Control of ventricular rate in atrial fibrillation: Pharmacologic therapy

Sunday, July 19, 2009

The ventricular response to atrial fibrillation (AF) is variable and in certain settings may provide important clinical clues to confounding factors. As an example, there is a circadian rhythm for both AV nodal refractoriness and concealed conduction, accounting for the circadian variation in ventricular response rate [1]. These are attenuated in patients with CHF in whom there is altered autonomic neural control with sympathetic nervous system activation and vagal withdrawal.

In the typical patient with AF, the ventricular rate during the day varies between 90 and 170 beats/min in the absence of atrioventricular (AV) nodal disease, drugs that affect conduction, or high vagal tone as may occur in a well conditioned athlete. In comparison, a ventricular rate below 60 beats/min in the absence of digitalis or some other drug that slows AV conduction suggests AV nodal disease, which is often associated with the sick sinus syndrome. On the other hand, a ventricular rate above 200 beats/min suggests catecholamine excess, parasympathetic withdrawal, or the existence of an accessory bypass tract as occurs in the preexcitation syndrome. The QRS complexes are widened in the latter situation and must be distinguished from a rate related or underlying bundle branch block. (See

"Tachyarrhythmias associated with the Wolff-Parkinson-White syndrome").

Physiologically, the AV node has been called a "slow response" tissue, since the generation of its action potential depends on calcium ions flowing through a kinetically slow channel. The activation and reactivation characteristics of these calcium channels results in normally slow conduction through the AV node. (See "Myocardial action potential and action of antiarrhythmic drugs"). Moreover, the AV node is richly supplied by both components of the autonomic nervous system: the sympathetic nerves increasing and the parasympathetic nerves decreasing AV nodal conduction. These electrophysiologic properties are depicted in Figure 1 (show figure 1). The advent of radiofrequency ablation has permitted a more detailed analysis of the electrophysiologic anatomy of the AV node. This technique established additional anatomic complexity related to the presence of slow and fast input tracts.

The pharmacologic therapies for achieving rate control in AF will be reviewed here. The role of radiofrequency ablation and other nonpharmacologic therapies for rate control of AF and an overview of the management of AF are discussed elsewhere. (See "Control of ventricular rate in atrial fibrillation: Nonpharmacologic therapy" and see "Overview of the presentation and management of atrial fibrillation").

PHARMACOLOGIC TREATMENT – The pharmacologic strategies used to control the ventricular rate in AF by slowing AV nodal conduction are based upon these physiologic mechanisms (show figure 2) [2,3]:

• Further blockade of the calcium channel as occurs with calcium channel antagonists, particularly verapamil and diltiazem.

• Decreased sympathetic tone resulting from beta blockade as produced by short, moderate, and long acting drugs.

• Enhancement of parasympathetic tone with vagotonic drugs, the most important of which are the digitalis glycosides, particularly digoxin.

• A combination of the above.

In general, the calcium antagonists are effective while the patient is at rest and during exercise, digitalis is more effective during rest than with exercise; and beta blockers are more effective during exercise than at rest. In one study of 12 patients with chronic AF, the effect of five different drug regimens (digoxin 0.25 mg daily, diltiazem-CD 240 mg daily, atenolol 50 mg daily, digoxin plus diltiazem, and digoxin plus atenolol) on heart rate were compared [4]. Digoxin plus atenolol was the most effect regimen for controlling the mean ventricular rate during 24 hours and reducing the peak heart rate during exercise; digoxin and diltiazem as single agents were the least effective (show figure 3).

Some patients have either an incomplete response to pharmacologic therapy or intolerable drug-induced side effects. Rarely such a patient will require nonpharmacologic intervention including surgery or radiofrequency AV nodal ablation or modification. (See "Nonpharmacologic strategies to prevent recurrent atrial fibrillation").

Digitalis – Digoxin remains the most widely used drug in the United States to control the ventricular rate in AF, acting primarily by vagotonic inhibition of AV nodal conduction. In one survey of office visits during 1994 to 1996 by patients in AF, 53 percent who were treated with a rate slowing agent were receiving digoxin alone while 15 percent were using a calcium channel blocker and 13 percent a beta blocker [5].

