Control of ventricular rate in atrial flutter

INTRODUCTION — Atrial flutter is a relatively common supraventricular arrhythmia characterized by rapid, regular atrial depolarizations at a characteristic rate around 300 beats/min and a regular ventricular rate corresponding to one-half or one-quarter of the atrial rate (150 or 75 beats/minute). It may remain as atrial flutter, it may degenerate into atrial fibrillation, or it may revert to sinus rhythm within hours or days. In patients who present with or who have recurrent episodes associated with a rapid ventricular rate, slowing of the rate may be necessary to either reduce symptoms or prevent tachycardia-mediated cardiomyopathy.

For the purpose of this topic, rate control means lowering the heart rate, which in the case of atrial flutter is usually difficult to achieve. Thus, for many patients, radiofrequency ablation (and permanent restoration of sinus rhythm) is the preferred long-term approach to patients with atrial flutter. (See "Atrial flutter: Maintenance of sinus rhythm", section on 'RF catheter ablation'.)

The physiologic and clinical rationales for ventricular rate control in atrial flutter and the modalities used to achieve this goal will be reviewed here. Other issues such as the causes of atrial flutter, the embolic risk associated with this arrhythmia, and the restoration and maintenance of sinus rhythm are discussed separately. (See "Overview of atrial flutter" and "Restoration of sinus rhythm in atrial flutter" and "Embolic risk and the role of anticoagulation in atrial flutter" and "Atrial flutter: Maintenance of sinus rhythm".)

PHYSIOLOGIC BASIS FOR THERAPY — The ventricular rate in atrial flutter is principally determined by the rate at which impulses exit the atrioventricular (AV) node. With a regular atrial rate of 300 beats/min, the ventricular rate is usually about 150 beats/min. This ventricular rate is determined by the refractory period of a healthy AV node, such that every other impulse (2:1) traverses the AV node and travels to the ventricles. In the absence of drugs that slow AV nodal conduction, a higher degree of AV block (eg, 3:1 or 4:1) suggests AV nodal disease; in these settings, the ventricular rates would be roughly 100 and 75 beats/min, respectively.

Even input/output ratios (eg, 2:1 or 4:1 conduction) are more common than odd ratios (eg, 3:1 or 5:1). Odd ratios probably reflect bilevel block in the AV node. Sometimes, variable conduction may occur with alternating or seemingly random patterns of 2:1, 3:1, 4:1, or other conduction patterns, again due to varying levels of block in the AV node. On the other hand, a 1:1 response with typical atrial flutter usually suggests possible hyperthyroidism, catecholamine excess, parasympathetic withdrawal, or the existence of an accessory bypass tract. (See "Anatomy, pathophysiology, and localization of accessory pathways in the preexcitation syndrome".)

An important exception can occur in patients taking antiarrhythmic drugs, which can slow the atrial flutter rate so that 1:1 conduction occurs. This occurs most commonly with the class IC drugs, particularly when used in the absence of concomitant AV nodal blocking agents, but can also occur with dronedarone or even amiodarone. Also, 1:1 conduction of "slow" atrial flutter can occur in patients with marked right atrial enlargement.

The AV node has been called a "slow response" tissue, since its action potential depends on calcium ions flowing through kinetically slow channels (figure 1). The activation and reactivation characteristics of these channels limit the rate of conduction through the AV node. The autonomic nervous system can modify the rate of conduction, which is increased by sympathetic activity and reduced by parasympathetic activity.

It is useful to consider the electrophysiologic differences between atrial fibrillation and atrial flutter, since they can impact therapy:

●Atrial fibrillation is characterized by multiple wandering wavelets, which result in the AV node being bombarded by 400 to 600 impulses per minute. Some impulses traverse the AV node and reach the specialized infranodal conduction system and then the ventricles. However, most of the atrial impulses penetrate the AV node for varying distances and then are extinguished by encountering the refractoriness of an earlier wavefront; this phenomenon of concealed conduction in turn creates a refractory wave that affects succeeding impulses. The lack of shortening of the refractory period with increasing rate (as occurs in the atria) further decreases the likelihood of an impulse traversing the AV node. (See "The electrocardiogram in atrial fibrillation".)

●In comparison, typical atrial flutter is a macroreentrant arrhythmia, resulting in approximately 300 impulses/min reaching the AV node. This slower rate produces less refractoriness within the AV node and therefore less concealed conduction than in atrial fibrillation.

