective patients. No statistically significant differences were found between prospectively and retrospectively enrolled patients for any aspect of the data evaluated. Therefore results of parameters evaluated are reported as one number, which reflects a combination of retrospectively and prospectively collected data. All patients on whom data were reported were included in an evaluation of demographics, therapy selection criteria, and safety. Patients who had missing or conflicting data were not included in a determination of initial clinical efficacy. RESULTS Patient

characteristics. Patient characteristics at the time of entry are listed in Table IV. Data on 217 patients were submitted for analysis. There were 149 (69%) patients from whom data were prospective and 68 (31%) from whom data were retrospective. One hundred twenty patients were men (55 % ) and 97 (45 % ) were women. Their ages ranged from 10 to 90 years (mean, 53 -+ 17.5 years). The great majority of patients, 193 (89%), did not have a history of CHF at the time of entry, whereas notably 24 (11%) had a history of CHF on entry. The number of patients with left ventricular ejection fraction (LVEF) measured on entry was 192, with values ranging from 18% to 80 % . It was noteworthy that 9 (5 % ) patients had an LVEF of <30% on entry, 18 (9%) had an LVEF of 30 % to 40 % , and 165 (85 % ) patients had an LVEF of >40% on entry. The most common heart disease observed in patients on admission to this study was

Use

Table

IV. Patient

of disopyramide

1575

post-CAST

characteristics

Characteristic

Total

No. of patients entered Prospective Retrospective Male/female ratio Age on entry Mean Range History of CHF on entry Yes No

LVEF “0 on entry* <30 30-40 .40 History of heart disease? None MVP CAD

217 149 (69)

68 (31) 120/97 (55/45) 53 t 17.5 yr IO-90 yr 24 (11) 193 (89) 9 (5) 18 (9) 165 (86) 88 (36) 16 (7) 46 (19)

8 36 7 51

IDC

Hypertensive IHSS Other

(“,)

(3) (15) (3) (21)

MVP, Mitral valve prolapse; CAD, coronary artery disease; IDC, idiopathic dilated cardiomegaly; IHSS, idiopathic hypertrophic suhaortic stenosis. *One hundred ninety-two (88’~)) patients had LVEF ‘A measured on entry. tTwo hundred fifty-two diseases noted for 217 patients.

Table V. Arrhythmia tients*) Arrhythmia

symptoms (381 events in 217 pa-

S,

Palpitations Dizziness/presyncope Shortness of breath Syncope Fatigue Chest pain Other *One hundred recorded.

twenty-six

Frequency of event (%)

166 a2 36 29 31

(44) (22) (9) (8) (8)

21 (6) 16 (4)

patients had more than one arrhythmia

symptom

coronary artery disease, which was noted in 46 (19 % ) patients, followed by hypertension in 36 patients (15%), mitral valve prolapse in 16 patients (7%), idiopathic dilated cardiomegaly in 8 patients (3 % ), and idiopathic hypertrophic subaortic stenosis in 7 patients (3 % ). Other types of heart disease reported in individual patients were congenital heart disease, rheumatic heart disease, sick sinus syndrome, aortic valve disease, aortic stenosis, aortic insufficiency, and mitral insufficiency. It was noteworthy that 88 (36 % ) patients had no recognized heart disease at the time of entry.

1576

Prystowsky

Table VI. Prior patients*)

et al.

American

antiarrhythmic

Agent

therapy No. of patients

“C of patients

68 45 49

31 21 23

12 9

6 4 5

Quinidine Procainamide &Blocker Mexiletine Encainide Flecainide Amiodorone Digitalis Tocainide Verapamil Other *One hundred reported.

six patients

(180 of 217 [83%]

