DIAGNOSIS
AND
TREATMENT
Digoxin for Atrial Fibrillation: A Drug Whose Time Has Gone? Rodney H. Falk, M D , and Jeffrey I. Leavitt, M D
For over 200 years digitalis compounds have been used to treat atrial fibrillation. The rapid ventricular response to atrial fibrillation is frequently treated with digoxin to produce a controlled heart rate. Digoxin has also been proposed as a treatment for terminating recent-onset atrial fibrillation, for maintaining sinus rhythm after an episode of atrial fibrillation, and as prophylactic therapy in patients with paroxysmal atrial fibrillation to prevent excessive tachycardia during a paroxysm. Perhaps because it has been used for so long, few of these indications have been studied scientifically until recently. Studies now suggest that in patients with atrial fibrillation, digoxin is a poor drug for controlling heart rate during exertion, has little or no effect in terminating the arrhythmia, and may occasionally aggravate paroxysmal atrial fibrillation. Despite adequate digitalization, the heart rate at the onset of a paroxysm of fibrillation in patients receiving the drug does not differ from the heart rate in patients not receiving it. This article discusses the current role of digoxin in the management of patients with chronic, recent-onset, or paroxysmal atrial fibrillation.
Annals of Internal Medicine. 1991;114:573-575.
From Boston City Hospital and Boston University School of Medicine, Boston, Massachusetts. For current author addresses, see end of text.
Atrial fibrillation is perhaps the most common cardiac arrhythmia encountered by both general internists and cardiologists. Depending on its cause, duration, and hemodynamic significance, as well as on the symptomatic state of the patient, the goal of treating atrial fibrillation is either to control the ventricular rate or to terminate the fibrillation. In the latter case, prevention of recurrence becomes an important consideration. Digoxin (and its predecessor, digitalis leaf) is the oldest therapy for atrial fibrillation. Originating from an herbal remedy, the purple foxglove, it has stood the test of time; after more than two centuries of use it is still the most commonly prescribed drug for ventricular rate control in atrial fibrillation. As with many therapies, digoxin's therapeutic use preceded an understanding of the mechanism of its action, and only recently has it been subjected to the rigorous clinical trials required of more modern drugs. Its value in congestive heart failure has been established (1). In contrast, although digoxin is frequently prescribed for atrial fibrillation, few careful studies exist regarding its value in this arrhythmia. We will examine several clinical situations for which digoxin is commonly prescribed: for ventricular rate control in chronic atrial fibrillation; for the termination of
recent-onset atrial fibrillation; and for the prevention of recurrent paroxysms of arrhythmia as well as for rate control should such a recurrence occur. Control of Ventricular Rate in Chronic Atrial Fibrillation Although digoxin does directly affect atrial tissue and the atrioventricular node, its predominant effect is mediated by the autonomic nervous system (2, 3). In the resting digitalized patient, vagal influences on the atrium and atrioventricular node are enhanced and, as a result of the effects on the node, the ventricular rate is slowed. The effect of vagal stimulation on the atrium is more complex, with shortening of the atrial refractory period and increased dispersion of refractoriness. This result is the opposite of digoxin's direct effect on atrial tissue, which causes a mild prolongation of the atrial refractory period and a decrease in the vulnerable zone for provocation of repetitive atrial firing (4). There is no doubt that appropriate doses of digoxin will slow the resting ventricular rate in most patients with chronic atrial fibrillation. Because the drug's predominant effect on the atrioventricular node is mediated by enhanced vagal tone, however, its beneficial effect on the resting heart rate is not always maintained during exertion, a period when vagal influences are withdrawn (5, 6). This may result in excessive tachycardia during normal daily activities manifesting as exertional palpitations, dyspnea, or fatigue. Both low-dose beta blockers (which block the effects of the sympathetic nervous system) and calcium-channel antagonists (which act directly to slow atrioventricular node conduction) may be highly effective in controlling heart rate during exertion. Indeed, in selected patients, such as young patients with normal ventricular function, one or the other of these classes of drugs may be preferable to digoxin monotherapy for atrial fibrillation (7-9). Restoration of Sinus Rhythm A common belief is that digoxin effectively restores sinus rhythm in patients with recent onset of atrial fibrillation. If congestive heart failure due to systolic dysfunction co-exists with recent-onset atrial fibrillation, the combination of digoxin's negative chronotropic and positive inotropic effects may improve hemodynamic variables enough that spontaneous reversion to sinus rhythm occurs. In the absence of congestive heart failure, however, digoxin does not act as an antiarrhythmic drug in the atrium. In a double-blind, randomized, placebo-controlled study of digoxin in recent-onset atrial fibrillation unassociated with congestive heart failure, no benefit was found for digoxin compared with placebo for the conversion of the arrhythmia to sinus ©1991 American College of Physicians