Despite these differences in utilization, digoxin is generally less effective for rate control than beta blockers or calcium channel blockers, is less likely to control the ventricular rate during exercise (when vagal tone is low and sympathetic tone is high), has little or no ability to terminate the arrhythmia, and often does not slow the heart rate with recurrent AF [6,7]. Thus, large doses of digoxin are often required for monotherapy, and patients frequently require the addition of a beta blocker [8-10] or calcium channel blocker for optimal rate control [11,12].

As a result, digoxin should no longer be used as a first-line drug, except for the patient with congestive heart failure [6,7]. In this setting, the increase in cardiac contractility and improvement in hemodynamics will both relieve symptoms of low output and reduce reflex sympathetic activation.

Digoxin can be administered orally, intravenously, or intramuscularly, although we do not use intramuscular injection because the absorption is erratic. (See "Method of digitalization" for a review of dosing regimens). Intravenous digoxin begins to act within 15 to 30 minutes, with a peak effect attained in one to five hours. This relatively slow onset of action may be undesirable in symptomatic patients who have AF and a rapid ventricular response. If such a patient is hemodynamically stable, we may choose to initiate therapy with a fast-acting intravenous calcium channel blocker (verapamil or diltiazem) or an intravenous beta blocker such as esmolol (see below). The simultaneous use of digoxin and esmolol is also effective in this setting [10].

Plasma digoxin levels should be monitored periodically. Although the correlation between drug concentration and ventricular rate control is poor, the presence of a low digoxin level is useful in that it allows a higher dose to be administered.

Junctional escape beats (as detected by the equality of all the longest observed R-R intervals on the electrocardiogram) are common when digitalis has successfully slowed the ventricular rate. Giving more digoxin in this setting will increase the degree of AV nodal block and produce periods of regular junctional rhythm. The change from single junctional escapes to periodic junctional rhythm usually signifies the development of digoxin toxicity. (See "Electrocardiographic and electrophysiologic features of atrial fibrillation-I", section on Effect of high degrees of AV nodal block and exit block on ventricular response for a review of the electrocardiographic manifestations of digitalis toxicity in this setting).

Verapamil – Verapamil increases refractoriness and decreases conduction velocity in the AV node It is therefore useful for reducing the ventricular response to AF [11-18] Although the drug is often used in combination with digoxin, monotherapy with oral verapamil is often possible [16-18].

Intravenous verapamil can be given acutely in a dose of 5 to 10 mg over two to three minutes; this dose can be repeated every 15 to 30 minutes, as necessary. The maintenance infusion rate is approximately 0.125 mg/min. The onset of action is within two minutes and the peak effect occurs in 10 to 15 minutes. Control of the ventricular response is lost in roughly 90 minutes if repeated boluses or a maintenance infusion are not given.

The initial dose of oral verapamil is 40 mg three or four times per day increased to a maximum of 480 mg/day if hepatic function is relatively normal. Side effects are common at this dose. The equivalent dose of sustained release verapamil can be used once per day, but a divided dose often must be used to maintain rate control. With either preparation, it should be remembered that the older patient metabolizes verapamil more slowly and is therefore more likely to develop side effects, especially cardiac,which are often related to the blood level.

Although it slows the ventricular rate, verapamil rarely reverts AF to sinus rhythm. It may also have the following additional actions:

• The effect on sinoatrial (SA) nodal function is variable. Although the drug has a direct effect of the sinus node (which generates a slow action potential mediated by calcium ion fluxes), the vasodilator effect of verapamil causes a reflex release of catecholamines that usually maintains or slightly accelerates the SA nodal rate. However, SA nodal function may be depressed in patients with the sick sinus syndrome, presumably via blockade of calcium channels and an inability of the sinus node to respond to catecholamines. Thus, if the normal reflex mechanism is impaired by therapy with a beta blocker, the addition a calcium channel blocker can lead to slowing or, rarely, failure of SA nodal function.

• Verapamil can produce high degree AV block (with or without underlying AV nodal disease) and therefore should not be given to patients with second or third degree AV block. For similar reasons, verapamil must be used with extreme caution when given with other drugs that slow AV nodal conduction (eg, beta blockers or digoxin).

• Verapamil can paradoxically increase the ventricular response in patients with AF and preexcitation by impairing conduction via the normal AV node-His-Purkinje system and therefore improving antegrade conduction over the accessory pathway.

• Verapamil has a negative inotropic effect. As a result, it should be used with caution in patients with heart failure and should not be given if the patient is hypotensive. It should also be used cautiously with other negative inotropes, such as beta blockers.

