Atrial fibrillation: Rate Control: Options, Advantages, Disadvantages

I. Atrial Fibrillation: What every physician needs to know.

There are three important reasons to control the ventricular rate in patients presenting with atrial fibrillation (AF). These are the patient’s symptomatic status, hemodynamic instability, and risk of developing tachycardia-medicated cardiomyopathy.

Patients with untreated AF seek medical treatment for ventricular rates that may at times be in excess of 150 beats per minute (bpm). When approaching a patient with AF and a rapid ventricular response, one must consider the urgency of therapy, as well as whether acute rate control or rhythm control would be more appropriate.

Many of the symptoms that patients suffer during AF, such as palpitations, shortness of breath, weakness, chest discomfort, and dizziness, are caused directly or indirectly by a rapid and irregular ventricular rate. The hemodynamic consequences of rapid ventricular rates include a fall in cardiac output, drop in blood pressure, and elevation in left atrial pressure.

If an average heart rate of more than 110 to 120 bpm persists for long periods (e.g., weeks to months), there is the risk of developing so-called “tachycardiomyopathy.” Tachycardiomyopathy refers to left ventricular systolic dysfunction occurring in patients with chronic rapid heart rates.

This complication can occur in some patients with AF and very rapid ventricular rates, and is reversible and preventable with adequate rate control. Patients with underlying structural heart disease are at higher risk for developing hemodynamic instability or worsening of preexisting cardiomyopathy.

The ventricular rate with which a patient presents is mostly dependent on the conduction properties of the atrioventricular (AV) node. A significant majority of the fibrillatory impulses do not conduct to the ventricles because of specialized AV nodal tissue referred to as “slow response” fibers.

Conduction in these fibers is mediated by slow inward calcium channels in comparison to most other myocardial cells that use rapid inward sodium channels. The AV node is also richly supplied by sympathetic and parasympathetic fibers of the autonomic nervous system.

Patients presenting with ventricular rates in excess of 200 bpm will often exhibit catecholamine excess and/or parasympathetic withdrawal. On the other hand, some patients will present with slower ventricular rates below, for example, 90 bpm. This is commonly the result of increased vagal tone, drugs that affect AV nodal conduction, and importantly AV nodal disease, especially when presenting rates are 60 to 70 bpm or less.

Pharmacologic and nonpharmacologic interventions allow care providers to alter the conduction properties of the AV node, thus controlling ventricular rates in AF. Pharmacologic therapy in most cases is sufficient to achieve successful rate control. The various pharmacologic and nonpharmacologic therapeutic options that are available to be used to achieve rate control, as well as the selection of an appropriate rate control regimen for particular patients are discussed below.

III. Management.

Rate versus rhythm control

In addition to appropriate anticoagulation, rate and rhythm control are the two main therapeutic strategies in patients with AF. Rate control allows persistence of AF and the use of drugs that slow conduction through the AV node. Rhythm control consists of cardioversion to normal sinus rhythm, usually followed by treatment with arrhythmic drugs or nonpharmacologic rhythm therapies (e.g., catheter ablation) aimed at maintenance of sinus rhythm.

Depending on associated risk factors for thromboembolism, chronic anticoagulation therapy should be administered to reduce the risk of stroke regardless of the chosen goal of AF therapy, whether rhythm control or rate control, or the specific AF therapies (pharmacologic or nonpharmacologic).

Although rhythm control is often the preferred strategy by many physicians, the presumed advantages of rhythm control on important clinical outcomes (stroke, mortality, cost, hospitalization) were not confirmed in Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) or Rate Control and Rhythm Control in Patients With Recurrent Persistent Atrial Fibrillation (RACE) and other randomized trials comparing rate versus rhythm control. Similar “no difference” results also were found for AF patients with congestive heart failure and reduced systolic function.

Therefore one can conclude from these trials that ventricular rate control of AF is an effective and acceptable treatment approach for some patients with AF. Rate control alone, however, is not necessarily better than rhythm therapy, and may not be an acceptable or suitable strategy for highly symptomatic patients despite rate control, in younger individuals, or in patients in whom exercise capacity is critical.