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19725/ by a University of California San Diego User on 05/04/2017
573
rhythm (10). This observation is supported by electrophysiologic evidence, noted above, that digoxin shortens the refractory period of atrial myocardium—an effect that would actually tend to increase fibrillatory rate and, at least theoretically, lessen the possibility of reversion to sinus rhythm (11-14). Maintenance of Sinus Rhythm In clinical practice, patients who have had an episode of paroxysmal atrial fibrillation still commonly receive digoxin during an acute episode. There is a tendency among many physicians to maintain such therapy for a prolonged or indefinite period in the belief that this may prevent recurrence of atrial fibrillation or slow the ventricular response should a recurrence occur. Preliminary retrospective data on the role of digoxin therapy in preventing recurrence of atrial fibrillation after electrical cardioversion showed that digoxin, when used alone, is ineffective in preventing recurrence of the arrhythmia. Interestingly, the data also suggest that digoxin may actually lessen the atrial antiarrhythmic effect of quinidine (12). Heart Rate Control in Paroxysmal Atrial Fibrillation A recent study by Rawles and colleagues (13) has added further evidence regarding the inefficacy of digoxin for preventing paroxysmal atrial fibrillation and for controlling the ventricular response during a paroxysm. These investigators examined 139 episodes of atrial fibrillation occurring during Holter monitoring in 72 patients with paroxysmal atrial fibrillation. Paroxysms of fibrillation clustered during waking hours suggesting that, in most cases, increased sympathetic tone may have been a precipitating factor. The paroxysms of atrial fibrillation were as frequent in patients taking digoxin as in those who were not and, despite adequate serum levels in those receiving the drug, the ventricular response at the onset of a paroxysm did not differ in patients who received digoxin and those who did not. The only difference was that the patients taking the drug had substantially more episodes of fibrillation lasting 30 minutes or longer. This apparent paradox—that digoxin has no effect on controlling ventricular rate in paroxysmal atrial fibrillation yet controls heart rate in chronic atrial fibrillation—can be explained by the high sympathetic tone occurring at the onset of a paroxysm. This state is analogous to exercise in the patient with chronic atrial fibrillation, a situation in which digoxin is minimally effective because the catecholamine release overcomes the vagotonic effect of the drug. Unfortunately, this study only reported the ventricular rates at the onset of episodes of atrial fibrillation, and thus no conclusion can be drawn as to whether digitalized patients developing atrial fibrillation will have a slower heart rate after the initial surge of sympathetic activity (13). Nevertheless, many patients with paroxysmal arrhythmias are most symptomatic from their tachycardia at the beginning of the arrhythmia—the very point at which digoxin has been shown to be ineffective. 574
Profibrillatory Effects Although most cases of atrial fibrillation are probably preceded by normal or heightened sympathetic tone, Coumel (14) has described a subgroup of patients with vagally mediated atrial fibrillation. The onset of the arrhythmia in these patients usually occurs at night or during relaxation and is preceded by a slowing of the sinus rate. Attempts to influence the paroxysms with digoxin in these patients often simply increase their frequency and duration. Occasionally, vagally induced paroxysmal atrial fibrillation in such patients may be converted into sustained arrhythmia by large chronic doses of digoxin. This has even been used therapeutically to avoid the symptoms that occur at the onset of a paroxysm (15). Digoxin and Atrial Fibrillation in the 1990s What then is the role, if any, of digoxin in managing sustained or paroxysmal atrial fibrillation? Some evidence suggests that preoperative digitalization of patients having coronary artery bypass grafting may reduce postoperative atrial fibrillation (16). It is possible that the mild