11

1 24

52 2

18 6

39 13 had more than

one prior

antiarrhythmic

therapy

Symptoms. There were 381 cardiovascular symptoms in 217 patients recorded at the time of entry; 126 (58%) patients had more than one symptom recorded (Table V). The most frequent symptom recorded was palpitations, which occurred in 44 % of patients, followed in frequency by dizziness/presyncope observed in 22% of patients. Shortness of breath, syncope, fatigue, and chest pain were observed in 9 % , 8 % , 8 % , and 6 % of patients, respectively. No other individual symptom was recorded in more than 4% of patients. Prior antiarrhythmic therapy. A total of 180 (83%) patients received antiarrhythmic therapy before entry (Table VI). The most frequently prescribed agents in order of frequency were quinidine, digitalis, &blockers, procainamide, and verapamil. Indications for therapy. There were 276 indications for disopyramide therapy recorded in 217 patients; 50 (23 % ) patients had more than one indication recorded (Table VII). More than two thirds of the arrhythmias treated were supraventricular in origin. The most frequent reason for therapy with disopyramide was atria1 fibrillation or flutter (35.1% of patients), followed by sustained ventricular tachycardia, which accounted for 9.8% of the reasons for therapy. Administration

and

concomitant

medication.

Con-

trolled-release disopyramide was used as initial therapy in 62 % of patients; the immediate-release preparation was used initially in 38% of patients (Fig. 2). On discharge the controlled-release preparation was used in 76% of patients and the immediate-release preparation in 24% of patients (Fig. 2). The mean initial total daily dose of disopyramide, including

May 1991 Heart Journal

immediate-release and controlled-release formulations, was 473 ? 177 mg/day (Table VIII); for the immediate-release preparation the mean was 487 -t 177 mg/day, and for the controlled-release preparation the mean was 464 I 176 mg/day (no statistically significant difference). The mean discharge total daily dose of disopyramide including both formulations was 491 rt. 193 mg/day (Table VIII); for the immediate-release preparation the mean was 519 & 202 mglday, and for the controlledrelease preparation the mean was 483 t 190 mg/day (no statistically significant difference). Also, there was no statistically significant difference between the total daily initial dose and the total daily discharge dose. Table IX shows the initial dose of disopyramide in relation to the arrhythmia treated. Although only small patient numbers are available, lower doses of disopyramide were used in patients treated for premature atria1 or ventricular complexes than in patients with other arrhythmia indications. A total of 63 (29% ) patients were treated with combination antiarrhythmic therapy (Table X). The most frequent combination was disopyramide and a P-blocker in 29 (14 % ) patients. The mean total daily dose of disopyramide for patients treated with combination antiarrhythmic medication was 500 mglday compared with 489 mglday for patients not treated with combination therapy, which is not statistically significant. Of note, digitalis was used as concomitant medication in 31(15 % ) patients, with a mean dose of 463 mglday of disopyramide in those patients, which is not significantly different than the mean dose of 497 mglday in patients not treated with digitalis. Response assessment. Response assessment was recorded for 211 of 217 patients (97%) by Holter monitoring, treadmill evaluation, electrophysiologic study, or other clinical parameters. It was notable that 117 of 211 (55%) patients had Holter monitoring, 3 of 211 (1%) had treadmill evaluation, and 57 of 211 (27 %) had electrophysiologic study evaluations. Disopyramide alone or in combination with another agent initially controlled the reported arrhythmia in 172 of 211 (82%) patients and did not control the arrhythmia in 39 of 211 (18%) patients, which was statistically significant for control with disopyramide (p < 0.01). The frequency with which disopyramide initially controlled the various reported arrhythmias is shown in Table XI. The initial outcome compared with the initial total daily dose for doses most commonly used is shown in Fig. 3. The most frequently used dose was 600 mglday, which achieved control in 80% (57/71) of patients.

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Use of disopyramide

m

CR

Disopyro

mide

m

past-CAST

1577

IR Disopyramide

10

1 I 0 L----

Initiation Fig.

Table

Indications

VII.

2.

Type of disopyramide

for treatment

Supraoentricular arrhythmias Atria1 fibrillation/flutter Atrioventricular reentry Atria1 tachycardia Paroxysmal supraventricular tachycardia Atrioventricular nodal reentry Premature atria1 complexes Wolff-Parkinson-White syndrome

Total *Fifty

( (‘0 ) patients

used. CR, Controlled

(276 indications Frequency 97/276 251276 18/276

(35.1) (9.1) (6.5)

19/276 13/276 11/276

(6.9) (4.7) (3.8)

4/276

(1.4)

for treatment

Ventricular arrhythmias Sustained ventricular tachycardia Premature ventricular complexes Nonsustained ventricular tachycardia Ventricular fibrillation Total

release.

