Shobha Rao, MD

Atrial fibrillation (AF), the most common arrhythmia seen in clinical practice, affects an estimated 2.2 million American adults.¹ The condition is associated with a 1.5- to 1.9-fold mortality risk independent of other risk factors² and about a 4- to 5-fold increase in the risk of strokes.³ Achieving rate control; restoring or maintaining sinus rhythm, when it’s feasible; and preventing stroke are the primary goals in treating patients with AF. Yet many physicians are not always sure about the best ways to achieve them.

Failure to provide adequate anticoagulation therapy—despite clear evidence that anticoagulation significantly reduces the risk of thromboembolic complications—may be the most common misstep physicians make in treating AF.⁴ But anticoagulation is not the only trouble spot. Choosing between a rate-control and rhythm-control strategy also has its share of challenges, as does deciding which drugs are best for which patients.

AF is an age-related condition, with the prevalence increasing from 0.5% among individuals <60 years old to 9% of those >80.⁵ An aging population will make your ability to manage AF even more critical in the years ahead. The text and tables that follow will help you refine your care. But first, a quick review.

Classification, causes, and clinical features

AF is classified primarily on the basis of duration:

Paroxysmal AF is the term for brief episodes (lasting <24 hours) and episodes that last up to 7 days but terminate spontaneously. Cardioversion is not needed for this self-limiting condition.

Persistent AF lasts longer than 7 days, and often requires electrical or pharmacological cardioversion.

Permanent AF is used to describe instances in which cardioversion has failed (or has not been attempted) and the arrhythmia is continuous.

These categories are not mutually exclusive—a patient may primarily have paroxysmal AF, with an occasional episode of persistent AF. The term recurrent AF is used when 2 or more episodes of paroxysmal or persistent AF occur.

Warfarin or aspirin? An anticoagulation risk tool

CHADS₂ is a validated risk stratification scheme that offers help in making decisions about anticoagulation therapy. Each of the letters in this acronym represents a risk factor, and carries a certain number of points:

Congestive heart failure (1 point)
Hypertension (1 point)
Age >75 years (1 point)
Diabetes (1 point)
Stroke (2 points)

Patients with a score of ≥3 are at high risk and need to be treated with warfarin; those with a score of 0 are at low risk and can be managed with aspirin. For patients with a score of 1 or 2, the choice of warfarin or aspirin should be based on clinician assessment and patient preference.

Source: Gage BF, et al. JAMA. 2001.²⁴

AF typically linked to heart conditions—but not always

Chronic cardiac conditions commonly associated with AF include ischemic heart disease, congestive heart failure (CHF), hypertension, and rheumatic mitral valve disease. Recurrent AF may also be associated with atrial flutter, Wolff-Parkinson-White (WPW) syndrome, or atrioventricular (AV) nodal reentrant tachycardia. It is essential to recognize the presence of such conditions, because treatment of the primary arrhythmia may reduce or eliminate the incidence of recurrent AF. ⁶

There are also noncardiac causes of AF—eg, excessive alcohol intake (“holiday heart syndrome”), pulmonary embolism and other pulmonary diseases, and hyperthyroidism and other metabolic disorders. Lone AF, a term used when the patient is younger than 60 years of age and has neither clinical nor echocardiographic evidence of cardiopulmonary disease, is a diagnosis of exclusion. About 30% to 45% of cases of paroxysmal AF and 20% to 25% of persistent AF are considered to be lone AF.¹

EKG, x-ray, and echo: The role of each

Although some patients are asymptomatic, AF patients typically present with palpitations, dyspnea, fatigue, chest pain, or dizziness. A stroke may also be the first indication that a patient has AF.

A normal pulse rules out AF,⁷ and an irregular pulse should be an indication for an electrocardiogram (EKG). In most cases, a diagnosis can be made from the results of a 12-lead EKG. However, when diagnosis is uncertain or symptoms are paroxysmal, a Holter monitor or event recorder may be required.