The clinician needs to adapt the therapeutic strategy to each individual patient. The Guidelines for the Management of Patients with Atrial Fibrillation highlight the need for adequate rate control in patients with persistent or permanent AF and they designate measurement of the heart rate at rest and control of the rate with pharmacologic agents as a Class I recommendation.

Pharmacologic therapy

Pharmacologic therapy can achieve adequate rate control in most patients with AF both during acute and long-term management. The pharmacologic therapies that can be used for AF rate control include:

1. beta-blockers

2. nondihydropyridine calcium channel blockers (verapamil or diltiazem)

3. digoxin

4. amiodarone

5. dronedarone

6. magnesium

7. clonidine

All these agents act by slowing AV nodal conduction and prolonging AV nodal refractoriness. The first three agents listed above are the primary drugs used for ventricular rate control during AF.

When using any of these pharmacologic agents, close monitoring and medication and dose adjustments usually are required, and combination therapy may be appropriate to achieve adequate rate control. Drug doses in general should be titrated to patient well-being, taking into regard the heart rate at rest and with activity (most effectively measured using ambulatory monitoring) and potential adverse effects from treatment.

A. Immediate management

Urgency of therapy

The goals of acute therapy related to ventricular rate control during AF are to improve symptoms and hemodynamics. Initial considerations when caring for a patient with AF and a rapid ventricular rate will depend on the severity of symptoms and the presence of hemodynamic instability. Depending on the presentation, therapy initiation can be emergent, urgent, or elective.

Mildly symptomatic or asymptomatic stable patients can be treated electively with the addition or increase of oral rate control medications. Hemodynamically stable, moderately or highly symptomatic patients should receive urgent therapy with intravenous AV nodal slowing agents.

Once better rate control is achieved and symptoms improve, then a decision can be made to pursue chronic rate or rhythm control. Patients who present with symptomatic hypotension, angina, myocardial ischemia, or heart failure should receive emergent therapy. Pharmacologic therapy is often very limited in patients presenting with hypotension.

AV nodal blocking agents are likely to compound hypotension or heart failure symptoms in the acute setting. Such presentations have a Class I indication for acute cardioversion as an initial approach. In patients with an adequate blood pressure, angina or myocardial ischemia, intravenous (IV) beta-blockers or calcium channel blockers may be useful and can be attempted before emergent cardioversion.

Beta-blockers

Acute intravenous therapy: For the immediate control of ventricular rate, intravenous beta-blockade is highly effective. Intravenous esmolol and metoprolol are the most commonly used acute therapy beta-blockers. Other intravenous beta-blockers include labetalol and propranolol.

The latter two choices are nonselective agents with affinity for both beta 1 and beta 2 receptors. Esmolol and metoprolol are beta 1 receptor selective agents. The nonselective agents may exhibit a greater hypotensive effect compared with beta 1 selective agents. Beta 1 selectivity is not absolute, but relative and dependent on dose.

Esmolol: Rapid acting with a short half-life. It is metabolized by red blood cell esterase within 10 to 20 minutes of administration. Given its short duration of action, esmolol is useful in patients with marginal hemodynamic stability when it is uncertain that a beta-blocker will be tolerated. Recommended dosing for esmolol is to bolus 500 mcg/kg over 1 minute, followed by 50 mcg/kg/min thereafter.

The maintenance dose may be increased by 50 mcg/kg/min every 4 minutes if the response to esmolol is inadequate. This can be repeated to a maximum dose of 200 mcg/kg/min. The bolus of 500 mcg/kg can be repeated up to two more times before every increase in infusion rate. For a less aggressive approach, infuse at 50 mcg/kg/min without a bolus being used. It can then be increased by 50 mcg/kg/min every 30 minutes to a max dose of 200 mcg/kg/min.

Metoprolol: More commonly used, can be given as intravenous boluses of 2.5 to 5.0 mg over 2 minutes. The dose may be repeated at 5-minute intervals with close monitoring of the patient’s blood pressure until an adequate heart rate is achieved.