Frequency

27/276

(W/

(9.8)

241276

(8.7)

19/276

(6.9)

61276 (2.2) 27.6

Other Syncope Palpitations Tachy-Brady syndrome Sick sinus syndrome

Total

Frequency

(%)

71276 (2.5) 2/276 (0.7) 21276 (0.7) 2/276

(0.7)

4.7

recorded

Side effects. Twenty-five

ported, XII).

release; IR, immediate

in 217 patients*)

(5)

67.7 had more than one indication

Discharge

side effects were remost of which were anticholinergic (Table

CHF and LVEF. Subset analyses of data were conducted for patients with a history of CHF and with an LVEF of 530% of entry into the study. The reasons for disopyramide therapy in patients with a history of CHF at the time of entry were similar to those patients without a history of CHF. There

was no statistically significant difference in the average initial or discharge daily dose of disopyramide between patients with and without a history of CHF at the time of entry (Table XIII). However, there was a statistically significant difference (p < 0.0001) in the type of disopyramide (immediate-release vs controlled-release) used initially for patients with a history of CHF compared with patients who had no history of CHF; the immediate-release formulation was

Prystowsky

1578

Table

et al.

Disopyramide administration

VIII.

Xl. Evaluation of disopyramide on initiation of therapy (271 events in 211 patients*) Table

Initial total daily dose (IR or CR) Mean, 473 k 177 mg/day Range, ZOO-1200 mg/day Discharge total daily dose (IR or CR) Mean, 491 & 193 mg/day Range, 100-1200 mg/day IR,

Immediate

release;

CR, controlled

Arrhythmia types

release.

Disopyramide doseby arrhythmia (279 arrhythmia symptoms in 217 patients*) Table

IX.

Arrhythmia

No. of patients

Atria1 fibrillation/flutter VT-S AVRT PVCS VT-NS Atria1 tachycardia PSVT AVNRT PACs VF Syncope Other

Average dose

97 27

500 565

25 24

516 375

19 18 19

455 458 416 463

13

11

336 617 457

6

7 13

Antiarrhythmic combination/concomitant ther-

Therapy

P-Blockers Calcium antagonists Mexilitine Amiodarone Tocainide Other Total taking combination therapy No combination antiarrhythmic medication Concomitant therapy with digitalis

Patients (%) 29 (14) 13 (6) 9 (4) 4 (2)

2 (1) 6 (3)

s;, Controlled

Mean disopyramide dose on discharge (mglday) 524 433 579 425

63 (29)

400 492 500

154 (71)

489

31 (15)

463

used more frequently for patients with a history of CHF than for those without a history of CHF (Table XIV). LVEF (%) was reported for 192 patients at the time of entry. The initial dose of disopyramide for various ranges of LVEF % and the arrhythmia con-

5 Not controlled

93

73/93

25 25

19/25 23/25

(78% ) (76%) (92 “i )

23

22/23

(96%)

19

17/19 (89%)

18

16/18

(89”;

PSVT AVNRT

19 13

16/19 12/13

(84%) (92%

PACs VF Syncope Other

11

lO/ll

6

2/6

7

5/l 10/12 225/271

12 271

TOTAL

20/93 6/25 2/25 l/23

(22“;b) ( 24 rc ) (8’;)) (4”;‘)

2/19 (11Pc) )

2/18

(llr,)

1

3/19 l/13

(16°C (8cc)

(91”; ) (33%#) (71Y) (83%) (83%)

1

l/l1 (9’< ) 4/6

(67”;

)

2/l (297 ) 2112 (175) 46/271 (17°C)

VT-S, Sustained ventricular tachycardia; AVRT, atrioventricular reentry: PVC’s, premature ventricular complexes; VT-NS, nonsustained ventricular tachycardia; PSVT, paroxysmal supraventricular tachycardia; AVNRT, atrioventricular nodal reentry; PA&, premature atria1 complexes; VF. ventricular *Data

Table

fibrillation. not available

XII.

for six patients.

Initial side effects in 217 patients

539

ventricular tachycardia; AVRT, atrioventricular reentry; PVCs, premature ventricular complexes; VT-N& nonsustained ventricular tachycardia; PSVT, paroxysmal supraventricular tachycardia; AVNRT, atrioventricular nodal reentry; PA&, premature atria1 complexes; VF, ventricular fibrillation. *Fifty patients were treated for more than one arrhythmia symptom.