Thyroid, renal, and hepatic function tests, serum electrolytes, and hemograms may help to rule out reversible causes of AF. Chest x-ray is valuable in diagnosing CHF, as well as lung pathology. Recent guidelines recommend that all patients who present with AF undergo echocardiography to evaluate for valvular heart disease, left and right atrial size, left ventricular size and function, left ventricular hypertrophy, and pericardial disease.¹ Transesophageal echocardiogram (TEE) should be used to detect intracardiac clots in patients who have had an embolic event or when AF has lasted for more than 48 hours and cardioversion is being considered.

Rate vs rhythm control: What the research reveals

For hemodynamically unstable patients who present with AF and a rapid rate associated with cardiogenic shock, pulmonary edema, acute myocardial infarction, or unstable angina, urgent direct-current cardioversion is indicated. In less urgent cases, treatment is not so clear cut. Spontaneous conversion to sinus rhythm occurs in up to 60% of patients within 24 hours, and in about 80% of patients within 48 hours.⁸

Intuitively, restoring normal sinus rhythm seems superior to rate control, but several randomized trials^9-12 and one meta-analysis¹³ found no support for that belief when researchers looked at mortality, thromboembolic events, and major hemorrhage.

One of the largest studies was the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM), which involved more than 4000 patients with paroxysmal and persistent AF who were randomized to either rate control or rhythm control.⁹ The research revealed a nonsignificant trend toward an increased death rate with the rhythm-control strategy—a 5-year mortality rate of 24% vs 21% for patients in the rate-control group. A trend toward higher risk of ischemic stroke, particularly associated with the lack of anticoagulation therapy, was also found in the rhythm-control group. That finding emphasizes the need for indefinite anticoagulation, independent of the use of a rate-control or rhythm-control approach.

A retrospective subanalysis of the AFFIRM trial that evaluated patients on the basis of a number of independent treatment variables found that sinus rhythm, in and of itself, was actually associated with a lower risk of death. But the antiarrhythmic agents that are often needed to achieve sinus rhythm are not associated with higher rates of survival. According to the researchers, this finding suggests that the drugs’ beneficial antiarrhythmic effects are offset by their adverse effects.¹⁴

Age is another confounding factor. Most of the AFFIRM subjects were relatively older, with a mean age of 69.7 years. In another study, rhythm control was found to be beneficial in young patients (mean age of 38.6 years) with AF and rheumatic valvular heart disease, in terms of morbidity and mortality.¹⁵

With no single treatment strategy emerging as the best approach, guidelines offer help in determining whether to pursue a rate-control or rhythm-control strategy for a particular patient. The recommendations of the British National Institute for Health and Clinical Excellence (NICE) guideline for AF,¹⁶ developed on the basis of a systematic literature review as well as expert consensus, are summarized here.

When should you opt for rate control?

The NICE guideline recommends rate control as the initial choice for patients who have persistent AF and:

• are >65 years of age
• have coronary artery disease
• do not have CHF
• are not candidates for cardioversion
• have contraindications to antiarrhythmic drugs.¹⁶

The American College of Cardiology (ACC), American Heart Association (AHA), and European Society of Cardiology (ESC) guidelines recommend maintaining a ventricular rate during AF of 60 to 80 beats per minute at rest and 90 to 115 beats per minute during exercise.¹

Which drug for which patient?

Beta-blockers and nondihydropyridine calcium channel blockers (verapamil and diltiazem) and digoxin slow conduction through the AV node. Compared with placebo, beta-blockers and calcium channel blockers are effective for controlling the ventricular rate in patients with AF, both at rest and during exercise.¹⁷ In the AFFIRM trial, rate control was achieved in 70% of patients treated with beta-blockers vs 54% of patients taking calcium channel blockers.⁹

That said, the type of drug you use to achieve rate control should be an individual decision based on characteristics of your particular patient. In general, beta-blockers are preferable for patients with myocardial infarction or ischemia, and for any patient in a high adrenergic state, whereas calcium channel blockers should be used for patients with severe asthma or chronic obstructive pulmonary disease. Consider using digoxin for patients with CHF or hypotension, because both beta-blockers and calcium channel blockers can precipitate hemodynamic deterioration in these patients.