atrial antiarrhythmic effect of digoxin in this subgroup may result from its direct effect on the atrium, because its vagotonic, profibrillatory action could be abolished by the high postoperative sympathetic drive. Not all studies have shown this effect, and other agents may be more effective (16). Many patients with chronic atrial fibrillation, because they are elderly or have cardiac disease, have a sedentary lifestyle. For these patients, a daily dose of digoxin is adequate to control the ventricular rate. Younger, more active patients with chronic arrhythmia may have uncontrolled heart rates during daily activity and should have Holter monitoring to assess their maximum daily heart rates. Exercise testing may also be of value, since an early, excessive rise indicates inadequate rate control. If the heart rate response is excessive, it can be controlled by a beta-blocking or calcium-channel-blocking agent (7-9). Better control of heart rate may sometimes be achieved with the latter class of agents if used in addition to digoxin (8), although verapamil should be used with caution as it may elevate serum digoxin levels (7), and beta blockade may actually decrease exercise tolerance in certain patients (17). For the patient presenting to the emergency department with new-onset atrial fibrillation and a rapid ventricular response, a careful clinical assessment is needed to determine whether there is concomitant congestive heart failure and to assess the degree of urgency for control of the ventricular rate. Oral or intravenous digitalization is still appropriate for the hemodynamically stable patient for whom there is no urgency. However, digoxin will be ineffective if there is associated fever, thyrotoxicosis, hypoxia, acute blood loss, or any other condition in which sympathetic tone is elevated. (A helpful question to ask is, if this patient were in sinus rhythm would he or she have a sinus tachycardia? If the answer is yes, then digoxin alone is unlikely to control the ventricular rate and other methods should be considered.) If more urgent rate control is required
1 April 1991 • Annals of Internal Medicine • Volume 114 • Number 7
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19725/ by a University of California San Diego User on 05/04/2017
but electrical cardioversion is not deemed necessary or is not indicated (for example, in a patient with chronic atrial fibrillation or acute embolic stroke believed to be of cardiac origin), then judicious use of an intravenous calcium-channel blocker or beta blocker is the best therapy (18, 19). An exception to the use of these agents is the patient with the Wolff-Parkinson-White syndrome and pre-excited atrial fibrillation in whom calcium-channel blockers may provoke severe hemodynamic compromise (20) and in whom digoxin may also have deleterious effects (21). For such patients, depending on the degree of urgency, direct-current cardioversion or intravenous procainamide should be strongly considered (22). The data by Rawles and coworkers (13) give clinical credence to the previously described pharmacologic and electrophysiologic effects of digoxin and confirm that the drug is generally ineffective in preventing paroxysmal atrial fibrillation and in controlling ventricular rate at the onset of a paroxysm. In patients with recurrent, refractory paroxysmal atrial fibrillation who are receiving digoxin alone or in combination with an atrial antiarrhythmic drug, it is reasonable to withdraw the digoxin and carefully assess the effect of this withdrawal on the frequency of paroxysms. Occasionally, such action will render a previously partially effective, concomitantly administered, atrial antiarrhythmic agent completely effective. In a patient with congestive heart failure due to systolic dysfunction who also has paroxysmal atrial fibrillation, digoxin may help prevent atrial fibrillation because such paroxysms may be precipitated by worsening of congestive failure, and digoxin has a positive inotropic action. Conclusion The history of digoxin therapy is interesting. Medicine has progressed a long way in the 200 years since William Withering first described the beneficial effects of digitalis leaf in heart failure. It is remarkable that digitalis, and its successor digoxin, have remained so popular for so long. It is perhaps more remarkable that only now are we beginning to realize that some of the firmly held beliefs about the properties of this drug are no more than medical myths rooted in a less scientific age. Although digoxin still has a role in the management of atrial fibrillation, it should no longer occupy center stage. Requests for Reprints: Rodney H. Falk, MD, Section of Cardiology, Talbot 227W, Boston City Hospital, 818 Harrison Avenue, Boston, MA 02118. Current Author Addresses: Dr. Falk: Section of Cardiology, Talbot 227W, Boston City Hospital, 818 Harrison Avenue, Boston, MA 02118.