X.

Total

Atria1 fibillation/flutter VT-S AVRT PVCS VT-NS Atria1 tachycardia

Problem

VT-S, Sustained

Table

May 1991 Heart Journal

American

Total Anticholinergic (total) Dry mouth only Constipation only Urinary retention only Two or more of the above Unspecified Mild CHF Blood pressure decrease Nausea Metallic taste, rash Unspecified

N 25

X of total patients

3

12 6 1

0 0

0 0

6 4

3 2

1 1 1 1 8


13

4

trol achieved within the ranges with the doses used are shown in Table XV. The indications for arrhythmia treatment in patients with an LVEF of <30% were as follows: VT-S in three patients, PVCs in two patients, VT-NS in one patient, atrioventricular reentry in one patient, atria1 fibrillation or flutter in one patient, and VT-NS and PVCs in one patient. Of note, there was no statistically significant difference in arrhythmia control observed for patients with an LVEF of <30% compared with patients having higher LVEFs. DISCUSSION

The findings of this study indicate that after CAST, arrhythmia specialists are using disopyramide for a wide range of patients with arrhythmias and generally are achieving desirable initial results.

"O,"me

121

Number

5

Use

EBB Control

300 mglday

m

of

disopyramide post-CAST

1579

No control

400 mg/day

Fig. 3. Initial Indications for therapy. Because disopyramide is approved by the Food and Drug Administration only for use in ventricular arrhythmias, the findings that disopyramide was prescribed for a broad spectrum of arrhythmias (Table VII) may at first seem surprising. However, data on the efficacy of disopyramide for the treatment of a variety of arrhythmias have been previously published and should be particularly known by specialists in arrhythmia management.47 Thus, the fact that supraventricular arrhythmias accounted for more than two thirds of the total indications for treatment by the participating physicians in the study perhaps could have been expected. Because atria1 fibrillation or flutter is commonly associated with hypertensive heart disease, the incidence (15 % ) of patients with hypertensive heart disease at the time of entry is not surprising. In fact, almost 50% of patients in this study who had hypertensive heart disease also had atria1 fibrillation or flutter. Also, not surprising is the 44% incidence of palpitations, a symptom often found in parallel with atria1 fibrillation or flutter. Surprising, however, is the 76% control achieved by patients with sustained ventricular tachycardia taking disopyramide (Table XI). This might reflect the use of disopyramide in patients with only moderately impaired ventricular function, evidenced by the finding that only 5 % of all patients had an LVEF of <30%. Also, the data showing prior therapy with other class IA agents in 52 % of patients (Table VI) indicate that lack of success or side effects with one class IA agent does not necessarily preclude the usefulness of another agent of the same class.

600 mgMay -

450 mgkhy

8QQmgfday

outcome. XIII. Average daily dose of disopyramide: CHF versus no CHF

Table

% Arrhythmias

Initial

initially

dose (mg)

History of CHF No history of CHF

Table

controlled

429 490

79 87

Type of disopyramide

XIV.

used on initiation

(n = 217)

History of CHF No history of CHF CR. Controlled-release;

Table

CR (56)

IR (?I)

3/24 (12) 122/193 (63)

21/24 (88) 71/193 (37)

IR. immediate-release.

XV. LVEF s and arrhythmia LVEF

<30 30-40 >40

“E

Initial dose (w/day)

300 491 484

control Control

(Xl

6/9 (67) 12/B (67) 123/165 (75)

Administration. Slightly less than half (38%) the patients were initially given immediate-release disopyramide. However, it is unclear why 24% of patients were continued on the immediate-release formulation at discharge. Assuming patients had no

1580

fiystowshy

et al.