Digoxin has a relatively slow onset of action, however, and is less effective than beta-blockers or calcium channel blockers for rate control. What’s more, digoxin is ineffective for slowing the heart rate during exercise or in hyperadrenergic states. Thus, combination therapy will be needed to achieve adequate rate control in many cases.

Agents that predominantly block AV conduction, such as beta-blockers, calcium channel blockers, and digoxin, are contraindicated in patients with WPW syndrome and wide-complex ventricular response related to the preexcitation syndrome. That’s because these drugs can trigger an antegrade conduction along the accessory pathway.¹⁸ In this subset of patients, use a Class 1 antiarrhythmic such as flecainide or procainamide, or amiodarone for rate control¹ (TABLE 1).

TABLE 1
Rate-control agents: A review of the options

When should you consider cardioversion?

The NICE guidelines recommend rhythm control as the initial choice for patients who:

• are symptomatic
• are <65 years old
• are presenting for the first time with lone AF or AF secondary to a condition that has been treated or corrected
• have CHF.¹⁶

While the guidelines recommend restoring sinus rhythm in patients with heart failure, a recent study suggests that rhythm control is no more effective for reducing the rate of death from cardiovascular causes compared to a rate-control strategy in this patient population.¹⁹ As with other aspects of AF management for which there is no definitive approach, individualized factors—including patient preference—should be your guide.

Electrical vs pharmacological cardioversion. Sinus rhythm can be established with electrical or pharmacological cardioversion. Electrical cardioversion, in which an external defibrillator delivers an electric shock that’s synchronized with the QRS complex, is usually well tolerated; embolization, pulmonary edema, and other arrhythmias are infrequent complications. Cardioversion with biphasic waveform defibrillation typically uses less energy and may have greater efficacy than monophasic waveforms.

The success rate of electrical cardioversion is higher than that of pharmacological cardioversion.⁸ But the use of electrical cardioversion is limited by the need for general anesthesia or conscious sedation for pain control. Pharmacological cardioversion is more effective for patients who have had AF for <48 hours; after that, the conversion rate drops considerably, and electrical cardioversion is often needed to restore sinus rhythm in a patient whose AF has lasted more than 7 days. A variety of antiarrhythmic drugs (TABLE 2), including propafenone, flecainide, ibutilide, and amiodarone, can be used to restore sinus rhythm. But because of the proarrhythmic potential of most of these agents, patients should be monitored in the hospital while drug therapy is initiated. After sinus rhythm is restored, maintenance therapy may be required.

Whether cardioversion is achieved by electrical or pharmacological means, it is associated with an increased risk of thromboembolism, especially in patients whose AF has persisted for >48 hours. Adequate anticoagulation with warfarin (international normalized rate of 2-3) should be achieved 3 weeks prior to cardioversion and continued for 4 weeks thereafter. Alternatively, excluding atrial thrombus by TEE paves the way for early cardioversion, using IV heparin or low-molecular-weight heparin for anticoagulation.

TABLE 2
Pharmacological cardioversion: Typical drugs and doses

Maintaining sinus rhythm: Choosing the right drug

Without chronic antiarrhythmic therapy, only about 30% of patients with AF will remain in normal sinus rhythm after a year.²⁰ Of the drugs that can be used to maintain sinus rhythm—amiodarone, disopyramide, flecainide, propafenone, and sotalol—amiodarone is the most effective. In the Canadian Trial of Atrial Fibrillation,²¹ 403 patients treated with amiodarone, sotalol, or propafenone were followed for 16 months. The recurrence rate for the amiodarone group was 35%, compared with 63% for those being treated with sotalol or propafenone.

Adverse effects to consider

Amiodarone is less proarrhythmic than the other antiarrhythmic agents, but it is associated with serious noncardiac toxicities, including pulmonary, thyroid, neurologic, hepatic, optic, and dermatologic adverse effects. In addition, amiodarone can increase plasma levels of several drugs, including digoxin and warfarin, and periodic monitoring of the doses of these medications is essential. Adding enalapril, an angiotensin-converting enzyme inhibitor, or irbesartan, an angiotensin receptor blocker, can enhance the efficacy of amiodarone in maintaining normal sinus rhythm after cardioversion.

