Role of Calciunl Antagonists for Heart Rate Control in Atrial Fibrillation Kenneth A. Ellenbogen,
Atrlalflbrlllatlonlsoneofthemostcommon sudahmd arrhythmias seen In cll* wwt-k cal practice. Many patiants wRh atrlal flbrlllatlon andaventrkutarresponse > 120 beats/mln will expeWncecardlacsyn#oms.Inthepast,controlofheartratelnthasepatlentswnsktedof admlnlstratlon of hltravenous dl&foxln, bul this oftenprovedtobel llemdlveoillmRedbytoxkRy. Recently, I~kckewssuchasesmololhavebeeausedtoskwtlisventrlcularrate durl~ atrlal arrhythmias, but In some studies thslrusehasbsenH~byhypotenslon.Atternatively, a bolus of.an Intmvenous calcium antagonlst, e.g., dlRlazem or verapamll, may be admlnlsteredtoachleveacuteskwlq#ofthe vantrkular reqwnse. An h&ravenous bolus of dlltlazemorverapamllmaybaeWectlve,butuseof eluler~beIlmttedbyttssholtdulWDllofaCtkn and the4 lnabllRy to admlnlster repeatad boluses to tightly control or ‘%a tune” the heart rate. However, a 7 boliis plus maintenance lnfuslontechnlquewlthdlR&emhasshownpromlse In lnltlal studlss. lt appears that In the future, contlnu~s-technlqueswRhlntravenous caklum aMagonWs will be avallabk that provlds safealrdeMctlvesustalnedcontrolofthsve4+ ttlcular response dum atrlal arrhythmias. (Am JCardlol1992;69:38&-408)
From the Department of Medicine, Medical College of Virginia, and the Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia. This work was supported in part by funds from Marion Merrell Dow Laboratories. Address for reprints: Kenneth A. Ellenbogen, MD, Cardiac Electrophysiology Laboratory, Box 53, MCV Station, Richmond, Virginia 23298. 368
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69
MD
A
trial fibrillation is the most commonly occurring sustained cardiac arrhythmia een in general clinical practice. Its overall prevalence varies with the age of the population studied, as well as the incidence of underlying heart disease. For example, with increasing age, the prevalence of atria1 fibrillation rises to 2-4% in patients over the age of 70.’ Its prevalence is increased as well among individuals with hypertension and structural heart disease, particularly those patients with mitral valvular disease and cardiomyopathies.* Treatment of atria1 fibrillation has 3 central goals. The first goal of treatment is to control the ventricular response when necessary. In about 6040% of patients with atria1 fibrillation, a rapid ventricular response is observed, and symptoms are usually present, depending on the length of time the arrhythmia is sustained and the presence and type of underlying heart disease. When the ventricular response is controlled in patients with atria1 fibrillation, the second goal of treatment becomes whether to treat with antiarrhythmic agents or electrical cardioversion to restore sinus rhythm. There are several new antiarrhythmic agents available (e.g., flecainide, propafenone) for the prevention of recurrent atria1 fibrillation and the maintenance of sinus rhythm. Finally, the third goal of treatment in atria1 fibrillation is to administer anticoagulants for prevention of embolic events. Several studies have shown the importance of warfarin or aspirin for prevention of embolic events in patients with atria1 fibrillation. A discussion of these aspects of the management of atria1 fibrillation is beyond the scope of this article; however, I will review the role of calcium antagonists and other agents for the control of heart rate during atria1 fibrillation. RATE DElERMlNATlON
During atria1 fibrillation, hemodynamic compromise may occur as a result of multiple factors. First, the sudden increase in ventricular rate prevents adequate filling of the left ventricle during diastole. MARCH 6, 1992
In addition, as ventricular rate increases, diastolic filling time decreases, and, consequently there is less time available for coronary blood flow. To quantitate these factors better, aortic blood flow was measured by continuous-wave Doppler examination in 60 patients with chronic atria1 fibrillation.3 The patient population was heterogeneous, one half with idiopathic atria1 fibrillation and one half with organic heart disease (mitral valve disease, coronary artery disease, or other organic heart disease). The ventricular rate was considered “controlled” when the slope of the ratio of cardiac output/ventricular rate was positive, and “uncontrolled” when the slope was negative (e.g., by decreasing the ventricular response, there is an increase in cardiac output). In this study, ventricular rate was controlled in all patients when the ventricular rate was ~90 beats/min and uncontrolled in every case when the ventricular rate was > 140 beats/min. At heart rates of 90-140 beats/min, the ventricular response was controlled in about 70% of patients and uncontrolled in about 30% of patients. Second, in patients with coronary artery disease, the increased heart rate during atria1 arrhythmias leads to an increase in oxygen demand and thus often causes an exacerbation of angina. Finally, there is a loss of the “atria1 kick,” which contributes variably to cardiac output. In patients with normal or hypertrophic left ventricles (e.g., relatively small ventricular volumes), loss of atria1 contraction may lead to a 25-30% decrease in cardiac output. On the other hand, in patients with moderate to severe left ventricular function defects, cardiac output is less dependent on the atria1 contribution to ventricular filling, and cardiac output may decrease by only 5-15% (Table I).