• Verapamil interacts with digoxin, resulting in an increase in digoxin levels. This is dose related (often occurring when verapamil doses are over 240 mg/day) and generally occurs after seven days of therapy with both agents. Similar to the digoxin-quinidine interaction, verapamil reduces the renal clearance of digoxin; it may also interfere with its hepatic metabolism [19-21]. (See "Digoxin drug interactions").

Diltiazem – Diltiazem may have a less pronounced negative inotropic effect than verapamil [22] and the intravenous preparation is useful for acute control of the ventricular rate in AF [23-25]. Unlike verapamil, there is an FDA approved regimen for a continuous, 24 hour intravenous infusion. The Diltiazem Atrial Fibrillation/Atrial Flutter Study Group regimen consists of a bolus of 20 mg alone or followed in 15 minutes by another 25 mg followed by a continuous infusion at a rate of 10 to 15 mg/h [24]. This regimen controlled the ventricular rate in 83 percent of patients, usually within four minutes. Oral therapy with diltiazem is also effective for chronic rate control, although the oral drug is not yet approved by the FDA for this indication [26,27]. There is, however, an FDA approved regimen for a continuous intravenous infusion.

In one study, the use of one or two boluses of intravenous diltiazem followed by a continuous infusion was evaluated in 84 consecutive patients with AF, atrial flutter, or both [25]. The first bolus was 20 mg given over two minutes, and, if no therapeutic response was seen (20 percent reduction in heart rate from the baseline, conversion to sinus rhythm, or a heart rate less than 100 beats/min) within 15 minutes, a second bolus of 25 mg was given over two minutes. Continuous infusions of 5, 10 and 15 mg/h were then given to responders, while nonresponders were withdrawn from the study.

• The overall response rate was 94 percent.

• The continuous infusion maintained adequate rate control for 10 hours or longer in a dose-dependent fashion – 47 percent at 5 mg/h; 68 percent after titration to 10 mg/h; and 76 percent after titration to 15 mg/h (show figure 4).

• By the end of infusion, 18 percent had converted to sinus rhythm.

• Hypotension occurred in 13 percent and was symptomatic in almost four percent. All patients responded to isotonic saline.

Diltiazem should be given with similar caution to verapamil in patients with severe congestive heart failure (NYHA class III or IV), although diltiazem is less likely to worsen myocardial function [25]; a history of sinus node disease; second- or third-degree AV block; the preexcitation syndrome since conduction in the accessory pathway may be facilitated; the concurrent intake of other drugs that slow AV conduction; and hypotension (systolic blood pressure less than 90 mmHg).

Esmolol and other beta blockers – Esmolol, a rapidly acting beta blocker that is administered intravenously, is useful for rate control in acute AF either alone or with digoxin [10,28,29]. Esmolol begins to act in one to two minutes, is metabolized by red blood cell esterase, and has a short duration of action of 10 to 20 minutes. A bolus of 0.5 mg/kg is infused over one minute, followed by 50 µg/kg/min for four minutes. If the response is inadequate, another bolus is given followed by an infusion of 100 µg/kg/min for another five minutes. The bolus is repeated and the infusion is increased by 50 µg/kg/min up to a maximum of 200 µg/kg/min. Alternatively, an infusion can be started at 50 µg/kg/min without a bolus, and the rate of administration can be increased by 50 µg/kg/min every 30 minutes.

Metoprolol and propranolol can also be given intravenously. However, these preparations are not always used for acute rate control because they have half-lives that are much longer than esmolol.

Oral beta blockers are widely used as primary therapy for rate control in chronic AF. Beta blockers decrease the resting heart rate and blunt the heart rate response to exercise. However, they may also reduce exercise tolerance [30,31].

Certain types of AF may be triggered by sympathetic surges [32], a setting in which beta blockers may in theory be beneficial. However, bradycardia-dependent or vagally-mediated AF may be more common, and the use of beta blockers may render such an individual more liable to AF by inducing sinus bradycardia.

Despite these potential concerns, beta blockers are used frequently alone or in combination with digoxin or calcium channel blockers for control of the ventricular response in patients with chronic AF.

Beta blockers may have adverse effects with which the clinician should be familiar. Some of these complications may be important in AF including worsening heart failure, hypotension, bronchospasm, and high-degree AV block.