Thus, the choice of medication to maintain sinus rhythm should be individualized, based on the patient’s underlying cardiac condition and the safety profile of the antiarrhythmics being considered. (TABLE 3). The ACC/AHA/ESC guidelines recommend class 1C agents flecainide and propafenone as first-line therapy for maintaining sinus rhythm in patients with structurally normal hearts.¹ But because of their proarrhythmic and negative ionotropic effects, class 1C agents should not be given to patients who have heart failure or ischemia. Amiodarone and dofetilide are the preferred agents for maintaining sinus rhythm in patients with heart failure and severe left ventricular hypertrophy, and dofetilide, amiodarone, and sotalol are best suited for patients with ischemic heart disease.

Pill-in-the-pocket. For selected patients with paroxysmal AF and a structurally normal heart, a “pill-in-the-pocket” strategy is an option—provided it has been tried in the hospital and proven to be safe. A patient using this strategy would self-administer a single dose of a class 1C antiarrhythmic agent—eg, 600 mg propafenone or 300 mg flecainide—at the onset of an acute episode of AF. Concomitant administration of a beta-blocker or calcium channel blocker is recommended to prevent development of atrial flutter with rapid AV conduction.

TABLE 3
Maintaining sinus rhythm in patients with AF

Using anticoagulation as prophylaxis

Judicious use of antithrombotic prophylaxis can significantly reduce the incidence of strokes associated with AF, regardless of whether you pursue a rate-control or rhythm-control strategy. Despite clear evidence of the efficacy of warfarin and aspirin in this patient population, anticoagulation remains underused in clinical practice.

If AF recurs or the patient develops chronic AF, the AFFIRM trial suggests the need for long-term anticoagulation for patients with thromboembolic risk factors.⁹

Adjusted-dose warfarin gets best results. A meta-analysis of 29 randomized trials from 1996 to 2007 involving 28,044 patients (mean age, 71 years; mean follow-up, 1.5 years) assessed the benefits of antithrombotic therapy for patients with AF.²² Compared with the controls, adjusted-dose warfarin (6 trials, 2900 participants) and antiplatelet agents (8 trials, 4876 participants) reduced stroke by 64% (95% confidence interval [CI], 49%-74%) and 22% (95% CI, 6%-35%), respectively.

Adjusted-dose warfarin was substantially more effective than antiplatelet therapy (12 trials, 12,963 participants; relative risk reduction, 39% [95% CI, 22%-52%]). The absolute risk reduction (ARR) with adjusted-dose warfarin in all strokes was 2.7% per year (number needed to treat [NNT] for 1 year to prevent 1 stroke was 37) for primary prevention and 8.4% per year (NNT, 12) for secondary prevention. Aspirin showed an ARR of 0.8% per year (NNT, 125) for primary prevention trials and 2.5% per year (NNT, 40) for secondary prevention trials. The absolute increase in major extracranial hemorrhage was small (≤0.3% per year).²²

A recent Cochrane review of 8 randomized trials with a total of 9598 patients concluded that adjusted-dose warfarin reduces stroke and other major vascular events in patients with nonvalvular AF by about one third, compared with antiplatelet therapy alone.²³

Warfarin or aspirin? Tools to help you decide

The risk of stroke varies considerably among patients with AF, depending on age and history of thromboembolic events, among other risk factors. What’s more, anticoagulation therapy carries an inherent risk of increased bleeding, making its use a complicated decision. A validated stroke risk stratification scheme like the CHADS₂ can help.²⁴ (See “Warfarin or aspirin? An anticoagulation risk tool”.)

The ACC/AHA/ESC guidelines recommend an alternate means of determining when anticoagulation is needed. The recommended risk stratification scheme divides risk factors for stroke into 3 categories:

• weak/less validated (female gender, age 65-74 years, coronary artery disease, thyrotoxicosis)
• moderate (≥75 years of age, hypertension, heart failure, LV ejection fraction ≤35%, diabetes mellitus)
• high (previous stroke, TIA, or embolism; mitral stenosis, prosthetic heart valve).