For > 200 years, digoxin has been the mainstay of the management of patients with a rapid ventricular response during atria1 fibrillation.4 Digoxin can be administered intravenously and has an elimination half-life of 1.5-3 hours. Digoxin is not given as a constant intravenous infusion, and it is difficult to titrate the dose acutely to achieve a predictable heart rate response. In fact, digoxin has a narrow therapeutic window and displays significant interactions with other drugs used to treat atria1 fibrillation (e.g., verapamil, quinidine, procainamide), making its administration problematic in some clinical circumstances. Finally, during acute illness or stress resulting in heightened sympathetic tone, even high doses of digoxin may be
TABLE I Pathophysiology Fibrillation
of Symptoms
During Atrial
Decreased diastolic filling time Decreased diastolic coronary perfusion time Exacerbation of angina due to increased oxygen demand (e.g., secondary to increased heart rate) Loss of atrial contribution to ventricular filling
insufficient to control the ventricular response.’ These facts have led some to conclude that the acute use of intravenous digoxin for ventricular rate control in atria1 fibrillation/flutter is rarely indicated, even after decades of use for this purpose.6 Beta blockers may be administered intravenously for control of the ventricular response during atria1 fibrillation/atria1 flutter.’ Esmolol is a B1 selective blocking agent with an elimination half-life of 9 minutes and has been approved by the Federal Drug Administration (FDA) for control of the ventricular response during atria1 fibrillation. In an open-label study comparing the efficacy of esmolol to verapamil for controlling the ventricular response in 45 patients with new-onset atria1 fibrillation/flutter, heart rate control was similar in both groups.’ Both verapamil and esmolol resulted in a heart rate reduction of about 28% (for esmolol from 139 to 100 beats/min and for verapamil from 142 to 97 beats/min). Symptomatic hypotension occurred in about &lo% of both treatment groups, whereas a decrease in systolic blood pressure to
Atrlalflbrlllatlonlsoneofthemostcommon sudahmd arrhythmias seen In cll* wwt-k cal practice. Many patiants wRh atrlal flbrlllatlon andaventrkutarresponse > 120 beats/mln will expeWncecardlacsyn#oms.Inthepast,controlofheartratelnthasepatlentswnsktedof admlnlstratlon of hltravenous dl&foxln, bul this oftenprovedtobel llemdlveoillmRedbytoxkRy. Recently, I~kckewssuchasesmololhavebeeausedtoskwtlisventrlcularrate durl~ atrlal arrhythmias, but In some studies thslrusehasbsenH~byhypotenslon.Atternatively, a bolus of.an Intmvenous calcium antagonlst, e.g., dlRlazem or verapamll, may be admlnlsteredtoachleveacuteskwlq#ofthe vantrkular reqwnse. An h&ravenous bolus of dlltlazemorverapamllmaybaeWectlve,butuseof eluler~beIlmttedbyttssholtdulWDllofaCtkn and the4 lnabllRy to admlnlster repeatad boluses to tightly control or ‘%a tune” the heart rate. However, a 7 boliis plus maintenance lnfuslontechnlquewlthdlR&emhasshownpromlse In lnltlal studlss. lt appears that In the future, contlnu~s-technlqueswRhlntravenous caklum aMagonWs will be avallabk that provlds safealrdeMctlvesustalnedcontrolofthsve4+ ttlcular response dum atrlal arrhythmias. (Am JCardlol1992;69:38&-408)
From the Department of Medicine, Medical College of Virginia, and the Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia. This work was supported in part by funds from Marion Merrell Dow Laboratories. Address for reprints: Kenneth A. Ellenbogen, MD, Cardiac Electrophysiology Laboratory, Box 53, MCV Station, Richmond, Virginia 23298. 368
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69
MD
A
trial fibrillation is the most commonly occurring sustained cardiac arrhythmia een in general clinical practice. Its overall prevalence varies with the age of the population studied, as well as the incidence of underlying heart disease. For example, with increasing age, the prevalence of atria1 fibrillation rises to 2-4% in patients over the age of 70.’ Its prevalence is increased as well among individuals with hypertension and structural heart disease, particularly those patients with mitral valvular disease and cardiomyopathies.* Treatment of atria1 fibrillation has 3 central goals. The first goal of treatment is to control the ventricular response when necessary. In about 6040% of patients with atria1 fibrillation, a rapid ventricular response is observed, and symptoms are usually present, depending on the length of time the arrhythmia is sustained and the presence and type of underlying heart disease. When the ventricular response is controlled in patients with atria1 fibrillation, the second goal of treatment becomes whether to treat with antiarrhythmic agents or electrical cardioversion to restore sinus rhythm. There are several new antiarrhythmic agents available (e.g., flecainide, propafenone) for the prevention of recurrent atria1 fibrillation and the maintenance of sinus rhythm. Finally, the third goal of treatment in atria1 fibrillation is to administer anticoagulants for prevention of embolic events. Several studies have shown the importance of warfarin or aspirin for prevention of embolic events in patients with atria1 fibrillation. A discussion of these aspects of the management of atria1 fibrillation is beyond the scope of this article; however, I will review the role of calcium antagonists and other agents for the control of heart rate during atria1 fibrillation. RATE DElERMlNATlON