Dr. Leavitt: Section of Cardiology, West Roxbury VA Hospital, 1400 VFW Parkway, West Roxbury, MA 02132. References 1. Guyatt GH, Sullivan MJ, Fallen EL, et al. A controlled trial of digoxin in congestive heart failure. Am J Cardiol. 1988;61:371-5. 2. Goodman DJ, Rossen RM, Cannom DS, Rider AK, Harrison DC. Effects of digoxin on atrioventricular conduction. Studies in patients with and without cardiac autonomic innervation. Circulation. 1975; 51:251-6. 3. Gillis RA, Quest J A. The role of the nervous system in the cardiovascular effects of digitalis. Pharmacol Rev. 1979;31:19-97. 4. Engel TR, Gonzalez AD. Effects of digitalis on atrial vulnerability. Am J Cardiol. 1978;42:570-6. 5. Beasley R, Smith DA, McHaffie DJ. Exercise heart rates at different serum digoxin concentrations in patients with atrial fibrillation. Br Med J [Clin Res]. 1985;290:9-11. 6. Meyler FL. An "account'' of digitalis and atrial fibrillation. J Am Coll Cardiol. 1985;5(Suppl. A):60A-68A. 7. Klein HO, Kaplinsky E. Digitalis and verapamil in atrial fibrillation and flutter. Is verapamil now the preferred agent? Drugs. 1986;31: 185-97. 8. Roth A, Harrison E, Mitani G, Cohen J, Rahimtoola SH, Elkayam U. Efficacy and safety of medium- and high-dose diltiazem alone and in combination with digoxin for control of heart rate at rest and during exercise in patients with chronic atrial fibrillation. Circulation. 1986; 73:316-24. 9. DiBianco R, Morganroth J, Freitag JA, et al. Effects of nadolol on the spontaneous and exercise-provoked heart rate of patients with chronic atrial fibrillation receiving stable dosages of digoxin. Am Heart J. 1984;108:1121-7. 10. Falk RH, Knowlton AA, Bernard SA, Gotlieb NE, Battinelli NJ. Digoxin for converting recent-onset atrial fibrillation to sinus rhythm. A randomized, double-blinded trial. Ann Intern Med. 1987; 106:503-6. 11. Rosen MR, Wit AL, Hoffman BF. Electrophysiology and pharmacology of cardiac arrhythmias: IV. Cardiac antiarrhythmic and toxic effects of digitalis. Am Heart J. 1975;89:391-9. 12. Grande P, Sonne B, Pedersen A. A controlled study of digoxin and quinidine in patients DC reverted from atrial fibrillation to sinus rhythm. [Abstract]. Circulation. 1986;74:11-101. 13. Rawles JM, Metcalfe MJ, Jennings K. Time of occurrence, duration, and ventricular rate of paroxysmal atrial fibrillation: the effect of digoxin. Br Heart J. 1990;63:225-7. 14. Coumel P. Neurogenic and humoral influences of the autonomic nervous system in the determination of paroxysmal atrial fibrillation. In: Atteul P, Coumel P, Janse MJ, eds. The Atrium in Health and Disease. Mount Kisco, New York: Futura Publishing Co; 1989: 213-32. 15. Kowey PR, DeSilva RA, Lown B. Sustained atrial fibrillation as a rhythm of choice [Abstract]. Circulation. 1979;60(Suppl 2):II-253. 16. Lauer MS, Eagle KA, Buckley MJ, DeSanctis RW. Atrial fibrillation following coronary artery bypass surgery. Prog Cardiovasc Dis. 1989;31:367-78. 17. Atwood JE, Sullivan M, Forbes S, et al. Effect of beta-adrenergic blockade on exercise performance in patients with chronic atrial fibrillation. J Am Coll Cardiol. 1987;10:314-20. 18. Platia EV, Michelson EL, Porterfield JK, Das G. Esmolol versus verapamil in the acute treatment of atrial fibrillation or atrial flutter. Am J Cardiol. 1989;63:925-9. 19. Salerno DM, Dias VC, Kleiger RE, et al. Efficacy and safety of intravenous diltiazem for treatment of atrial fibrillation and atrial flutter. The Diltiazem-Atrial Fibrillation/Flutter Study Group. Am J Cardiol. 1989;63:1046-51. 20. Garratt C, Antoniou A, Ward D, Camm AJ. Misuse of verapamil in pre-excited atrial fibrillation. Lancet. 1989;1:367-9. 21. Sellers TD Jr, Bashore TM, Gallagher JJ. Digitalis in the preexcitation syndrome. Analysis during atrial fibrillation. Circulation. 1977;50:260-7. 22. Wellens HJ, Atie J, Penn OC, Gorgels AP, Brugada P, Smeets JL. Diagnosis and treatment of patients with accessory pathways. Cardiol Clin. 1990;8:503-21.