Nondihydropyridine calcium channel blockers

The two drugs belonging to this group used in clinical practice are verapamil and diltiazem. Both can increase myocardial tissue refractoriness and decrease conduction velocity in the AV node, thus reducing ventricular rates in AF. There is no clear evidence that one agent is superior to the other. Diltiazem and verapamil are contraindicated in patients with acute myocardial infarction and associated systolic left ventricular dysfunction and congestive heart failure.

Acute intravenous therapy

Verapamil: Given intravenously in a dose of 5 to 10 mg over 2 minutes followed by a maintenance infusion rate of approximately 0.125 mg/minute. The bolus dose can be repeated every 15 to 30 minutes as needed. The onset of action is within 2 minutes and the peak effect occurs in 10 to 15 minutes.

Diltiazem: A bolus of 0.25 mg/kg (average 20 mg) is given intravenously over 2 minutes. A second bolus of 0.35 mg/kg (average 25 mg) can be given 10 to 15 minutes after the first bolus, if the first bolus is tolerated but does not produce an adequate response. This is then followed by an infusion at a rate of 5 to 15 mg/hour. A desired effect is usually achieved within 4 to 5 minutes.

Digoxin: Given the availability of more effective acute rate control agents, digoxin usually is not considered first-line therapy for rapid, immediate management of AF, except perhaps in patients with heart failure or LV dysfunction. There is a delay of at least 60 minutes before onset of a therapeutic effect in most patients and the peak effect does not occur for up to 6 hours.

Acute dosing: Commonly administered intravenously or orally, rapid “digitalization” is used for rate control in atrial fibrillation.

• The digitalization dose is usually between 0.75 to 1.5 mg with intravenous administration and 1 to 2 mg with oral administration.

• Rapid digitalization is achieved by the intravenous route with an initial dose of 0.25 to 0.5 mg of digoxin given over several minutes. This is followed by 0.25 mg every 4 to 6 hours until a total of 0.75 to 1.5 mg has been given.

• Likewise rapid oral digitalization is accomplished by giving 0.5 mg initially followed by 0.25 mg or 0.5 mg every 6 hours until the target dose is achieved.

• Slow oral digitalization can be attained using only a maintenance dose of 0.125 to 0.25 mg daily. In patients with moderate to severe renal insufficiency, a dose of 0.06125 mg daily or 0.125 mg every other day should be used to avoid digoxin toxicity.

Amiodarone: Intravenous amiodarone may be an effective short-term agent for ventricular rate in acutely ill or postoperative patients. Intravenous amiodarone is generally well tolerated in critically ill patients who develop rapid atrial tachyarrhythmias refractory to conventional treatment and may be less likely to cause systemic hypotension than intravenous calcium channel blockers or beta-blockers.

The ACC/AHA/HRS guidelines recommend that intravenous amiodarone be used for heart rate control in patients with AF and heart failure who do not have an accessory pathway (class I indication), and also suggest that intravenous amiodarone can be useful to control the heart rate in patients with AF when other measures are unsuccessful or contraindicated (class IIa indication). The recommended dose is 150 mg over 10 minutes followed by a maintenance dose of 0.5 to 1 mg/min intravenously.

Magnesium sulfate: Intravenous magnesium may have modest rate control properties in AF patients via calcium channel antagonism. Small studies have shown some benefit in rate control with IV magnesium sulfate (2.5 g over 20 minutes followed by 2.5 g over 2 hours) when compared with a placebo. However, effects are modest, with a decrease in mean ventricular rate of only around 10 to 15 bpm. Side effects include hypotension and flushing.

Clonidine: A few reports suggest that clonidine can be used for acute ventricular rate control in AF. The role of clonidine in slowing the ventricular rate in AF is thought to be due to its central sympatholytic activity. In a randomized controlled trial in an emergency room setting in hemodynamically stable patients with AF and rapid ventricular rates, oral clonidine (0.075 mg) reduced ventricular rates when compared to a no treatment control group. In a comparative trial of clonidine, digoxin, and verapamil, it was found that clonidine controlled ventricular rate in new onset AF with an efficacy comparable to that of digoxin and verapamil.