Based upon these observations, it would be expected that atrial fibrillation would be more sensitive than atrial flutter to drugs that affect AV nodal refractoriness; this prediction has been confirmed clinically. Stated another way, control of the ventricular rate in atrial flutter is more difficult than in atrial fibrillation. (See 'Rate control with drugs' below.)

INDICATIONS FOR RATE CONTROL — There are three principle situations in which rate control should be considered:

●Immediate rate control to reduce symptoms during a first or subsequent episode in which a patient has not reverted to sinus rhythm (or spontaneously converted to atrial fibrillation); cardioversion should be considered, as it has a high likelihood of success. (See "Restoration of sinus rhythm in atrial flutter", section on 'Indications'.)

It should be kept in mind that acute rate control in asymptomatic/minimally symptomatic patients with atrial flutter rarely works in the absence of coincident atrioventricular node disease. In the majority of patients, we focus on restoring sinus rhythm with cardioversion.

●Chronic therapy to prevent symptoms in patients who are likely to have recurrent atrial flutter and are not scheduled to undergo radiofrequency ablation of the atrial flutter. (See "Atrial flutter: Maintenance of sinus rhythm", section on 'RF catheter ablation'.)

●Chronic therapy to prevent tachycardia-mediated cardiomyopathy (see "Arrhythmia-induced cardiomyopathy") in the uncommon patient with chronic atrial flutter who does not undergo radiofrequency ablation of the atrial flutter.

●Atypical atrial flutter may result after an atrial fibrillation ablation procedure. Frequently, these patients may be more symptomatic with faster heart rates than when in atrial fibrillation. It may be difficult to rate control these patients, and antiarrhythmic agents, cardioversion, and/or atrial flutter ablation are frequently necessary. (See "Atrial fibrillation: Catheter ablation", section on 'Arrhythmic complications'.)

The following two characteristics of atrial flutter render the need to decide about the initiation of rate slowing uncommon:

●Atrial flutter may be an electrically unstable rhythm, meaning that it may degenerate into the less organized atrial fibrillation or revert to sinus rhythm within hours or days. Spontaneous reversion of paroxysmal atrial flutter to a sinus mechanism may occur after predisposing problems are improved, such as decompensated heart failure and the sequelae of cardiac surgery.

●Persistent atrial flutter is less common than persistent atrial fibrillation and is frequently associated with structural heart disease, atrial enlargement, prior cardiac surgery or atrial fibrillation ablation, or congenital heart disease. In these patients, chronic therapy to control the ventricular response is generally difficult unless there is concomitant atrioventricular (AV) node dysfunction.

●Atrial flutter, particularly the typical cavotricuspid-isthmus-dependent variety, is usually curable with catheter ablation. If patients have both atrial flutter and fibrillation, ablation of the cavotricuspid isthmus will not necessarily eliminate recurrent atrial fibrillation. This strategy may still be useful in selected patients in whom rapid rates during atrial flutter are highly symptomatic, but episodes of atrial fibrillation are well tolerated.

RATE CONTROL GOALS — Although rate control targets have been described for atrial fibrillation [1], they are less useful in atrial flutter since, as noted above, atrioventricular block tends to go in steps (eg, 2:1, 3:1, and 4:1). For most patients, we believe a ventricular rate at rest of less than 80 beats/min is reasonable for symptomatic patients and less than 110 beats/min may be reasonable for asymptomatic patients with normal left ventricular systolic function. Rate control should be assessed both at rest and with exertion.

RATE CONTROL WITH DRUGS — The goal of therapy with drugs that slow atrioventricular (AV) conduction is to improve symptoms and prevent the development of a tachycardia-mediated cardiomyopathy. For patients who require immediate rate slowing, and for whom cardioversion (and the restoration of sinus rhythm) is not chosen, we prefer intravenous diltiazem or esmolol to other options. For patients who will be placed on long-term oral therapy for rate control, we prefer either diltiazem or verapamil.

The rate at which impulses from the atria exit the AV node is the principle determinant of the ventricular rate. (See 'Physiologic basis for therapy' above.) Thus, rate control in atrial flutter is achieved principally with drugs that slow conduction through the AV node.

The pharmacologic agents for controlling the ventricular rate in atrial flutter are based as follows:

●Blockade of the calcium channel with the nondihydropyridine calcium channel blockers diltiazem and verapamil.

●Decrease sympathetic tone using beta-blockers.

●Enhancement of parasympathetic tone with vagotonic drugs, most frequently digoxin.

●The use of amiodarone, which slows AV nodal conduction and increases AV nodal refractoriness.