The guidelines recommend warfarin therapy for any patient with any high-risk factor or 2 or more moderate-risk factors; aspirin therapy for patients with no moderate- or high-risk factors; and aspirin or warfarin for patients with 1 moderate-risk factor.¹

When conventional therapy fails

For patients who do not respond to conventional therapy, other options, including radiofrequency catheter ablation and pacemakers, may be effective in controlling symptoms and improving quality of life. In a recent RCT of 70 patients 18 to 75 years of age who experienced monthly symptomatic episodes of AF, the recurrence rate at the end of the 12-month follow-up was 13% after pulmonary vein isolation with radiofrequency ablation compared with 63% after treatment with antiarrhythmic drugs (P<.001). The rate of hospitalization was also significantly lower in the radiofrequency ablation group: 9% compared with 54% in the antiarrhythmia group (P<.001).²⁵ Another option to consider for patients who require cardiac surgery for other reasons is left atrial appendage (LAA) occlusion or ligation at the time of surgery. This may prevent cardiac embolization, because the vast majority of thrombi in nonvalvular AF involve the LAA.

Correspondence
Shobha Rao, MD, University of Texas Southwestern Family Medicine Residency Program, 6263 Harry Hines Blvd., Clinical 1 Building, Dallas, TX 75390; [email protected].

Atrial fibrillation (AF), the most common arrhythmia seen in clinical practice, affects an estimated 2.2 million American adults.¹ The condition is associated with a 1.5- to 1.9-fold mortality risk independent of other risk factors² and about a 4- to 5-fold increase in the risk of strokes.³ Achieving rate control; restoring or maintaining sinus rhythm, when it’s feasible; and preventing stroke are the primary goals in treating patients with AF. Yet many physicians are not always sure about the best ways to achieve them.

Failure to provide adequate anticoagulation therapy—despite clear evidence that anticoagulation significantly reduces the risk of thromboembolic complications—may be the most common misstep physicians make in treating AF.⁴ But anticoagulation is not the only trouble spot. Choosing between a rate-control and rhythm-control strategy also has its share of challenges, as does deciding which drugs are best for which patients.

AF is an age-related condition, with the prevalence increasing from 0.5% among individuals <60 years old to 9% of those >80.⁵ An aging population will make your ability to manage AF even more critical in the years ahead. The text and tables that follow will help you refine your care. But first, a quick review.

Classification, causes, and clinical features

AF is classified primarily on the basis of duration:

Paroxysmal AF is the term for brief episodes (lasting <24 hours) and episodes that last up to 7 days but terminate spontaneously. Cardioversion is not needed for this self-limiting condition.

Persistent AF lasts longer than 7 days, and often requires electrical or pharmacological cardioversion.

Permanent AF is used to describe instances in which cardioversion has failed (or has not been attempted) and the arrhythmia is continuous.

These categories are not mutually exclusive—a patient may primarily have paroxysmal AF, with an occasional episode of persistent AF. The term recurrent AF is used when 2 or more episodes of paroxysmal or persistent AF occur.

Warfarin or aspirin? An anticoagulation risk tool

CHADS₂ is a validated risk stratification scheme that offers help in making decisions about anticoagulation therapy. Each of the letters in this acronym represents a risk factor, and carries a certain number of points:

Congestive heart failure (1 point)
Hypertension (1 point)
Age >75 years (1 point)
Diabetes (1 point)
Stroke (2 points)

Patients with a score of ≥3 are at high risk and need to be treated with warfarin; those with a score of 0 are at low risk and can be managed with aspirin. For patients with a score of 1 or 2, the choice of warfarin or aspirin should be based on clinician assessment and patient preference.

