Rate vs. Rhythm Control in Atrial Fibrillation

Unlike acute myocardial infarction, atrial fibrillation is on the rise in the United States, and it is now known to be a risk factor for overall mortality even in the absence of valvular disease. For patients with a recent onset of this disorder, the author outlines an approach to the difficult choice between rate control and rhythm control and explains the corresponding therapeutic strategies.

By Morton A. Diamond, MD, FACP, FACC, FAHA

Dr. Diamond is a professor and medical director of the physician assistant program at Nova Southeastern University, Fort Lauderdale, Florida.

Atrial fibrillation (AF) continues to exact a considerable health care toll in the United States, with substantial morbidity related to the aging of the American population. While the incidence of and mortality associated with acute myocardial infarction (AMI) is decreasing, AF and congestive heart failure (CHF) are cardiac conditions that are increasing in frequency in this country. The incidence of AF nearly doubles during each decade of adult life, ranging from two to three new cases per 1000 population per year between 55 and 64 years of age to 35 new cases between ages 85 and 94. Approximately 10% of the population over 70 years of age has AF.

The presence of AF in the patient free of valvular disease is no longer regarded as a benign disorder. Recent clinical data reveal that AF is an independent risk factor for increased mortality after adjustment for other known risk factors. The mortality associated with AF in women is significantly higher than that in males. In patients who have systolic left ventricular dysfunction, AF increases the risk for all-cause mortality and is associated with worsening left ventricular function.

Atrial fibrillation may be acute (paroxysmal) or chronic. It may occur in patients with normal hearts and in those with diseased hearts. "Lone AF" refers to the presence of the arrhythmia in a patient without underlying structural heart disease or history of hypertension. In these patients, no apparent cause of the AF can be identified. Approximately 3% of all AF patients have lone AF. Recurrent AF in these patients is usually infrequent at first, but over time approximately 20% develop chronic AF. Lone AF must be distinguished from AF associated with non-cardiac diseases such as diabetes mellitus, hyperthyroidism, chronic obstructive pulmonary disease, and pulmonary embolism, and with acute alcohol or drug ingestion.

Atrial fibrillation is common in atherosclerotic and hypertensive heart disease, congestive and hypertrophic cardiomyopathy, acute and chronic pericarditis, atrial septal defect, atrial myxoma, rheumatic heart disease, sick sinus syndrome, pre-excitation, non-rheumatic valvular disease, and the early postoperative cardiac surgery period. In the setting of AMI, AF independently predicts an increased 30-day mortality and greater risk of stroke, despite appropriate anticoagulation. The arrhythmia occurs in approximately 20% of AMI cases and is associated with a 40% mortality. It may occur in approximately 10% of patients who have pre-excitation, with life-threatening clinical consequences.

This review will provide a rational approach for the primary care physician who is treating the patient with recent-onset AF. Recent onset is defined as AF that has not lasted more than seven days.

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Management of AF represents a rigorous challenge in contemporary cardiology. The primary issue that must be addressed is rhythm control versus rate control. Should the physician attempt to convert the patient to normal sinus rhythm (NSR)? Or should it be accepted that the patient with recent-onset AF will eventually develop chronic AF and that the focus therefore should be on controlling ventricular rate with therapy?

Potential advantages of conversion to NSR include improved hemodynamics, avoidance of electrical and anatomic atrial remodeling, enhanced exercise capacity, improved quality of life, and reduced incidence of thromboembolic events. Disadvantages include proarrhythmia (defined as the onset of ventricular tachycardia), recurrent AF despite maintenance medication, organ toxicity, and patient intolerance of pharmacologic therapy. Medications used in the conversion of recent-onset AF and for maintenance of NSR include flecainide, propafenone, procainamide, quinidine, disopyramide, sotalol, dofetilide, and amiodarone. Ibutilide is also used for conversion of recent-onset AF, but because it can only be administered intravenously, it is not a maintenance medication.