However, as discussed above, the smaller amount of concealed conduction in the AV node because of the slower atrial rate in atrial flutter means that greater AV nodal refractoriness must be produced. As a result, higher doses of a single drug are required, and combination therapy at conventional doses is frequently needed to minimize toxicity. Difficulties with pharmacologic rate control make patients with atrial flutter excellent candidates for a catheter ablation procedure, which is often curative. (See "Atrial flutter: Maintenance of sinus rhythm", section on 'RF catheter ablation'.)

Nonpharmacologic therapy to convert back to normal sinus rhythm including direct current cardioversion, pace termination, or catheter ablation are reasonable treatments if the patient is having adverse hemodynamic consequences from the arrhythmia, if pharmacologic therapies are unsuccessful or not tolerated, or if the patient has pre-excitation syndrome.

Calcium channel blockers — The nondihydropyridine calcium channel blockers diltiazem and verapamil may be useful for acute rate control in non-pre-excited atrial flutter when given intravenously and can produce long-term rate slowing when given orally (see "Major side effects and safety of calcium channel blockers" and "Calcium channel blockers in the treatment of cardiac arrhythmias" and "Calcium channel blockers in the treatment of cardiac arrhythmias", section on 'Atrial fibrillation and flutter'):

●Diltiazem – Intravenous diltiazem is often the drug of choice for acutely controlling the rapid ventricular response in atrial flutter [2-4]. Diltiazem increases AV nodal refractoriness and slows conduction velocity in the AV node, thereby decreasing the ventricular response. Diltiazem has a less pronounced negative inotropic effect than verapamil [5].

There is a Food and Drug Administration-approved regimen for a continuous 24-hour intravenous diltiazem infusion [2-4]. This regimen consists of an intravenous bolus of 0.25 mg/kg (average adult dose 20 mg) over two minutes followed 15 minutes later by a second bolus of 0.35 mg/kg (average adult dose 25 mg) over two minutes if the first dose is tolerated but does not produce the desired response (20 percent reduction in heart rate from the baseline, conversion to sinus rhythm, or a heart rate less than 100 beats/min); this is followed by a continuous infusion at a rate of 10 to 15 mg/h in responders but not nonresponders; some patients respond to a 5 mg/h infusion [4]. This regimen usually controls the ventricular rate within four to five minutes [2].

Oral diltiazem is used far more commonly than verapamil for chronic rate control. Monotherapy with oral diltiazem can be used to treat patients with persistent atrial flutter, as well as patients who have recurrent or persistent atrial fibrillation with episodic atrial flutter. The initial dose is 30 mg every six hours, and is increased to a maximum of 360 mg/day. Sustained release diltiazem is most commonly used as a once a day drug.

●Verapamil – Intravenous verapamil is very rarely used for acute control. Its use is associated with a higher frequency of hypotension than that with diltiazem.

Verapamil, like diltiazem, increases refractoriness and decreases conduction velocity in the AV node, leading to reductions in the ventricular response in atrial flutter [6-10]. 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 5 mg/hour. 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.

Similar to diltiazem, oral verapamil may be used to treat patients with persistent atrial flutter or patients with recurrent or persistent atrial fibrillation who have episodic atrial flutter. The initial dose of oral verapamil is 40 to 80 mg every six hours. This dose can be increased to a maximum of 360 mg/day if hepatic function is relatively normal. The sustained-release formulation is used for chronic therapy.

Clinical cautions — Diltiazem and verapamil should not be given to patients with severe heart failure (New York Heart Association class III or IV) and should be given with caution to patients with sinus node dysfunction, second- or third-degree AV block, the pre-excitation syndrome, hypotension, or the concurrent intake of other drugs that inhibit sinoatrial (SA) nodal function or slow AV nodal conduction.

Calcium channel blockers have a number of characteristics that need to be considered when they are administered to patients with atrial flutter:

●The effect on SA nodal function is variable, which is important if the patient has paroxysmal atrial flutter with episodes of normal sinus rhythm also. Although both verapamil and diltiazem have an inhibitory effect on the sinus node (which generates a slow action potential mediated by calcium fluxes), their vasodilator effects cause a reflex release of catecholamines that can maintain or slightly accelerate the SA nodal rate. However, SA nodal function is depressed in patients with the sinus node dysfunction, at least in part due to 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 of a calcium channel blocker can lead to slowing or, rarely, failure of SA nodal function. (See "Sinus node dysfunction: Epidemiology, etiology, and natural history".)

●Both drugs (verapamil perhaps more than diltiazem) can produce high-degree AV block and therefore should not be given to patients with underlying second- or third-degree AV block. For similar reasons, calcium channel blockers must be used with caution when given with other drugs that slow AV nodal conduction (eg, beta blockers, digoxin).