significant side efffects, it would appear reasonable that responders should be converted to the controlled-release formulation to improve compliance. More important, most patients who are candidates for disopyramide can be started on the controlledrelease formulation without adverse sequelae as long as potentially high-risk situations, such as poor ventricular function, are avoided. In general, the doses used were within the generally recommended range, with 600 mg/day the most frequently used dose. However, a lower total daily dose of disopyramide was used and was reasonably effective in selected patients with an LVEF of <30%, which seems prudent. Special considerations. This study confirms that anticholinergic side effects are the major adverse reactions noted during treatment with disopyramide. Although these side effects were only observed in 12 % of patients in this study, in some reports the incidence is more than 20 % of patientsll, 48,4g; the most common manifestations were dry mouth, nose or eyes, nausea, abdominal discomfort, constipation, blurred vision, and urinary hesitancy. However, most of these previous studies were conducted with the immediate-release formulation, but the controlledrelease preparation, which provides more uniform blood levels and lower risk of side effects, was more commonly prescribed in this investigation. In addition, anticholinergic side effects are dose related, and most patients received a total daily dose of disopyramide of 5600 mg, a dose level that infrequently causes major anticholinergic symptoms. For patients who have substantial anticholinergic side effects, the use of the acetylcholinesterase inhibitor pyridostigmine as a sustained-release tablet (Mestinon Timespan, Roche Laboratories, Nutley, N.J.) in doses of 90 to 180 mg every 12 hours can reverse these symptoms without decreasing antiarrhythmic efficacy.‘l, l2 Published data have indicated that disopyramide should not be given to patients with CHF or even a history of CHF. 33 However, it is interesting to note that in this survey, 11% of the patients had CHF, most probably compensated, and the participating physicians felt comfortable with close monitoring and reduced dosage to prescribe disopyramide. Therefore, although not generally recommended, it is possible to use disopyramide for the treatment of arrhythmias in selected patients with a history of CHF, provided the patient is followed closely. CONCLUSIONS

This study of the post-CAST use of a specific class IA agent, disopyramide, by arrhythmia specialists

demonstrates that the prime use of disopyramide by these physicians is for supraventricular and not ventricular tachyarrhythmias. The early outcome regarding safety and efficacy was excellent for a variety of tachyarrhythmias. Initial use of controlled-release disopyramide yielded relatively few disabling side effects, in part possibly because of its favorable pharmacokinetic profile versus the immediate-release preparation, but probably also because of the use of a daily dose of 600 mg or less in most patients. Notably absent were any serious proarrhythmic effects in this select series of patients. Indeed, in postCAST use by arrhythmia specialists, disopyramide emerges as a “broad-spectrum” antiarrhythmic, deserving renewed attention for the treatment of supraventricular tachycardias and ventricular tachycardias, particularly in patients with an LVEF 240 % and even 230 5%. REFERENCES 1.

2.

3I

4.

<5

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7. 8. 9.

10.

11.

12.

13. 14. 15.

The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report. Effect of encainide and fiecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989;321:406-12. Bigger JT Jr. Implications of the cardiac arrhythmia suppression trial for antiarrhythmic drug treatment. Am J Cardiol 1990;65:3D-10D. Ruskin JN. The cardiac arrhythmia suppression trial (CAST). N Engl J Med 1989:321:386-8. Akhtar M, Breithardt G. Camm AJ. CAST and beyond: implications of the cardiac arrhythmia suppression trial. Circulation 1990;81:1123-7. Pratt CM, Moye LA. The cardiac arrhythmia suppression trial: background, interim results and implications. Am J Cardiol 1990;65:20B-9B. Prystowsky EN, Katz A, Knilans TK. Ventricular arrhythmias: risk stratification and approach to therapy after the cardiac arrhythmia suppression trial (CAST). PACE 1990: 13:1480-7. Market Measures Inc. Arrhythmia Drug Market Study IX. May 1990. Dean RR. The pharmacology of Norpace. Angiology 1975; 26(suppl):67-84. Siddoway LA. Selecting appropriate first-line antiarrhythmic agents: comparative pharmacologic profiles. PACE 1990; 13:1488-500. DiBianco R. Disopyramide for the treatment of cardiac arrhythmia. In: Giles T, Garbus S, eds. Use of longer-acting agents in cardiac therapy: recent advances. Fort Lee: Health Care Communications, Inc., 1989:129-47. Teichman SL, Fisher JD. Matos JA, Kim SG. Disopyramidepyridostigmine: report of a beneficial drug interaction. d Cardiovasc Pharmacol 1985;7:108-13. Teichman SL, Ferrick A, Kim SG, Matos JA, Waspe LE, Fisher JD. Disopyramide-pyridostigmine interaction: selective reversal of anticholinergic symptoms with preservation of anticholinergic effect. J Am Co11 Cardiol 1987;10:633-41. Singh BN, Hauswirth 0. Comparative mechanisms of action of antiarrhythmic drugs. AM HEART J 1974;87:367-82. Niarchos AP. Disopyramide: serum level and arrhythmia conversion. AM HEART J 1976;92:57-64. Patterson E, Stetson P, Lucchesi BR. Disopyramide plasma and myocardial tissue concentrations as they relate to antiarrhythmic activity. J Cardiovasc Pharmacol 1979;1:541-50.

