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
1572
Prystowsky
et al.
American
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,
Volume Number
121 5
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 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*
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
1572
Prystowsky
et al.
American
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,
Volume Number
121 5
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
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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 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*