●Verapamil has a negative inotropic effect that is more pronounced than that of diltiazem. 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 serum digoxin. This interaction 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 [11-13].

Beta blockers — There is little literature on the use of intravenous or oral beta blockers (excluding esmolol) as primary therapy for atrial flutter. Anecdotal reports suggest that these drugs can slow the ventricular rate, particularly if given in combination with digoxin or diltiazem.

Among the beta blockers, atenolol and nadolol have the advantage of a long half-life, and atenolol, in our experience, has the least adverse effect on the sensorium. Long-acting propranolol and metoprolol preparations are also effective. We generally begin with atenolol, 25 mg/day, and increase the daily dose to 100 mg and sometimes 200 mg if necessary. Beta blockers are particularly useful for patients who also have coronary artery disease or chronic heart failure.

Beta blockers may have a variety of adverse effects. Some of these complications may be important in patients with atrial flutter, including worsening heart failure, hypotension, bradycardia, bronchospasm, and high-degree AV block. (See "Major side effects of beta blockers".)

●Esmolol – Esmolol, a rapidly acting beta blocker with additional electrophysiologic properties, is administered intravenously, and is useful for rate control in acute non-pre-excited atrial flutter [14,15]. Esmolol is preferred to other intravenous beta blockers in this setting due to its rapid onset of action and a greater clinical experience. 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. The following esmolol regimen is recommended for acute rate control:

●A bolus of 0.5 mg/kg is infused over one minute, followed by 50 mcg/kg per min

●If, after four minutes, the response is inadequate, another bolus is given followed by an infusion of 100 mcg/kg per min.

●If, after four minutes, the response is still inadequate, a third and final bolus can be given followed by an infusion of 150 mcg/kg per min.

●If necessary, the infusion can be increased to a maximum of 200 mcg/kg per min after another four minutes

Alternatively, an infusion can be started at 50 mcg/kg per min without a bolus, and the rate of administration can be increased by 50 mcg/kg per min every 30 minutes.

Digoxin — Digoxin historically was the most commonly used drug to control the ventricular rate in atrial flutter in the nonemergent setting. However, calcium channel blockers and beta blockers, singly or in combination, have largely supplanted digoxin for both initial intravenous rate control and chronic oral therapy.

The use of digoxin for the treatment of heart failure is discussed separately. (See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Optional therapies'.)

We generally reserve digoxin for patients whose rate has not adequately been controlled with the use of a calcium channel blocker, a beta blocker, or both. It is not as effective as these two categories of drug, and its use is associated with higher mortality in patients at higher digoxin levels. It may not be appropriate for use in older patients. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".)

Digoxin can be administered orally, intravenously, or intramuscularly, although we do not use the intramuscular route because absorption is erratic. Intravenous digoxin begins to act within 15 to 30 minutes, with a peak effect attained in one to five hours. The relatively slow onset of action of digoxin is undesirable in patients with a rapid ventricular response. Since digoxin has a slow onset of action, there is rarely a reason for parenteral administration in patients who can take oral medications.

A larger dose of digoxin than used in atrial fibrillation is required to control the ventricular rate in atrial flutter; as noted above, the smaller amount of concealed conduction in the AV node because of the slower atrial rate in atrial flutter means that greater AV nodal refractoriness must be produced [16]. Serum digoxin levels should be monitored periodically in patients on persistent therapy. Although the correlation between drug concentration and ventricular rate control is poor, the presence of a low value is useful since it allows a higher dose to be administered. The use of high doses of digoxin is potentially hazardous if electric cardioversion is performed, since this combination increases the risk of serious ventricular arrhythmias.

Junctional escape beats (as detected by similarity of the longest observed recurring R-R intervals on the electrocardiogram [ECG]) are common when digoxin has successfully slowed the ventricular rate. Giving additional 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 suggests the development of digoxin toxicity. If the pulse is palpated but ECG not reviewed, it may be mistakenly assumed that the patient is in sinus rhythm.

However, it may be difficult to distinguish on the ECG between digoxin-induced complete heart block during atrial flutter and a slow, regular ventricular rate. In complete heart block, the R-R interval will not be an exact multiple of the atrial cycle length (A-A interval). In addition, the relationship between the QRS complex and flutter wave (ie, the point on the flutter wave where the QRS complex begins) is variable during complete heart block.