Source: Gage BF, et al. JAMA. 2001.²⁴

AF typically linked to heart conditions—but not always

Chronic cardiac conditions commonly associated with AF include ischemic heart disease, congestive heart failure (CHF), hypertension, and rheumatic mitral valve disease. Recurrent AF may also be associated with atrial flutter, Wolff-Parkinson-White (WPW) syndrome, or atrioventricular (AV) nodal reentrant tachycardia. It is essential to recognize the presence of such conditions, because treatment of the primary arrhythmia may reduce or eliminate the incidence of recurrent AF. ⁶

There are also noncardiac causes of AF—eg, excessive alcohol intake (“holiday heart syndrome”), pulmonary embolism and other pulmonary diseases, and hyperthyroidism and other metabolic disorders. Lone AF, a term used when the patient is younger than 60 years of age and has neither clinical nor echocardiographic evidence of cardiopulmonary disease, is a diagnosis of exclusion. About 30% to 45% of cases of paroxysmal AF and 20% to 25% of persistent AF are considered to be lone AF.¹

EKG, x-ray, and echo: The role of each

Although some patients are asymptomatic, AF patients typically present with palpitations, dyspnea, fatigue, chest pain, or dizziness. A stroke may also be the first indication that a patient has AF.

A normal pulse rules out AF,⁷ and an irregular pulse should be an indication for an electrocardiogram (EKG). In most cases, a diagnosis can be made from the results of a 12-lead EKG. However, when diagnosis is uncertain or symptoms are paroxysmal, a Holter monitor or event recorder may be required.

Thyroid, renal, and hepatic function tests, serum electrolytes, and hemograms may help to rule out reversible causes of AF. Chest x-ray is valuable in diagnosing CHF, as well as lung pathology. Recent guidelines recommend that all patients who present with AF undergo echocardiography to evaluate for valvular heart disease, left and right atrial size, left ventricular size and function, left ventricular hypertrophy, and pericardial disease.¹ Transesophageal echocardiogram (TEE) should be used to detect intracardiac clots in patients who have had an embolic event or when AF has lasted for more than 48 hours and cardioversion is being considered.

Rate vs rhythm control: What the research reveals

For hemodynamically unstable patients who present with AF and a rapid rate associated with cardiogenic shock, pulmonary edema, acute myocardial infarction, or unstable angina, urgent direct-current cardioversion is indicated. In less urgent cases, treatment is not so clear cut. Spontaneous conversion to sinus rhythm occurs in up to 60% of patients within 24 hours, and in about 80% of patients within 48 hours.⁸

Intuitively, restoring normal sinus rhythm seems superior to rate control, but several randomized trials^9-12 and one meta-analysis¹³ found no support for that belief when researchers looked at mortality, thromboembolic events, and major hemorrhage.

One of the largest studies was the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM), which involved more than 4000 patients with paroxysmal and persistent AF who were randomized to either rate control or rhythm control.⁹ The research revealed a nonsignificant trend toward an increased death rate with the rhythm-control strategy—a 5-year mortality rate of 24% vs 21% for patients in the rate-control group. A trend toward higher risk of ischemic stroke, particularly associated with the lack of anticoagulation therapy, was also found in the rhythm-control group. That finding emphasizes the need for indefinite anticoagulation, independent of the use of a rate-control or rhythm-control approach.

A retrospective subanalysis of the AFFIRM trial that evaluated patients on the basis of a number of independent treatment variables found that sinus rhythm, in and of itself, was actually associated with a lower risk of death. But the antiarrhythmic agents that are often needed to achieve sinus rhythm are not associated with higher rates of survival. According to the researchers, this finding suggests that the drugs’ beneficial antiarrhythmic effects are offset by their adverse effects.¹⁴

Age is another confounding factor. Most of the AFFIRM subjects were relatively older, with a mean age of 69.7 years. In another study, rhythm control was found to be beneficial in young patients (mean age of 38.6 years) with AF and rheumatic valvular heart disease, in terms of morbidity and mortality.¹⁵

With no single treatment strategy emerging as the best approach, guidelines offer help in determining whether to pursue a rate-control or rhythm-control strategy for a particular patient. The recommendations of the British National Institute for Health and Clinical Excellence (NICE) guideline for AF,¹⁶ developed on the basis of a systematic literature review as well as expert consensus, are summarized here.