Potential advantages of ventricular rate control include avoidance of proarrhythmia, low medication cost, reasonable control of patient symptoms, and prevention of CHF. Disadvantages are reduced cardiac output related to loss of the atrial component to ventricular diastolic filling (the so-called atrial kick), the need for long-term anticoagulation, and development of atrial remodeling. There are patients in whom ventricular rate control is clearly preferred: those who have a significantly dilated left atrium; those who have AF of long duration; those who have demonstrated drug refractoriness; and older patients who have a sedentary lifestyle. Medications used to control ventricular rate in the AF patient include the calcium channel blockers diltiazem and verapamil, digoxin, the beta adrenergic blockers (most commonly esmolol, metoprolol, and propranolol), and the Vaughn Williams class III agent amiodarone.

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Ongoing trials of treatment strategies include the STAF trial (Strategies of Treatment of Atrial Fibrillation), the RACE trial (Rate Control versus Electrical Cardioversion for Persistent AF), and the AFFIRM trial (AF Follow-up Investigation of Rhythm Management). The STAF trial is following 200 patients randomized to rate control versus cardioversion (serial, if necessary) plus antiarrhythmic therapy. The primary endpoints of the study are cardiopulmonary resuscitation, stroke, systemic embolism, and death; secondary endpoints are quality of life, bleeding complications, and cost. Pilot-phase observations have found no difference between the two treatment strategies regarding the primary endpoints. Mortality in both groups was low. Only 23% of patients in the rhythm control group were in NSR at 36 months despite repeated cardioversion and antiarrhythmic therapy. On the other hand, almost all embolic events had occurred in the rate control group.

The primary focus of RACE is to determine in a randomized cohort the cost benefit of serial electrical cardioversion and antiarrhythmic medication versus rate control in patients with persistent AF. Primary endpoints are mortality, morbidity, and quality of life. Secondary endpoints are the number of patients adhering to their initial treatment strategy and an economic evaluation. Results are expected later this year.

The AFFIRM trial, randomizing 4300 patients in 200 clinical sites in the United States and Canada, will compare the survival of patients following an antiarrhythmic treatment strategy designed to maintain NSR with those receiving therapy to control ventricular rate in AF. Patients will be followed for an average of 3.5 years. For treatment in the rhythm control cohort, physicians can choose amiodarone (two dose levels), sotalol, flecainide, quinidine, disopyramide, procainamide, or moricizine. Medications to slow atrioventricular conduction are given as appropriate. Agents used in the rate control group include a beta adrenergic blocker, calcium channel blocker, digoxin, or a combination of these.

The primary study endpoint is to determine whether persistent AF with adequate rate control and antithrombotic agents has the same mortality as restoration of NSR using antiarrhythmic medication. Secondary endpoints include percentage of patients in NSR, adequacy of ventricular rate control, stroke, major hemorrhage, cardiac arrest, quality of life, and cost of therapy. Results are also expected later this year.

While we await the results of these clinical trials, available data suggest no clear advantage of one therapeutic approach over the other. There presently is no difference in symptom control or serious morbidity and mortality. Also, it is important to remember that long-term maintenance of NSR is difficult even with serial cardioversion and multiple medications.

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Electrical and Anatomic Remodeling

The longer AF persists, the more difficult it is to restore NSR and prevent recurrence. The reason for this appears to be that AF causes electrical and anatomic remodeling. The electrical changes, which occur within minutes of the onset of AF, are associated with shortening of the atrial refractory period and increased intracellular calcium in atrial cells.

There are specific clinical expressions related to electrical remodeling. First, precipitating factors in AF, such as emotional stress, caffeine ingestion, cigarette smoking, and hypoxia, all shorten the atrial refractory period. Further, heightened vagal tone and thyrotoxicosis can trigger AF, and these too are associated with shortening of the atrial refractory period. Also, recent clinical data have demonstrated that the addition of the calcium channel blocker verapamil to antiarrhythmic medication before cardioversion may reduce the recurrence of AF.