Amiodarone — Amiodarone can be used for rate control, but it should be remembered that intravenous amiodarone can possibly promote reversion to sinus rhythm, albeit infrequently. Since cardioversion is associated with an increased risk of thromboembolism, amiodarone should generally not be used in patients who are not candidates for conversion to sinus rhythm because of inadequate anticoagulation. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation" and "Atrial fibrillation: Cardioversion", section on 'Less effective or ineffective drugs' and "Atrial fibrillation: Cardioversion", section on 'Specific antiarrhythmic drugs'.)

Intravenous amiodarone slows conduction through the AV node and prolongs the effective refractory period of the AV node [17]. It has been used for rate control in critically ill patients with atrial tachyarrhythmias, mostly atrial fibrillation with some cases of atrial flutter [18,19]. This includes patients with heart failure, since amiodarone has less negative inotropic activity than beta blockers or calcium channel blockers [20]. (See "The management of atrial fibrillation in patients with heart failure".)

The efficacy of slowing of the ventricular rate with amiodarone and diltiazem was compared in a study of 60 critically ill patients with recent onset atrial tachyarrhythmias, almost all atrial fibrillation [19]. Amiodarone was given as a 300 mg bolus, with or without a continuous infusion of 45 mg/h for 24 hours. Diltiazem was given as a 25 mg bolus, followed by a continuous infusion of 20 mg/h for 24 hours. Rate control was achieved with both drugs; the degree of slowing was somewhat better with diltiazem, an effect that was offset by a significantly higher incidence of hypotension that required discontinuation of diltiazem.

Amiodarone may promote the appearance of "slow" atrial flutter in patients with atrial tachyarrhythmia. However, 1:1 AV conduction is generally not a problem in this setting due to the inhibitory effect of amiodarone on AV nodal conduction.

In summary, amiodarone is an alternative rate control agent in patients with atrial flutter and severe hemodynamic compromise, although it has not been approved by the United States Food and Drug Administration for this purpose. Because of the long-term risk of adverse effects, amiodarone is generally not recommended for persistent rate control in patients with atrial flutter. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".)

RADIOFREQUENCY ABLATION OF THE ATRIOVENTRICULAR NODE — Radiofrequency ablation of the AV junction (AV node and/or His bundle) is uncommonly performed in patients with pure atrial flutter because of the high rate of success with radiofrequency ablation of the re-entrant circuit, which maintains sinus rhythm [21,22]. The main indication for AV junction ablation is in patients with atrial flutter who have coincident atrial fibrillation. (See "Atrial flutter: Maintenance of sinus rhythm", section on 'RF catheter ablation'.)

PATIENTS WITH PRE-EXCITATION SYNDROME — Among patients with atrial flutter and pre-excitation, therapy is aimed at reversion to sinus rhythm and subsequent treatment of the accessory pathway rather than rate control. The atrioventricular (AV) nodal blocking drugs (calcium channel blockers, beta blockers, and digoxin) can paradoxically increase the ventricular response in patients with atrial flutter and pre-excitation by impairing conduction via the normal AV node-His-Purkinje system. This decreases retrograde concealed conduction in the accessory pathway, thereby improving antegrade conduction over the pathway. Acute treatment should be directed toward converting to normal sinus rhythm in these patients. (See "Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome", section on 'When to avoid AV nodal blockers'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".)

SUMMARY AND RECOMMENDATIONS

●There are three principle clinical situations for which rate control should be considered in patients with atrial flutter: to treat symptoms during a first episode or recurrent episode; to prevent symptoms in patients who are likely to have recurrent atrial flutter; and to prevent tachycardia-mediated cardiomyopathy in the patient with chronic atrial flutter. (See 'Indications for rate control' above.)

●Rate control in atrial flutter is often more difficult than in atrial fibrillation. For many patients, atrial flutter ablation, which permanently restores sinus rhythm in a high percentage of patients, is the preferred long-term approach. (See 'Indications for rate control' above.)

●For most patients, we believe a ventricular rate at rest of less than 80 beats/min is reasonable for symptomatic patients and less than 110 beats/min may be reasonable for asymptomatic patients with normal left ventricular systolic function. (See 'Rate control goals' above.)

●For patients who require immediate rate slowing, and for whom cardioversion is not chosen, we suggest intravenous diltiazem or esmolol rather than other drug options (Grade 2C). The choice between these two should take into account practitioner familiarity. (See 'Rate control with drugs' above.)

●For patients who will be placed on long-term oral therapy for rate control, we suggest oral diltiazem or verapamil rather than other oral agents (Grade 2C). (See 'Rate control with drugs' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review.