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12 1

Number

5

16. Woosley RL, Shand DG. Pharmacokinetics of antiarrhythmic drugs. Am J Cardiol 1978;41:986-95. 17. Meffin PJ, Robert EW, Winkle RA, Harapat S, Peters FA, Harrison DC. The role of concentration-dependent plasma protein binding in disopyramide disposition. J Pharmacokinet Biopharm 1979;7:29-46. 18. Heel RC, Brogden RN, Speight TM, Avery GS. Disopyramide: a review of its pharmacological properties and therapeutic use in treating cardiac arrhythmias. Drugs 1978;15:331-68. 19. Arif M, Laidlaw JC, Oshrain C, et al. Randomized doubleblind parallel group comparison of disopyramide-phosphate and quinidine in patients with cardiac arrhythmias. Angiology 1983;34:393-400. 20 Trimarco B, Ricciardelli B, DeLuca N, et al. Disopyramide, mexiletine and procainamide in the long-term oral treatment of ventricular arrhythmias: antiarrhythmic efficacy and hemodynamic effects. Curr Ther Res 1983;33:472-87. 21. Kimura E, Mashima S, Tanka T. Clinical evaluation of antiarrhythmic effects of disopyramide by multiclinical controlled double-blind methods. Int J Clin Pharmacol Ther Toxic01 1980;18:338-43. 22. Ruskin JN, McGovern B, Garan H, DiMarco JP, Kelly E. Antiarrhythmic drugs: a possible cause of out-of-hospital cardiac arrest. N Engl J Med 1983;309:1302-6. 23. Velebit V, Podrid PJ, Lown B, Cohen BH, Graboys TB. Aggravation and provocation of ventricular arrhythmias by antiarrhyt.hmic drugs. Circulation 1982;65:886-94. 24. Podrid PJ. Aggravation of arrhythmia: a potential complication of theraov. Prim Cardiol 1983:9:75-87. 25. Minardo JD,‘Heger JJ, Miles WM, Zipes DP, Prystowsky EN. Clinical characteristics of patients with ventricular fibrillation during antiarrhythmic drug therapy. N Engl J Med 1988; 319:257-62. 26. Stanton MS, Prystowsky EN, Fineberg NS, Miles WM, Zipes DP, Heger JJ. Arrhythmogenic effects of antiarrhythmic drugs: a study of 506 patients treated for ventricular tachycardia or fibrillation. J Am Co11 Cardiol 1989;14:209-15. 27. Holland DB, Nixon JV, Kuhnert L. Diuretic-induced ventricular ectopic activity. Am J Med 1981;70:762-8. 28. Morganroth J, Horowitz LN. Incidence of proarrhythmic effects from quinidine in the outpatient treatment of benign or potentially lethal arrhythmia. Am J Cardiol 1985;56:585-7. 29. Aronson RS, Siskind S, Sonnenblick EH. Assessment of the hemodynamic and inotropic effects of antiarrhythmic drugs. In: Morganroth J, Moore EN, Dreifus LS, et al., eds. The evaluation of new antiarrhythmic drugs. The Hague: Martinus Nijhoff Publishers, 1981:247-65. 30. Wisenberg G, Zawadowski AG, Gebhardt VA, et al. Effects on ventricular function of disopyramide, procainamide and quinidine as determined by radionuclide angiography. Am J Cardiol 1984;53:1292-7. 31. Story JR, Abdulla AM, Frank MJ. Cardiogenic shock and disopyramide phosphate. JAMA 1979:242:654-5. 32. Sinatra ST,-La&y AB, Galle JS, Amato J. Cardiogenic shock associated with disopyramide phosphate. *JAMA 1980; 243:113’. 33. Podrid PJ, Schoenberger A, Lown B. Congestive heart failure caused by oral disopyramide. N Engl J Med 1980;302:614-7. 34. Gottdiener JS, DiBianco R. Bates R, Saverbrunn BJ. Fletcher RD. Effects of disopyramide on left ventricular function: assessment by radionuclide cineangiography. Am J Cardiol 1983;51:1554-8. 35. DiBianco R. Chronic venricular arrhythmias: which drug for which patient? Am J Cardiol 1988;6i:83A-94A. 36. Desai JM, Scheinman M. Peters RW. O’Younz J. Electrophysiologic effects of disopyramide in’patients”with bundle branch block. Circulation 1979;59:215-25. 37. Khan MM. Logan KR, McComb JM, Adgey AAJ. Management of recurrent ventricular tachyarrhythmias associated with Q-T prolongation. Am J Cardiol 1981;47:1301-8. 38. Duff HJ, Rosen D, Drimon K, Oates JA, Woosley RL. Mexiletine in the treatment of resistant ventricular arrhythmias:

Use of disopyramide

39.

40.

41 42.

43.

44.

enhancement of efficacy and reduction of dose-related side effect,s in combination with quinidine. Circulation 1983;57: 1124.8. Greenspan AM, Spielman SR, Webb CR, Sokoloff NM, Rae AP, Horowitz LN. Efficacy of combination therapy with mexiletine and a type IA agent for inducible ventricular tachyarrhythmias secondary to coronary artery disease. Am J Cardiol 1985;56:277-84. Kim S, Mercando AD, Tam S, Fisher JD. Combination of disopyramide and mexiletlne for better tolerance and addictive effects for treatment of ventricular arrhythmias. J Am Coil Cardiol 1989;13:659-64. Morgan TO, Nowson C, Murphy J, Snowden R. Compliance and the elderly hypertensive. Drugs 1986;31:(suppl4):174-83. Zema MJ. Serum drug concentrations and adverse effects in cardiac patients after administration of a new controlledrelease disopyramide preparation. Ther Drug Monit 1984;6: 192-B. Siddoway LA, Barbey JT, Roden DM, Woosley RL. Pharmacologic evaluation of standard and controlled-release disopyramide. Angiology 1987;38:184-7. Forssell G, Graffner C, Nordlander R, Nyquist 0. Comparative bioavailabilitv of disonvramide aft,er multinle dosine with standard capsules and controlled release tablets. Eur J Clin Pharmacol 1980;17:209-.13. Bechgaard H, Nielsen GH. Controlled release multiple units and single unit doses. A literature review. Drug Dev Ind Pharma 1978:4:53-67. Karim A, Shubert EN, Burns TS, Palmer M, Zinny MA. Disopyramide plasma concentrations following single and multiple doses of the immediate-release and controlled-release capsules. Angiology 1983;34:375-92. Wharton JM, Prystowsky EN. Disopyramide. In: Messerli FH, ed. Cardiovascular drug therapy. Philadelphia: WB Saunders co. 1990:1324-52. Koch-Weser J. Drug therapy: disopyramide. N Engl J Med 1979;300:957-62. Podrid PJ, Kowey PR. Disopyramide: when is it justified? ,J Cardiovasc Med 1981;6:997-1007. _

45.

46.

47.

48. 49.

I 58 1

post-CAST

I

0

Appendix Arrhythmia

specialist

Gur C. Adhar, MD Pittsburgh, PA Masood Akhtar, MD Milwaukee, WI A. Reid Allison, Jr., MD State College, PA Barry Alpert, MD Pittsburgh, PA Jean Barbey, MD Washington, D.C. Thomas E. Bump, MD Chicago, IL A. John Camm, MD London, SWIT ORE Mark D. Carlson, MD Cleveland, OH Brian Chesnie, MD Tustin, CA Donald Chilson, MD Spokane, WA