Anatomic remodeling refers to mechanical dysfunction of the atria, which can result from prolonged episodes of AF lasting a month or longer. Atrial dilatation is one important consequence of anatomic remodeling that contributes to the persistence of the cardiac rhythm disturbance.

Remodeling predisposes paroxysmal AF to become chronic AF. It also causes atrial stunning, which is the delay in the return of effective mechanical contractility of the atria after conversion to NSR. Stunning occurs after electrical, pharmacologic, and spontaneous conversion. It is stunning that is responsible for the embolization noted after resumption of NSR unless anticoagulation is continued for three to four weeks post-cardioversion. The fact that remodeling occurs so quickly in AF has convinced some physicians to pursue a course of early cardioversion in the patient who has recent-onset AF.

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Silent Atrial Fibrillation

Paroxysmal AF is associated with multiple symptoms, including palpitations, dizziness, breathlessness, anxiety, chest discomfort, and pre-syncope. In contrast, patients with chronic AF typically experience more generalized symptoms such as lethargy and chronic fatigue.

Atrial fibrillation is often discovered in patients during routine physical examinations, preoperative assessments, and population surveys. Ambulatory cardiac monitoring in paroxysmal AF has demonstrated that episodes of silent (or asymptomatic) AF occur 10 to 12 times more frequently than symptomatic AF. A prospective clinical study has concluded that patients with asymptomatic AF have a higher mortality than those whose AF is symptomatic.

There are two important issues here. First, patients with asymptomatic AF are at increased risk for developing CHF because their arrhythmia is unrecognized and untreated. Secondly, the fact that the symptomatic patient presenting with recent-onset AF may also have had asymptomatic episodes raises important questions concerning anticoagulation and the need for antiarrhythmic therapy. Certainly, the physician must be more liberal in prescribing antithrombotic therapy in the patient who has only rare symptomatic attacks of AF.

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Evaluation of the Patient

A careful history and physical examination will help guide the therapeutic strategy. The history should determine the time of onset of the arrhythmia, seeking clues to what triggered the AF, characterizing its pattern of recurrence, defining an underlying cause, and recognizing cardiac complications. The physical examination should look for evidence of hypertension, valvular disease, CHF, pulmonary disease, and hyperthyroidism.

Electrocardiography should be conducted to confirm the arrhythmia, determine the QT interval, demonstrate bundle branch block, and define evidence of myocardial ischemia or infarction. A chest x-ray is most valuable for revealing the presence of underlying pulmonary pathology and for assessing the pulmonary vasculature. A transthoracic echocardiogram should be performed in all AF patients to determine the dimensions of the atria and ventricles, measure left ventricular wall thickness, recognize valvular or pericardial disease, note pulmonary artery pressure, and assess left ventricular systolic and diastolic function. Complete blood count, serum electrolyte levels, and thyroid function studies are indicated.

Additional tests may include ambulatory cardiac monitoring to determine recurrence of AF and to assess heart rate during daily activity. Exercise testing will reveal heart rate during vigorous exercise and evidence of myocardial ischemia, which would preclude the use of class Ic antiarrhythmic agents. Transesophageal echocardiography (TEE) is the most sensitive indicator of potential sources of cardiogenic emboli originating in the left atrium or atrial appendage. Screening of the left atrium and appendage with TEE may guide the clinician toward early cardioversion in recent-onset AF. If the ultrasound study reveals thrombus or spontaneous echoes ("smoke") in the left atrium or appendage, anticoagulation with warfarin is indicated for three to four weeks before and four weeks after elective cardioversion. Additionally, TEE may demonstrate significant atherosclerosis in the proximal aorta, which is believed to be the origin of embolic strokes in many elderly patients.

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Therapeutic Strategies

The approach to treatment of AF that has lasted less than seven days embraces many clinical considerations (see algorithm below). First is the decision as to whether hospitalization is necessary. Certainly, if CHF, hypotension, angina pectoris, or marked subjective symptoms are present, the patient should be admitted.