1 April 1991 • Annals
of Internal
Medicine
• V o l u m e 114 • N u m b e r 7
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19725/ by a University of California San Diego User on 05/04/2017
575
AND
TREATMENT
Digoxin for Atrial Fibrillation: A Drug Whose Time Has Gone? Rodney H. Falk, M D , and Jeffrey I. Leavitt, M D
For over 200 years digitalis compounds have been used to treat atrial fibrillation. The rapid ventricular response to atrial fibrillation is frequently treated with digoxin to produce a controlled heart rate. Digoxin has also been proposed as a treatment for terminating recent-onset atrial fibrillation, for maintaining sinus rhythm after an episode of atrial fibrillation, and as prophylactic therapy in patients with paroxysmal atrial fibrillation to prevent excessive tachycardia during a paroxysm. Perhaps because it has been used for so long, few of these indications have been studied scientifically until recently. Studies now suggest that in patients with atrial fibrillation, digoxin is a poor drug for controlling heart rate during exertion, has little or no effect in terminating the arrhythmia, and may occasionally aggravate paroxysmal atrial fibrillation. Despite adequate digitalization, the heart rate at the onset of a paroxysm of fibrillation in patients receiving the drug does not differ from the heart rate in patients not receiving it. This article discusses the current role of digoxin in the management of patients with chronic, recent-onset, or paroxysmal atrial fibrillation.
Annals of Internal Medicine. 1991;114:573-575.
From Boston City Hospital and Boston University School of Medicine, Boston, Massachusetts. For current author addresses, see end of text.
Atrial fibrillation is perhaps the most common cardiac arrhythmia encountered by both general internists and cardiologists. Depending on its cause, duration, and hemodynamic significance, as well as on the symptomatic state of the patient, the goal of treating atrial fibrillation is either to control the ventricular rate or to terminate the fibrillation. In the latter case, prevention of recurrence becomes an important consideration. Digoxin (and its predecessor, digitalis leaf) is the oldest therapy for atrial fibrillation. Originating from an herbal remedy, the purple foxglove, it has stood the test of time; after more than two centuries of use it is still the most commonly prescribed drug for ventricular rate control in atrial fibrillation. As with many therapies, digoxin's therapeutic use preceded an understanding of the mechanism of its action, and only recently has it been subjected to the rigorous clinical trials required of more modern drugs. Its value in congestive heart failure has been established (1). In contrast, although digoxin is frequently prescribed for atrial fibrillation, few careful studies exist regarding its value in this arrhythmia. We will examine several clinical situations for which digoxin is commonly prescribed: for ventricular rate control in chronic atrial fibrillation; for the termination of
recent-onset atrial fibrillation; and for the prevention of recurrent paroxysms of arrhythmia as well as for rate control should such a recurrence occur. Control of Ventricular Rate in Chronic Atrial Fibrillation Although digoxin does directly affect atrial tissue and the atrioventricular node, its predominant effect is mediated by the autonomic nervous system (2, 3). In the resting digitalized patient, vagal influences on the atrium and atrioventricular node are enhanced and, as a result of the effects on the node, the ventricular rate is slowed. The effect of vagal stimulation on the atrium is more complex, with shortening of the atrial refractory period and increased dispersion of refractoriness. This result is the opposite of digoxin's direct effect on atrial tissue, which causes a mild prolongation of the atrial refractory period and a decrease in the vulnerable zone for provocation of repetitive atrial firing (4). There is no doubt that appropriate doses of digoxin will slow the resting ventricular rate in most patients with chronic atrial fibrillation. Because the drug's predominant effect on the atrioventricular node is mediated by enhanced vagal tone, however, its beneficial effect on the resting heart rate is not always maintained during exertion, a period when vagal influences are withdrawn (5, 6). This may result in excessive tachycardia during normal daily activities manifesting as exertional palpitations, dyspnea, or fatigue. Both low-dose beta blockers (which block the effects of the sympathetic nervous system) and calcium-channel antagonists (which act directly to slow atrioventricular node conduction) may be highly effective in controlling heart rate during exertion. Indeed, in selected patients, such as young patients with normal ventricular function, one or the other of these classes of drugs may be preferable to digoxin monotherapy for atrial fibrillation (7-9). Restoration of Sinus