Amiodarone – Amiodarone has been approved by the Food and Drug Administration only for the treatment of life-threatening ventricular arrhythmias. It is, however, quite effective in the treatment of AF and flutter, both for rate control and for maintenance of sinus rhythm after successful cardioversion [33-35]. In one study, for example intravenous amiodarone (7 mg/kg), flecainide, or placebo was given to 98 patients with recent onset AF (0.5 to 72 hours) [35]. Even when AF did not revert to sinus rhythm, amiodarone promptly slowed the ventricular rate during the eight hour observation period (show figure 5).

These beneficial effects on the AV node with slowing of the ventricular rate can be achieved at low doses (200 to 400 mg/day) of amiodarone that minimize its potentially serious toxicity. This agent may be particularly indicated when other AV nodal blocking agents fail to adequately slow the ventricular rate or when these agents are not well tolerated.

RECOMMENDATIONS – The following recommendations should be considered as guidelines for controlling the ventricular response that may need to be amended in individual patients with a particular confounding factor. It should be appreciated, however, that the best therapy of AF may be reversion to and maintenance of normal sinus rhythm. Restoration of sinus rhythm will diminish symptoms and prevent potentially life-threatening thromboembolic events, at the risk of potentially serious complications from antiarrhythmic drugs. Some small trials have compared these two approaches. The data suggest that suggest that both are acceptable and that the choice should be individualized for the needs of the patient. (See "Overview of the presentation and management of atrial fibrillation", section on Rhythm control versus rate control with anticoagulation).

Acute rate control – Intravenous diltiazem, using the regimen and paying attention to the cautions described above, has become our drug of choice, even in patients with heart failure. Intravenous digoxin may also be useful in patients with heart failure. Although intravenous esmolol is also very effective, many patients have contraindications or relatively contraindications to the use of beta blockers. However, the very short half life of esmolol permits a therapeutic trial to be performed at reduced risk. These drugs can be given in combination as indicated.

Amiodarone also appears to be effective for acute control of the ventricular response to AF. However, more studies remain to be performed and amiodarone does not have FDA approval for this indication.

Chronic rate control – Similar considerations apply to chronic control of the ventricular rate (show algorithm 1). A beta blocker or calcium channel blocker is preferred in patients not in heart failure. Beta blockers are often contraindicated or relatively contraindicated, and many patients cannot tolerate the associated decrease in exercise tolerance and other side effects and toxicities. We reserve digoxin for patients with CHF or for those who cannot take or who respond inadequately to one of the other AV nodal blocking agents. The effect of digoxin is additive to both beta blockers and calcium channel blockers.

The choice between a beta blocker or a calcium channel blocker is frequently based upon physician and patient preference, although it may be influenced by other problems that are present. As an example, beta blockers are particularly useful when the ventricular response increases to inappropriately high rates during exercise, after an acute myocardial infarction, and when exercise-induced angina pectoris is also present. On the other hand, a calcium channel blocker is preferred in patients with chronic lung disease. The use of both a beta blocker and calcium channel blocker should be avoided if possible.

Among the beta blockers, atenolol and nadolol have the advantages of a long half-life, and atenolol, in our experience, produces less central nervous system side effects than other beta blockers. Long-acting propranolol and metoprolol preparations are also effective if tolerated. We generally begin with 25 mg of atenolol per day and gradually increase the daily dose to 100 mg, and sometimes 200 mg, if necessary.

Among the calcium channel blockers, verapamil has a somewhat greater blocking effect on the AV node than diltiazem, and the choice between these agents is often dictated by side effects. Diltiazem may be preferred in patients with heart failure.

The use of amiodarone is problematic given existing FDA regulations. There is a feeling, however, that amiodarone may soon be considered the best drug for long-term control of the ventricular response in AF, especially in patients with congestive heart failure. It may also be the best drug for maintaining sinus rhythm after successful cardioversion.

Interventional therapy – Consideration should be given to complete AV ablative therapy and the use of a pacemaker in patients in whom adequate heart rate control cannot be achieved pharmacologically (show algorithm 1). Surgery for the maintenance of normal sinus rhythm is still experimental, and surgical ablation of the AV node or His bundle has no theoretical advantage over radiofrequency catheter ablation. (See "Control of ventricular rate in atrial fibrillation: Nonpharmacologic therapy").

Radiofrequency ablation of one of the AV nodal inputs, modifying but not destroying the AV node, is an alternative. With continued technical improvements, this procedure may become preferred over drugs or complete AV ablation.


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