The physician must then determine whether heart disease, hyperthyroidism, or other organic pathology is present. In particular, evidence of myocardial ischemia and CHF must be sought, and the need for cardioversion, including its timing and method, must be weighed. Myocardial ischemia unresponsive to initial therapy or the presence of CHF may be an indication for urgent cardioversion, which would necessitate hospitalization.

While the patient is in AF there must be proper pharmacologic control of the ventricular response. Anticoagulation must be considered in order to prevent embolic stroke. The physician must weigh the risk to the patient if he remains in AF against the potential side effects of antiarrhythmic medication.

Until the results of the cited clinical trials are reported, the physician's treatment strategy will be based on the above factors which, in total, relate to the chances of short- and long-term maintenance of NSR, the specific risks of therapeutic options, and the patient's preference.

The following clinical criteria favor a strategy of rate control rather than cardioversion in the patient with recent-onset AF: an asymptomatic patient, left atrial dimension greater than 50 mm, left ventricular systolic dysfunction (ejection fraction less than 40%), CHF (New York Heart Association II), sick sinus syndrome, three or more prior cardioversions, a history of drug-induced proarrhythmia or demonstrated proarrhythmic risk factors, advanced age with sedentary lifestyle, and no contraindication to chronic anticoagulation. In patients who do not meet these criteria, the physician must choose between rate control and rhythm control based on individual patient circumstances.

Physicians should be aware that in up to two thirds of patients who have AF that has lasted less than 24 hours, spontaneous conversion to NSR occurs. If AF has lasted more than 24 hours, however, spontaneous conversion is rare.

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Therapies for Rate Control

Ventricular rate in the untreated patient with recent-onset AF is usually between 110 and 130 beats per minute. A resting ventricular rate of more than 150 per minute should alert the physician to the presence of fever, acute hypovolemia, or hyperthyroidism.

Intravenous medications that slow atrioventricular nodal conduction are given to control ventricular response (see table below). The nondihydropyridine calcium-blocking agents diltiazem and verapamil are effective for this purpose, but they are not effective in restoring NSR. These medications are preferred in the patient who has obstructive lung disease, diabetes mellitus, or peripheral arterial disease. In the patient whose recent-onset AF is complicated by systolic left ventricular dysfunction, these agents must be used with caution. However, diltiazem appears to be less risky than verapamil in CHF patients.

After initial slowing of the heart rate in the acute setting, diltiazem and verapamil can be used effectively to control heart rate at rest and during exercise. The dihydropyridine calcium-blocking agent nifedipine has no such effect on AV nodal conduction and therefore should not be used.

Intravenous beta blockers are also effective in slowing ventricular rate in the acute setting, particularly in the patient who has coronary artery disease. Though propranolol and metoprolol appear to be the most commonly used drugs, other beta blockers may be administered. In the AF patient known to have prior sinus node dysfunction, pindolol, with its intrinsic sympathomimetic effect, is preferred.

Contraindications to beta blocker therapy include obstructive lung disease, severe systolic left ventricular dysfunction, and atherosclerotic peripheral vascular disease. Diabetes mellitus is a relative contraindication. In the insulin-dependent diabetic patient, the symptoms of hypoglycemia may be masked by nonselective beta blockers. However, these drugs have been used safely in patients with type 2 diabetes.

Digoxin exerts an indirect action on the atrioventricular node through its vagomimetic effect. It is less effective in ventricular rate control in patients who are in hyperadrenergic states such as CHF, anemia, and fever. However, while it is less effective than other agents, digoxin may be used in combination with them. A further limitation of this glycoside is its slow onset of action; maximal slowing of the heart rate does not occur until several hours after the initial intravenous dose. Hypokalemia and hypomagnesemia must be corrected because they increase the likelihood of digitalis intoxication. Additional precautions include the necessity for a reduced dose in patients who have renal disease and the advisory that oral erythromycin and tetracycline may increase digoxin levels by 10% to 40%.