Rhythm A common belief is that digoxin effectively restores sinus rhythm in patients with recent onset of atrial fibrillation. If congestive heart failure due to systolic dysfunction co-exists with recent-onset atrial fibrillation, the combination of digoxin's negative chronotropic and positive inotropic effects may improve hemodynamic variables enough that spontaneous reversion to sinus rhythm occurs. In the absence of congestive heart failure, however, digoxin does not act as an antiarrhythmic drug in the atrium. In a double-blind, randomized, placebo-controlled study of digoxin in recent-onset atrial fibrillation unassociated with congestive heart failure, no benefit was found for digoxin compared with placebo for the conversion of the arrhythmia to sinus ©1991 American College of Physicians
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19725/ by a University of California San Diego User on 05/04/2017
573
rhythm (10). This observation is supported by electrophysiologic evidence, noted above, that digoxin shortens the refractory period of atrial myocardium—an effect that would actually tend to increase fibrillatory rate and, at least theoretically, lessen the possibility of reversion to sinus rhythm (11-14). Maintenance of Sinus Rhythm In clinical practice, patients who have had an episode of paroxysmal atrial fibrillation still commonly receive digoxin during an acute episode. There is a tendency among many physicians to maintain such therapy for a prolonged or indefinite period in the belief that this may prevent recurrence of atrial fibrillation or slow the ventricular response should a recurrence occur. Preliminary retrospective data on the role of digoxin therapy in preventing recurrence of atrial fibrillation after electrical cardioversion showed that digoxin, when used alone, is ineffective in preventing recurrence of the arrhythmia. Interestingly, the data also suggest that digoxin may actually lessen the atrial antiarrhythmic effect of quinidine (12). Heart Rate Control in Paroxysmal Atrial Fibrillation A recent study by Rawles and colleagues (13) has added further evidence regarding the inefficacy of digoxin for preventing paroxysmal atrial fibrillation and for controlling the ventricular response during a paroxysm. These investigators examined 139 episodes of atrial fibrillation occurring during Holter monitoring in 72 patients with paroxysmal atrial fibrillation. Paroxysms of fibrillation clustered during waking hours suggesting that, in most cases, increased sympathetic tone may have been a precipitating factor. The paroxysms of atrial fibrillation were as frequent in patients taking digoxin as in those who were not and, despite adequate serum levels in those receiving the drug, the ventricular response at the onset of a paroxysm did not differ in patients who received digoxin and those who did not. The only difference was that the patients taking the drug had substantially more episodes of fibrillation lasting 30 minutes or longer. This apparent paradox—that digoxin has no effect on controlling ventricular rate in paroxysmal atrial fibrillation yet controls heart rate in chronic atrial fibrillation—can be explained by the high sympathetic tone occurring at the onset of a paroxysm. This state is analogous to exercise in the patient with chronic atrial fibrillation, a situation in which digoxin is minimally effective because the catecholamine release overcomes the vagotonic effect of the drug. Unfortunately, this study only reported the ventricular rates at the onset of episodes of atrial fibrillation, and thus no conclusion can be drawn as to whether digitalized patients developing atrial fibrillation will have a slower heart rate after the initial surge of sympathetic activity (13). Nevertheless, many patients with paroxysmal arrhythmias are most symptomatic from their tachycardia at the beginning of the arrhythmia—the very point at which digoxin has been shown to be ineffective. 574
Profibrillatory Effects Although most cases of atrial fibrillation are probably preceded by normal or heightened sympathetic tone, Coumel (14) has described a subgroup of patients with vagally mediated atrial fibrillation. The onset of the arrhythmia in these patients usually occurs at night or during relaxation and is preceded by a slowing of the sinus rate. Attempts to influence the paroxysms with digoxin in these patients often simply increase their frequency and duration. Occasionally, vagally induced paroxysmal atrial fibrillation in such patients may be converted into sustained arrhythmia by large chronic doses of digoxin. This has even been used therapeutically to avoid the symptoms that occur at the onset of a paroxysm (15). Digoxin and Atrial Fibrillation in the 1990s What then is the role, if any, of digoxin in managing sustained or paroxysmal atrial fibrillation? Some evidence suggests that preoperative digitalization of patients having coronary artery bypass grafting may reduce postoperative