Acute therapy recommendations: In the absence of hypotension or heart failure symptoms, administration of either an intravenous beta-blocker or nondihydropyridine calcium channel blocker is a reasonable initial acute approach. When uncertain if patients will tolerate intravenous beta-blockers or calcium channel blockers, an ultra short-acting agent (e.g., esmolol) may be a good choice. This allows a therapeutic trial at reduced risk.

• If an adequate response to initial monotherapy with beta-blockers or calcium channel blockers is not achieved, digoxin can be added as a second agent. An alternative approach would be to discontinue the initial therapy with beta-blockers and try calcium channel blockers or vice versa.

• Some refractory cases may necessitate the use of a beta-blocker and calcium channel blocker together with or without digoxin. This, however, must be done with caution and only in patients without heart failure symptoms or hypotension.

• Intravenous amiodarone may be an effective short-term option for ventricular rate in critically ill or pos-operative patients.

• In patients with significant hypotension or symptomatic heart failure, a reasonable first approach can be intravenous digoxin, amiodarone, or emergent/urgent cardioversion.

B. Long-term Management.

Target Heart Rates and Monitoring

The primary goal of long-term ventricular rate control in patients with AF is to prevent symptoms and development of tachycardia-medicated cardiomyopathy. However, the targets and parameters that define optimal rate control in AF have not been well studied or determined adequately. Furthermore no standard method for assessment of heart rate control has been established to guide management of patients with AF.

Definitions of adequate rate control are largely empirical and are based primarily on clinical experience and expert opinion derived from short-term hemodynamic and symptomatic benefits. Short-term studies indicate that administering drugs to slow ventricular response during AF in symptomatic patients yields benefits.

However, ideal long-term ventricular rate control has been less well studied with respect to regularity or irregularity of the ventricular response to AF, quality of life, or symptoms or development of cardiomyopathy. More research on long-term rate control for AF is needed.

The efficacy of heart rate control therapy should be assessed at rest in all patients with persistent or permanent AF. However, in patients with exertional symptoms and persistent or permanent AF, the heart rate during exercise also should be assessed. For sedentary patients, measuring heart rate after walking around the office or up stairs may be sufficient.

A more formalized exertional protocol can be performed, such as measuring the distance walked in 6 minutes or obtaining submaximal or maximal exercise ECG testing. For younger active patients who are symptomatic, an exercise ECG test or an ambulatory Holter monitor during activities of daily living including exercise is recommended.

Some patients with AF may have chronotropic incompetence (an inability to increase heart rate with exertion). If the heart rate is <100 bpm with moderate exercise, rate control is not necessarily advisable and symptomatic status may be worsened in such patients with AV nodal blocking drugs. It should be noted that rate control in paroxysmal AF is largely empirical, and heart rate targets often are impractical to achieve or to monitor for during brief AF episodes.

The 2006 ACC/AHA AF guidelines state that the criteria for AF rate control vary with patient age, but usually involve achieving a resting heart rate between 60 and 80 bpm and between 90 and 115 bpm during moderate exercise such as a 6-minute walk test. These criteria are similar to the target rates used in the AFFIRM and RACE trials of rate versus rhythm control.

The 2011 Focused Update on the Management of Patients with Atrial Fibrillation trial further clarified the issue of optimal rate control in patients with AF by assigning a “strict” rate (<80 bpm at rest or <110 bpm during a 6-minute walk) class III recommendation (no evidence of benefit). This new guideline update was prompted by the results of the Rate Control Efficacy in Permanent Atrial Fibrillation-II (RACE-II) trial, which suggested that aiming for a heart rate <110 bpm at rest in AF may be adequate.

The RACE-II trial randomly assigned 614 patients with permanent AF to either a lenient rate control strategy (resting heart rate <110 bpm) or a strict rate control strategy (resting heart rate <80 bpm and heart rate during moderate exercise <110 bpm). The primary outcome was a composite of cardiovascular death, hospitalization for heart failure, and stroke; systemic embolism; bleeding; and life-threatening arrhythmic events over 3 years.