No. of patients enrolled 1 4 12 3 4

1 1

2 5 3

1588

May1991

Butman

American

ents.“s-41 The risk is apparently greater in patients who are receiving immunosuppressive agents, or fibric acid derivatives, such as gemfibrozil.42 While serum cholesterol can be significantly reduced, over one third of patients receiving 20 mg a day of lovastatin may need to stop this drug because of myalgias or asymptomatic creatine kinase increases.4”$ 44 Significantly higher serum levels of lovastatin are found in transplant recipients given standard doses, and monitoring blood levels may be important, since lower doses may achieve the desired serum cholesterol level without precipitating lovastatin’s potential significant ill effects.4” Administration of compactin, an HMG CoA reductase inhibitor chemically similar to lovastatin, induces lymphomas in dogs.46 Transplant recipients are already at risk for lymphoma because of their immunosuppressive therapy.47 While this side effect has not been reported in man, more widespread and chronic drug use may become a concern in this highrisk group. Cooperative long-term studies and better reporting of this entity may be needed to identify this life-threatening response to lipid-lowering therapy. Slowing

the progression

of coronary

atherosclerosis.

Regression of coronary atherosclerosis after 2 years of a stringent drug and diet regimen was seen in 16 % of colestipol-niacin treated patients, while it was seen in 2.4% of a control gr0up.l The stringent compliance required for both diet and drug therapy resulted in a 26 % reduction of total cholesterol, from a mean of 246 mg/dl to a normal mean value of 180 mg/dl. Triglycerides were reduced 22% to a mean of 110 mg/dl, and LDL cholesterol fell 43 % to a low normal value of 97 mg/dl. HDL rose 37 % in the drug-treated group, from 44.6 to 60.8 mg/dl, again into the upper range of normal. Such improvement may not be achieved or even be desirable in the transplant recipient who must also take a variety of other medications, and who is at particular risk of adverse experiences. The high cholesterol and triglyceride levels seen in this population will require substantial dietary changes and drug therapy, if regression or a lack of progression of the coronary arterial disease is our end point. With older transplant recipients now being accepted worldwide and with survival improving, retarding the progression or the development of peripheral or cerebral atherosclerosis is also a worthy consideration, but the benefits and risks of our treatments and the end points we desire must be defined. The cost of the newer, better tolerated drugs is substantial, and must also be factored into any therapeutic equation. Finally, the increased mortality from accidents and violence seen in several choles-

Heart

Journal

terol-lowering drug trials remains unexplained and should also be considered in this high-risk patient group.48 Recommendations. Monitoring of lipids after cardiac transplantation is worthwhile, and dietary intervention should begin before and early after surgery to minimize the intake of saturated fats and cholesterol. A reduction in steroid dosage appears safe in combination with cyclosporine and azathioprine, and may further limit the progressive rise in lipid levels seen early after transplantation. Immunosuppressive drugs that are currently being developed will hopefully not adversely affect serum lipoproteins in such an aggressive manner, and concomitant therapy to reduce the daily dose of cyclosporine may help lower the high cholesterol levels seen. 4s Coronary angiography is currently the only in vivo method for detecting early changes in the coronary anatomy.50 Beginning with a baseline coronary angiogram prior to hospital discharge after cardiac transplantation will permit serial and quantitative comparisons of angiograms from year to year.“’ Use of lipid-lowering drug therapy should only be considered for patients in whom there is reasonable hope of benefit, with an appreciation that this is currently undefined. We do not know at what level serum cholesterol requires therapy, and we do not have a target level once therapy has been instituted. The relative weight of a lowered serum cholesterol level in improving longevity should be considered in the transplant recipient, in whom one or more of the other factors discussed above may play a more significant role. In a computer model based on the risk factor data available, smoking and high blood pressure were much more significant predictors than serum cholesterol in improving longevity in the general population. 52Whether the incidence of infection, rejection, or malignancy is more common, is unchanged, or is less frequent with drug therapy for high lipids in patients following transplantation is unknown. Cardiac transplantation offers a second chance for life for many patients, and they and their physicians justifiably feel that everything should be done in an effort to prevent a repeat of their earlier cardiac demise. At this time it seems prudent for us to be particularly aware and wary of some of our therapies, while continuing our efforts to more precisely identify the role of lipids and other factors in the development of graft atherosclerosis. Cooperative retrospective studies are needed to identify levels for which therapy may be of use and target levels after therapy has been instituted. Controlled prospective studies will ultimately answer our concerns and provide us with the necessary information re-