atrial fibrillation (16). It is possible that the mild atrial antiarrhythmic effect of digoxin in this subgroup may result from its direct effect on the atrium, because its vagotonic, profibrillatory action could be abolished by the high postoperative sympathetic drive. Not all studies have shown this effect, and other agents may be more effective (16). Many patients with chronic atrial fibrillation, because they are elderly or have cardiac disease, have a sedentary lifestyle. For these patients, a daily dose of digoxin is adequate to control the ventricular rate. Younger, more active patients with chronic arrhythmia may have uncontrolled heart rates during daily activity and should have Holter monitoring to assess their maximum daily heart rates. Exercise testing may also be of value, since an early, excessive rise indicates inadequate rate control. If the heart rate response is excessive, it can be controlled by a beta-blocking or calcium-channel-blocking agent (7-9). Better control of heart rate may sometimes be achieved with the latter class of agents if used in addition to digoxin (8), although verapamil should be used with caution as it may elevate serum digoxin levels (7), and beta blockade may actually decrease exercise tolerance in certain patients (17). For the patient presenting to the emergency department with new-onset atrial fibrillation and a rapid ventricular response, a careful clinical assessment is needed to determine whether there is concomitant congestive heart failure and to assess the degree of urgency for control of the ventricular rate. Oral or intravenous digitalization is still appropriate for the hemodynamically stable patient for whom there is no urgency. However, digoxin will be ineffective if there is associated fever, thyrotoxicosis, hypoxia, acute blood loss, or any other condition in which sympathetic tone is elevated. (A helpful question to ask is, if this patient were in sinus rhythm would he or she have a sinus tachycardia? If the answer is yes, then digoxin alone is unlikely to control the ventricular rate and other methods should be considered.) If more urgent rate control is required
1 April 1991 • Annals of Internal Medicine • Volume 114 • Number 7
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19725/ by a University of California San Diego User on 05/04/2017
but electrical cardioversion is not deemed necessary or is not indicated (for example, in a patient with chronic atrial fibrillation or acute embolic stroke believed to be of cardiac origin), then judicious use of an intravenous calcium-channel blocker or beta blocker is the best therapy (18, 19). An exception to the use of these agents is the patient with the Wolff-Parkinson-White syndrome and pre-excited atrial fibrillation in whom calcium-channel blockers may provoke severe hemodynamic compromise (20) and in whom digoxin may also have deleterious effects (21). For such patients, depending on the degree of urgency, direct-current cardioversion or intravenous procainamide should be strongly considered (22). The data by Rawles and coworkers (13) give clinical credence to the previously described pharmacologic and electrophysiologic effects of digoxin and confirm that the drug is generally ineffective in preventing paroxysmal atrial fibrillation and in controlling ventricular rate at the onset of a paroxysm. In patients with recurrent, refractory paroxysmal atrial fibrillation who are receiving digoxin alone or in combination with an atrial antiarrhythmic drug, it is reasonable to withdraw the digoxin and carefully assess the effect of this withdrawal on the frequency of paroxysms. Occasionally, such action will render a previously partially effective, concomitantly administered, atrial antiarrhythmic agent completely effective. In a patient with congestive heart failure due to systolic dysfunction who also has paroxysmal atrial fibrillation, digoxin may help prevent atrial fibrillation because such paroxysms may be precipitated by worsening of congestive failure, and digoxin has a positive inotropic action. Conclusion The history of digoxin therapy is interesting. Medicine has progressed a long way in the 200 years since William Withering first described the beneficial effects of digitalis leaf in heart failure. It is remarkable that digitalis, and its successor digoxin, have remained so popular for so long. It is perhaps more remarkable that only now are we beginning to realize that some of the firmly held beliefs about the properties of this drug are no more than medical myths rooted in a less scientific age. Although digoxin still has a role in the management of atrial fibrillation, it should no longer occupy center stage. Requests for Reprints: Rodney H. Falk, MD, Section of Cardiology, Talbot 227W, Boston City Hospital, 818 Harrison Avenue, Boston, MA 02118. Current Author Addresses: Dr. Falk: Section of Cardiology, Talbot 227W, Boston City Hospital, 818 Harrison Avenue, Boston, MA 02118.