The study showed that the lenient rate control was noninferior to strict rate control (12.9% versus 14.9% cumulative outcome rates respectively; hazard ratio 0.84; 90% CI 0.58-1.21). Adverse cardiac remodeling (echocardiographic changes in left atrial size and left ventricular end-diastolic diameter) did not occur to any greater extent with lenient versus strict rate control and quality of life was not influenced by the stringency of heart rate control.

Importantly however, relatively few patients randomized to lenient rate control had resting heart rates >100 to 110 bpm and the mean heart rates achieved in both groups in RACE II were <100 to 110 bpm. At the end of follow-up, mean heart rates were not dramatically different between the lenient versus strict control groups: 85±14 versus 76±14 bpm (P <.001), respectively. Thus one cannot conclude from these data that resting heart rates >100 bpm in AF are acceptable.

On the other hand, the findings of RACE II do suggest that a strategy of lenient rate control may be adopted as a reasonable strategy in patients with permanent AF and that being overly aggressive with rate control is not necessary in patients with AF as long as they are minimally symptomatic. Lenient rate control may be more convenient, require fewer outpatient visits and examinations, and shorten length of hospital stays.

An additional important consideration when following patients with AF treated with rate control is that LV function should be monitored periodically to screen patients for development of a tachycardia-mediated cardiomyopathy.

The 2011 focused AF guideline states that “treatment to achieve strict rate control of heart rate (<80 bpm at rest or <110 bpm during a 6-minute walk) is not beneficial compared to achieving a resting heart rate <110 bpm in patients with persistent AF who have stable ventricular function (left ventricular ejection fraction >0.40) and no or acceptable symptoms related to the arrhythmia, though uncontrolled tachycardia may over time be associated with a reversible decline in ventricular performance.”

Most clinicians treating AF patients use beta-blockers or calcium channel blockers as drugs of first choice for ventricular rate control as they are effective at rest and during exertion. A number of comparative drug trials comparing these drugs have been performed but none have shown major advantages of one agent over another.

In a post hoc analysis of long-term rate control in the AFFIRM trial, patients initially treated with a beta-blocker were significantly less likely than those treated with calcium channel blockers to have their drug regimen changed. Some patients have a greater degree of rate control with a beta-blocker than with a calcium channel blocker, and vice versa. Thus, in patients who have an inadequate response to one of these drugs, switching to a drug from the other class should be considered.

In certain patient groups, however, one type of drug may be preferred to the other. In patients with coronary disease after myocardial infarction or with LV systolic dysfunction or heart failure, beta-blockers clearly are preferred.

In younger patients who have normal left ventricular function and are more active, calcium channel blockers may be preferable to beta-blockers. Calcium channel blockers are associated with better exercise tolerance than beta-blockers in patients with AF, but may be less effective at controlling the ventricular response. Calcium channel blockers may be preferred in patients with contraindications to beta-blockers such as in patients with bronchospastic pulmonary disease.

Digoxin is often added to beta-blockers or calcium channel blockers to avoid using high doses of either of the latter two agents. In a small crossover study of 12 patients with chronic AF, patients were treated over 2-week intervals with 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. Digoxin plus atenolol was the most effective regimen for controlling the mean ventricular rate and reducing the peak heart rate during exercise.

Some patients may require a combination of a calcium channel blockers and beta-blockers or triple therapy (including digoxin) to achieve adequate rate control. If patients have persistently rapid ventricular rates with symptoms despite the use of calcium channel blockers, beta-blockers, and digoxin at maximal doses, underlying disorders that shorten AV nodal refractory periods should be considered; for example, thyrotoxicosis, catecholamine excess, sepsis, or cardiomyopathy with elevated sympathetic tone and heart failure.

Beta-blockers

Chronic oral therapy

Oral beta-blockers are prescribed commonly as primary therapy for rate control in AF. They are effective in reducing resting and exercise ventricular rates. The more commonly used beta-blockers include metoprolol, atenolol, nadolol, carvedilol, propranolol, bisoprolol and pindolol.