The patient with recent-onset AF complicated by systolic CHF presents a special challenge. Traditionally, digoxin has been given, but its efficacy is limited by its slow onset of action. However, beta blockers or diltiazem may be infused cautiously in combination with digoxin. Intravenous amiodarone is effective for heart rate control in heart failure and when other medications have failed to slow the heart rate, but it should only be used in the patient who is fully anticoagulated because it may restore sinus rhythm, which may increase the risk of embolization.

Patients whose recent-onset AF is associated with pre-excitation represent a potentially life-threatening clinical state. In pre-excitation, antegrade conduction via accessory bypass tracts can allow the ventricular rate to be as high as 300 beats per minute. Profound hypotension or degeneration of AF into ventricular fibrillation may develop. Medications that slow atrioventricular conduction, such as digoxin, calcium channel blockers, and beta blockers, are contraindicated. Emergent direct current cardioversion may be employed. If the physician opts for medical therapy to effect heart rate control in the pre-excited AF patient, parenteral procainamide, propafenone, flecainide, sotalol, ibutilide, or amiodarone may be administered. (Procainamide, amiodarone, and sotalol are not FDA-approved for use in AF, but they are commonly used for this purpose in clinical practice.)

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Therapies for Rhythm Control

The physician whose treatment strategy for the patient with recent-onset AF is rhythm control must first acknowledge that patient safety takes precedence over AF suppression. Recurrences of AF are likely in the absence of a correctable underlying disorder. Total prevention of recurrent AF with antiarrhythmic drugs is improbable. A realistic goal would be fewer, less symptomatic, and briefer paroxysms of recurrent AF rather than complete suppression of the arrhythmia.

If the acute onset of AF creates a life-threatening situation, such as AMI, pulmonary edema, intractable ischemia, or hypotension, immediate electrical cardioversion is indicated. In less emergent cases, pharmacologic conversion of recent-onset AF is highly effective if the medications are given early and in adequate doses. Continuous electrocardiographic monitoring is indicated for 48 to 72 hours after initiation of antiarrhythmic therapy.

If the AF has lasted less than 48 hours, early conversion is a practical and safe option for the patient who is not at high risk for embolism. It must be emphasized, however, that symptomatic AF patients often have episodes of silent AF. Therefore, the physician must be sure of the duration of the arrhythmia before initiating early conversion without prior anticoagulation. Early cardioversion may be electrical or pharmacologic.

Medications used for early pharmacologic cardioversion of AF include the Vaughan Williams class Ia agents quinidine, procainamide, and disopyramide; class Ic agents propafenone and flecainide; and class III agents amiodarone, sotalol, dofetilide, and ibutilide (see table below). The choice of antiarrhythmic medication will depend on whether organic heart disease is present, and if so, its etiology and the hemodynamic status of the patient.

Proarrhythmia is the most serious complication of pharmacologic therapy. Class Ia and III medications may produce torsades de pointes, whereas class Ic agents produce sustained ventricular tachycardia, particularly in patients who have impaired systolic left ventricular function. The most important risk factor for the development of torsades de pointes is the presence of structural heart disease. Other risk factors include medication dosage, baseline QT interval, left ventricular hypertrophy, hypokalemia, hypomagnesemia, bradycardia, and female gender. Drug-induced torsades de pointes is more common in women. Recent investigation has demonstrated that ibutilide-induced QT prolongation occurs to a greater degree during the first half of the menstrual cycle when progesterone serum levels are at their lowest. It is thought that progesterone exerts an inhibitory effect on ibutilide's tendency to prolong the QT interval.