During atria1 fibrillation, hemodynamic compromise may occur as a result of multiple factors. First, the sudden increase in ventricular rate prevents adequate filling of the left ventricle during diastole. MARCH 6, 1992
In addition, as ventricular rate increases, diastolic filling time decreases, and, consequently there is less time available for coronary blood flow. To quantitate these factors better, aortic blood flow was measured by continuous-wave Doppler examination in 60 patients with chronic atria1 fibrillation.3 The patient population was heterogeneous, one half with idiopathic atria1 fibrillation and one half with organic heart disease (mitral valve disease, coronary artery disease, or other organic heart disease). The ventricular rate was considered “controlled” when the slope of the ratio of cardiac output/ventricular rate was positive, and “uncontrolled” when the slope was negative (e.g., by decreasing the ventricular response, there is an increase in cardiac output). In this study, ventricular rate was controlled in all patients when the ventricular rate was ~90 beats/min and uncontrolled in every case when the ventricular rate was > 140 beats/min. At heart rates of 90-140 beats/min, the ventricular response was controlled in about 70% of patients and uncontrolled in about 30% of patients. Second, in patients with coronary artery disease, the increased heart rate during atria1 arrhythmias leads to an increase in oxygen demand and thus often causes an exacerbation of angina. Finally, there is a loss of the “atria1 kick,” which contributes variably to cardiac output. In patients with normal or hypertrophic left ventricles (e.g., relatively small ventricular volumes), loss of atria1 contraction may lead to a 25-30% decrease in cardiac output. On the other hand, in patients with moderate to severe left ventricular function defects, cardiac output is less dependent on the atria1 contribution to ventricular filling, and cardiac output may decrease by only 5-15% (Table I).
For > 200 years, digoxin has been the mainstay of the management of patients with a rapid ventricular response during atria1 fibrillation.4 Digoxin can be administered intravenously and has an elimination half-life of 1.5-3 hours. Digoxin is not given as a constant intravenous infusion, and it is difficult to titrate the dose acutely to achieve a predictable heart rate response. In fact, digoxin has a narrow therapeutic window and displays significant interactions with other drugs used to treat atria1 fibrillation (e.g., verapamil, quinidine, procainamide), making its administration problematic in some clinical circumstances. Finally, during acute illness or stress resulting in heightened sympathetic tone, even high doses of digoxin may be
TABLE I Pathophysiology Fibrillation
of Symptoms
During Atrial
Decreased diastolic filling time Decreased diastolic coronary perfusion time Exacerbation of angina due to increased oxygen demand (e.g., secondary to increased heart rate) Loss of atrial contribution to ventricular filling
insufficient to control the ventricular response.’ These facts have led some to conclude that the acute use of intravenous digoxin for ventricular rate control in atria1 fibrillation/flutter is rarely indicated, even after decades of use for this purpose.6 Beta blockers may be administered intravenously for control of the ventricular response during atria1 fibrillation/atria1 flutter.’ Esmolol is a B1 selective blocking agent with an elimination half-life of 9 minutes and has been approved by the Federal Drug Administration (FDA) for control of the ventricular response during atria1 fibrillation. In an open-label study comparing the efficacy of esmolol to verapamil for controlling the ventricular response in 45 patients with new-onset atria1 fibrillation/flutter, heart rate control was similar in both groups.’ Both verapamil and esmolol resulted in a heart rate reduction of about 28% (for esmolol from 139 to 100 beats/min and for verapamil from 142 to 97 beats/min). Symptomatic hypotension occurred in about &lo% of both treatment groups, whereas a decrease in systolic blood pressure to