Some beta-blockers may be more effective for ventricular rate control than others. For example, carvedilol is a less potent beta-adrenergic blocking agent compared with metoprolol. The use of beta-blockers for AF rate control carries an added benefit in patients with other cardiovascular diseases, such as coronary artery disease, and diastolic and systolic heart failure. Beta-blockers also may reduce the incidence of AF recurrence caused by surges in sympathetic tone, such as during exercise or perioperative states.

Metoprolol succinate, atenolol, bisoprolol, and nadolol have the advantages of longer half-lives and a single daily dosing, as well as affordability. Being of low lipophilicity, atenolol and nadolol also have the advantage of less central nervous system side effects when compared to other beta-blockers.

However, both atenolol and nadolol are mostly renally cleared and should be avoided in patients with renal dysfunction or in the elderly with lower than expected creatinine clearance. Both these populations of patients often present with beta-blocker toxicity when treated with chronic atenolol or nadolol.

Adverse effects of beta-blockers can be seen at standard doses or as a result of toxicity. The major complications of beta-blocker therapy include bradycardia, high-degree AV block, hypotension, acute worsening of heart failure symptoms, reduced exercise tolerance, fatigue, and bronchospasm.

Nondihydropyridine calcium channel blockers

Chronic oral therapy

Verapamil: Initial dose is 40 mg, three or four times per day. This can be increased to a maximum of 360 mg/day in divided doses. The equivalent dose of sustained release verapamil can be used once per day or divided into twice a day to better maintain rate control. Caution should be taken in patients on concomitant digoxin therapy. Verapamil reduces renal clearance and hepatic metabolism of digoxin and increases serum levels of digoxin.

Diltiazem: Initial dose is 30 mg, four times daily. The usual maximum dose is a total of 360 mg daily divided over four times a day. Sustained release diltiazem is given in the same total daily dose as a single tablet or divided twice a day.

Diltiazem and verapamil do have their share of adverse effects. These drugs are negative inotropic agents and should be avoided in patients with heart failure or LV dysfunction.

They should not be given to patients with decompensated heart failure symptoms and especially those taking beta-blockers since beta-blockers will have a negative inotropic effect themselves. Calcium channel blockers should not be used in patients presenting with significant hypotension or AF with preexcitation syndrome.

These drugs should be avoided or given with extreme caution to patients with sinus node dysfunction or marked first-degree heart block. Diltiazem and verapamil can exacerbate these conditions leading to severe bradycardia especially in patients on other drugs that inhibit sinoatrial node function or slow AV nodal conduction.

Digoxin: Digoxin is not recommended as a first-line agent for rate control, especially as monotherapy because it affects only the resting ventricular rate and has a slow onset of action. Digoxin is less effective than beta-blockers and calcium channel blockers in the slowing of ventricular rates during AF.

Digoxin acts by potentiating vagal tone, thereby slowing AV nodal conduction. For this reason, digoxin is ineffective when vagal tone is low and sympathetic tone is high, such as during exercise. Digoxin is not effective as a sole rate control agent in active, younger patients.

Older individuals may benefit from digoxin therapy if they have mild symptoms related to rapid heart rates and are not likely to be physically active. However, it should be noted that digoxin may lead to nighttime slowing of ventricular rates, occasionally with long nocturnal pauses, when vagal tone is enhanced and sympathetic tone is low.

Although beta-blockers are preferred agents in patients with heart failure and LV systolic dysfunction, low doses of digoxin can be added to therapy with beta-blockers when target heart rate in not achieved with monotherapy, when increased beta-blocker dose is not well tolerated or when the added benefit of increased contractility is needed for heart failure symptom control.

Likewise when calcium channel blockers (verapamil or diltiazem) are being used for ventricular rate control, addition of digoxin has added benefit without substantial risk and may be preferred over the use of large doses of a calcium channel blocker.

High doses of digoxin should be avoided due to the risks of digitalis toxic rhythm disturbances including bradycardia, bidirectional ventricular tachycardia, and AV block. Successful digoxin effect has been classically described with junctional escape beats (detected by the equality of all of the longest observed R-R intervals on the electrocardiogram) during AF.

However, the change from single or occasional junctional escapes to periodic or consistent junctional rhythm signifies the development of digoxin toxicity and can reflect complete AV block.