Dr. Leavitt: Section of Cardiology, West Roxbury VA Hospital, 1400 VFW Parkway, West Roxbury, MA 02132. References 1. Guyatt GH, Sullivan MJ, Fallen EL, et al. A controlled trial of digoxin in congestive heart failure. Am J Cardiol. 1988;61:371-5. 2. Goodman DJ, Rossen RM, Cannom DS, Rider AK, Harrison DC. Effects of digoxin on atrioventricular conduction. Studies in patients with and without cardiac autonomic innervation. Circulation. 1975; 51:251-6. 3. Gillis RA, Quest J A. The role of the nervous system in the cardiovascular effects of digitalis. Pharmacol Rev. 1979;31:19-97. 4. Engel TR, Gonzalez AD. Effects of digitalis on atrial vulnerability. Am J Cardiol. 1978;42:570-6. 5. Beasley R, Smith DA, McHaffie DJ. Exercise heart rates at different serum digoxin concentrations in patients with atrial fibrillation. Br Med J [Clin Res]. 1985;290:9-11. 6. Meyler FL. An "account'' of digitalis and atrial fibrillation. J Am Coll Cardiol. 1985;5(Suppl. A):60A-68A. 7. Klein HO, Kaplinsky E. Digitalis and verapamil in atrial fibrillation and flutter. Is verapamil now the preferred agent? Drugs. 1986;31: 185-97. 8. Roth A, Harrison E, Mitani G, Cohen J, Rahimtoola SH, Elkayam U. Efficacy and safety of medium- and high-dose diltiazem alone and in combination with digoxin for control of heart rate at rest and during exercise in patients with chronic atrial fibrillation. Circulation. 1986; 73:316-24. 9. DiBianco R, Morganroth J, Freitag JA, et al. Effects of nadolol on the spontaneous and exercise-provoked heart rate of patients with chronic atrial fibrillation receiving stable dosages of digoxin. Am Heart J. 1984;108:1121-7. 10. Falk RH, Knowlton AA, Bernard SA, Gotlieb NE, Battinelli NJ. Digoxin for converting recent-onset atrial fibrillation to sinus rhythm. A randomized, double-blinded trial. Ann Intern Med. 1987; 106:503-6. 11. Rosen MR, Wit AL, Hoffman BF. Electrophysiology and pharmacology of cardiac arrhythmias: IV. Cardiac antiarrhythmic and toxic effects of digitalis. Am Heart J. 1975;89:391-9. 12. Grande P, Sonne B, Pedersen A. A controlled study of digoxin and quinidine in patients DC reverted from atrial fibrillation to sinus rhythm. [Abstract]. Circulation. 1986;74:11-101. 13. Rawles JM, Metcalfe MJ, Jennings K. Time of occurrence, duration, and ventricular rate of paroxysmal atrial fibrillation: the effect of digoxin. Br Heart J. 1990;63:225-7. 14. Coumel P. Neurogenic and humoral influences of the autonomic nervous system in the determination of paroxysmal atrial fibrillation. In: Atteul P, Coumel P, Janse MJ, eds. The Atrium in Health and Disease. Mount Kisco, New York: Futura Publishing Co; 1989: 213-32. 15. Kowey PR, DeSilva RA, Lown B. Sustained atrial fibrillation as a rhythm of choice [Abstract]. Circulation. 1979;60(Suppl 2):II-253. 16. Lauer MS, Eagle KA, Buckley MJ, DeSanctis RW. Atrial fibrillation following coronary artery bypass surgery. Prog Cardiovasc Dis. 1989;31:367-78. 17. Atwood JE, Sullivan M, Forbes S, et al. Effect of beta-adrenergic blockade on exercise performance in patients with chronic atrial fibrillation. J Am Coll Cardiol. 1987;10:314-20. 18. Platia EV, Michelson EL, Porterfield JK, Das G. Esmolol versus verapamil in the acute treatment of atrial fibrillation or atrial flutter. Am J Cardiol. 1989;63:925-9. 19. Salerno DM, Dias VC, Kleiger RE, et al. Efficacy and safety of intravenous diltiazem for treatment of atrial fibrillation and atrial flutter. The Diltiazem-Atrial Fibrillation/Flutter Study Group. Am J Cardiol. 1989;63:1046-51. 20. Garratt C, Antoniou A, Ward D, Camm AJ. Misuse of verapamil in pre-excited atrial fibrillation. Lancet. 1989;1:367-9. 21. Sellers TD Jr, Bashore TM, Gallagher JJ. Digitalis in the preexcitation syndrome. Analysis during atrial fibrillation. Circulation. 1977;50:260-7. 22. Wellens HJ, Atie J, Penn OC, Gorgels AP, Brugada P, Smeets JL. Diagnosis and treatment of patients with accessory pathways. Cardiol Clin. 1990;8:503-21.
1 April 1991 • Annals
of Internal
Medicine
• V o l u m e 114 • N u m b e r 7
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19725/ by a University of California San Diego User on 05/04/2017
575