Oral quinidine, which has been used for decades to treat AF, is effective for conversion, but its long-term safety has been questioned. Therefore, it should not be used for maintenance. Procainamide and disopyramide may be used for conversion in patients without structural heart disease. These class Ia agents should be started in the hospital. Propafenone and flecainide share several important clinical attributes. Both can be administered either orally or intravenously. However, neither is presently available for intravenous use in the United States. A common contraindication is ischemic or structural heart disease. Both should be given only after the AF patient has taken medication to slow the ventricular rate.

Amiodarone has one of the lowest proarrhythmic potentials of any antiarrhythmic medication. It is particularly valuable in converting the recent-onset AF patient who has a contraindication to class Ic agents—namely, those who have sustained an AMI or who have reduced left ventricular ejection fraction. Amiodarone potentiates the anticoagulant effect of warfarin and raises digoxin levels.

Ibutilide is gaining increasing acceptance as an agent for pharmacologic conversion in the lone-AF patient. The incidence of torsades de pointes or sustained ventricular tachycardia is 1% to 4%. Women are more often affected than men. Ibutilide should not be infused in patients who have long QT intervals. Serum potassium and magnesium deficits must be corrected prior to administration.

The therapy of choice for torsades de pointes is intravenous magnesium sulfate, administered in a dose of 1 to 2 grams over 10 to 15 minutes.

Dofetilide must be given in the hospital. It appears to be effective in converting recent-onset AF in the patient without structural heart disease, but it may also be used in the patient who has coronary heart disease, systolic left ventricular dysfunction, and left ventricular hypertrophy.

Sotalol does not appear to be effective for conversion. Its efficacy in AF appears to be limited to maintenance of NSR after cardioversion in the patient who has ischemic heart disease or left ventricular hypertrophy from systemic hypertension.

If recent-onset AF has lasted more than 48 hours or the duration is unknown, then the physician has two options. The first strategy is rate control with medication and anticoagulation with warfarin for three to four weeks (target INR, 2.0-3.0), followed by electrical cardioversion. The alternative strategy is TEE-guided cardioversion. If the left atrium and appendage are free of thrombus or spontaneous echoes ("smoke"), direct current cardioversion may be performed safely as long as the patient is anticoagulated during and after the procedure.

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Guidelines for Anticoagulation

Patients with both valvular and non-valvular AF are at risk for stroke and systemic embolism. Paroxysmal and chronic AF appear to have the same risk for cardiogenic embolization.

All patients whose recent-onset AF has converted to NSR should receive anticoagulation therapy for at least three to four weeks post-conversion. Moreover, it is prudent to continue warfarin for three months post-conversion in all patients unless a contraindication exists. Patients with recent-onset AF who have valvular disease, including those with prosthetic valves, should receive chronic warfarin therapy unless a contraindication exists (target INR, 2.0-3.0).

In patients who do not have valvular disease but do have recent-onset AF, the physician must determine whether there are clinical findings contributing to a high risk for embolism. These independent high-risk factors include hypertension, diabetes mellitus, previous stroke or transient ischemic attack, reduced left ventricular ejection fraction, left atrial dimension greater than 2.5 cm/m2, and age over 65 years. Recent-onset AF patients having one or more of these high-risk factors should be maintained on chronic warfarin therapy regardless of whether conversion occurs or chronic AF persists. In contrast, the patient who has lone AF, without structural heart disease or hypertension, may be treated with one adult aspirin daily until age 65 years, after which warfarin therapy is advised.

Suggested Reading ACC/AHA/ESC Guidelines for the Management of Patients with Atrial Fibrillation: Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences. J Am Coll Cardiol 38:1238, 2001. Carlsson J, et al.: Therapy of atrial fibrillation: rhythm control versus rate control. Pace 23:891, 2000. Falk FH: Medical progress: atrial fibrillation. N Eng J Med 344:1067, 2001. Pelosi F Jr, et al.: Cardiac arrhythmias: evaluation and management of atrial fibrillation. Med Clin N Amer 85:225, 2001. Reiffel JA: Drug choices in the treatment of atrial fibrillation. Am J Cardiol 85:12D, 2000.