Plasma digoxin levels should be monitored periodically to avoid digoxin toxicity in high-risk individuals. Caution with digoxin dosing is advised in patients with chronic kidney disease and with concomitant use of drugs that increase serum digoxin levels (e.g., p-glycoprotein intestinal and renal transport molecule inhibitors, such as amiodarone, dronedarone, and verapamil).

A post hoc analysis of the Digitalis Investigation Group (DIG) trial reported that a serum digoxin level of more than 1.2 ng/ml was associated with a significant increase in death from cardiovascular causes not related to heart failure.

Amiodarone: Oral amiodarone has significant rate-controlling properties in addition to its antiarrhythmic actions and may be useful in refractory patients for ventricular rate control during AF. Oral amiodarone is unlikely to cause hypotension when administered at recommended doses. Due to of the risk of toxicity and long-term side effects, amiodarone is used for chronic rate control only in refractory cases when other therapies are contraindicated or fail to result in adequate rate control.

Dronedarone: Dronedarone is a multichannel blocking, antiarrhythmic agent developed as an analogue of amiodarone that inhibits sodium, potassium, and calcium channels and has antiadrenergic activity. Dronedarone has rate and rhythm controlling properties in AF.

Dronedarone (400 mg bid) was more effective than placebo in slowing ventricular rate at rest and with exertion with mean rate decreases around 10 to 15 and 20 to 25 bpm, respectively, in patients with permanent AF in the ERATO (Efficacy and Safety of Dronedarone for the Control of Ventricular Rate During Atrial Fibrillation) trial.

Dronedarone, however, should not be used as a rate control agent in patients with permanent AF due to its adverse safety profile in this patient population based on the results of the PALLAS (Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy) study. Dronedarone’s rate-controlling properties may be of benefit in patients with nonpermanent (paroxysmal or persistent) AF and associated cardiovascular risk factors.

In the ATHENA (A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg bid for the Prevention of Cardiovascular Hospitalization or Death From Any Cause in Patients With Atrial Fibrillation/Atrial Flutter) trial, dronedarone treatment was associated with a 24% reduction in the combined risk of cardiovascular hospitalization or all-cause death.

Nonpharmacologic therapy

AV nodal ablation: The principle, nonpharmacologic approach to rate control in AF involves radiofrequency ablation (RFA) of the AV node and is sometimes considered if ventricular rate control cannot be achieved with AV nodal blocking drugs. AV junction ablation results in complete AV block, thus rendering permanent pacing device implantation necessary.

Therefore, it is important to remember that this approach: involves “trading one disease for another,” (i.e., treating atrial fibrillation but creating iatrogenic AV block and pacemaker dependency). Another concern is the potential long-term risk of developing left ventricular failure with chronic right ventricular pacing.

Given these issues, this treatment is reserved for patients who do not respond to or who cannot tolerate pharmacologic rate-control therapy, but in general is being performed less and less often in most electrophysiology practices. The ACC/AHA/HRS Guidelines indicate that it is reasonable to perform ablation of the AV node in conjunction with permanent pacemaker implantation to control heart rate when pharmacologic therapy is insufficient or associated with side effects (class IIa recommendation).

AV nodal ablation is acutely successful in over 97% of patients in achieving complete heart block and rate control. About 96% of patients will demonstrate persistent AV block during long-term follow-up. Patient symptoms and quality of life are improved in patients who undergo AV nodal ablation and permanent pacemaker implantation when adequate rate control could not be achieved with drug therapy.

These patients usually have significantly less physician office visits and hospitalizations. They report fewer symptoms and greater exercise tolerance. AV nodal ablation with permanent pacing has not demonstrated any improvement in overall survival.

It is important to note that AV nodal ablation has been associated with a small increase in risk of ventricular fibrillation and sudden cardiac death. The rate of sudden death after AV node ablation is around 3% and appears to occur more commonly in the period soon after ablation.

The incidence of ventricular fibrillation appears to be greater when patients’ pacemakers are set to lower rates (<70 bpm). A higher pacing rate (80 to 90 bpm) for the first few months after the ablation may reduce the risk of ventricular fibrillation after AV node ablation.

Endocardial vagal stimulation to achieve rate control during AF: Endocardial stimulation of efferent AV nodal vagal fibers is an investigational approach for long-term, device-based modulation of AV nodal conduction. This approach to control ventricular rate during AF is not approved but promising preliminary results have been published both in animal models and in humans. The data from acute and chronic studies suggest that this approach should continue to be studied and developed.

Chronic rate control therapy recommendations

• Initial therapy for patients who require chronic rate control during AF should begin with an oral beta-blocker or a nondihydropyridine calcium channel blocker.
• Beta blockers are preferred in patients with coronary heart disease and heart failure.
• A nondihydropyridine calcium channel blocker is preferred in patients with reactive airway disease or chronic obstructive pulmonary disease and in patients who do not tolerate beta-blocker therapy.-Addition of digoxin as the second agent when adequate rate control is not achieved with beta-blockers or calcium channel blockers at reasonable doses.

• When rates are not adequately controlled on a beta-blocker plus digoxin or calcium channel blocker plus digoxin, a third rate-control agent (a beta-blocker in those receiving a calcium channel blocker and vice versa) can be added.
• In occasional refractory cases, chronic amiodarone or dronedarone therapy for rate control can be considered prior to nonpharmacologic therapies.
• Some patients will not achieve adequate heart rate control with pharmacologic therapies. Alternative therapies with either rhythm control strategy or nonpharmacologic therapies to control the ventricular rate should be considered to prevent development of a tachycardiomyopathy.

E. Common Pitfalls and Side-Effects of Management

IV. Management with Co-Morbidities

An important caveat to always keep in mind when considering acute ventricular rate control in a patient presenting with AF is to be certain that one is not dealing with the WPW (Wolff-Parkinson-White) syndrome and an accessory AV connection. During preexcited AF, antegrade conduction down an accessory pathway can result in very rapid ventricular rates coupled with hemodynamic instability.

Preexcited AF should be considered with any rapid (200 to 300 bpm) sustained, highly irregular wide QRS complex tachycardia. Rapid antegrade accessory pathway conduction during preexcited AF can predispose patients with WPW to developing ventricular fibrillation (VF), which may be precipitated by administering AV nodal blocking drugs. Therefore in patients with preexcited AF, drugs that block AV nodal conduction (digoxin, nondihydropyridine calcium channel blockers, beta-blockers, and adenosine) are contraindicated. These drugs can facilitate antegrade conduction over the accessory pathway during AF and paradoxically can increase ventricular rates during AF.

Decreased conduction through the AV node reduces retrograde concealed conduction up the accessory pathway, thus increasing antegrade conduction down the accessory pathway. Initial therapy in patients with preexcited AF should be aimed at reversion to sinus rhythm. When the arrhythmia is associated with hemodynamic compromise, early direct current cardioversion is indicated.

In hemodynamically stable patients with preexcitation, type I (procainamide) or type III (ibutilide) antiarrhythmic agents may be administered intravenously. Amiodarone should be used with caution in the case of preexcited AF as case reports have described the occurrence of VF after intravenous administration.

AFs that should be approached with caution are those presenting with a controlled or slow resting ventricular rate (≤ 60 to 75 bpm) in the absence of any rate controlling medications. Such patients usually have underlying AV nodal disease, and rate-controlling medications are generally not advisable as symptomatic bradycardia can ensue.

A specific caution is advised with IV beta-blocker administration in the setting of an acute myocardial infarction (MI). Although adequate ventricular rate control is critical in patients with AF in the setting of chronic coronary artery disease or acute coronary syndromes, IV beta-blockers should not be administered to patients with suspected acute MI who have signs of heart failure or evidence of a low output state or in those who are at increased risk for developing cardiogenic shock (age >70 years, systolic blood pressure <120 mm Hg). Likewise, diltiazem and verapamil are contraindicated in patients with systolic LV dysfunction and CHF.

What’s the evidence for specific management and treatment recommendations?

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Fuster, V, Ryden, LE, Cannom, DS. “2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines”. Circulation.. vol. 123. 2011. pp. e269-e367.

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