When should you opt for rate control?

The NICE guideline recommends rate control as the initial choice for patients who have persistent AF and:

• are >65 years of age
• have coronary artery disease
• do not have CHF
• are not candidates for cardioversion
• have contraindications to antiarrhythmic drugs.¹⁶

The American College of Cardiology (ACC), American Heart Association (AHA), and European Society of Cardiology (ESC) guidelines recommend maintaining a ventricular rate during AF of 60 to 80 beats per minute at rest and 90 to 115 beats per minute during exercise.¹

Which drug for which patient?

Beta-blockers and nondihydropyridine calcium channel blockers (verapamil and diltiazem) and digoxin slow conduction through the AV node. Compared with placebo, beta-blockers and calcium channel blockers are effective for controlling the ventricular rate in patients with AF, both at rest and during exercise.¹⁷ In the AFFIRM trial, rate control was achieved in 70% of patients treated with beta-blockers vs 54% of patients taking calcium channel blockers.⁹

That said, the type of drug you use to achieve rate control should be an individual decision based on characteristics of your particular patient. In general, beta-blockers are preferable for patients with myocardial infarction or ischemia, and for any patient in a high adrenergic state, whereas calcium channel blockers should be used for patients with severe asthma or chronic obstructive pulmonary disease. Consider using digoxin for patients with CHF or hypotension, because both beta-blockers and calcium channel blockers can precipitate hemodynamic deterioration in these patients.

Digoxin has a relatively slow onset of action, however, and is less effective than beta-blockers or calcium channel blockers for rate control. What’s more, digoxin is ineffective for slowing the heart rate during exercise or in hyperadrenergic states. Thus, combination therapy will be needed to achieve adequate rate control in many cases.

Agents that predominantly block AV conduction, such as beta-blockers, calcium channel blockers, and digoxin, are contraindicated in patients with WPW syndrome and wide-complex ventricular response related to the preexcitation syndrome. That’s because these drugs can trigger an antegrade conduction along the accessory pathway.¹⁸ In this subset of patients, use a Class 1 antiarrhythmic such as flecainide or procainamide, or amiodarone for rate control¹ (TABLE 1).

TABLE 1
Rate-control agents: A review of the options

When should you consider cardioversion?

The NICE guidelines recommend rhythm control as the initial choice for patients who:

• are symptomatic
• are <65 years old
• are presenting for the first time with lone AF or AF secondary to a condition that has been treated or corrected
• have CHF.¹⁶

While the guidelines recommend restoring sinus rhythm in patients with heart failure, a recent study suggests that rhythm control is no more effective for reducing the rate of death from cardiovascular causes compared to a rate-control strategy in this patient population.¹⁹ As with other aspects of AF management for which there is no definitive approach, individualized factors—including patient preference—should be your guide.

Electrical vs pharmacological cardioversion. Sinus rhythm can be established with electrical or pharmacological cardioversion. Electrical cardioversion, in which an external defibrillator delivers an electric shock that’s synchronized with the QRS complex, is usually well tolerated; embolization, pulmonary edema, and other arrhythmias are infrequent complications. Cardioversion with biphasic waveform defibrillation typically uses less energy and may have greater efficacy than monophasic waveforms.

The success rate of electrical cardioversion is higher than that of pharmacological cardioversion.⁸ But the use of electrical cardioversion is limited by the need for general anesthesia or conscious sedation for pain control. Pharmacological cardioversion is more effective for patients who have had AF for <48 hours; after that, the conversion rate drops considerably, and electrical cardioversion is often needed to restore sinus rhythm in a patient whose AF has lasted more than 7 days. A variety of antiarrhythmic drugs (TABLE 2), including propafenone, flecainide, ibutilide, and amiodarone, can be used to restore sinus rhythm. But because of the proarrhythmic potential of most of these agents, patients should be monitored in the hospital while drug therapy is initiated. After sinus rhythm is restored, maintenance therapy may be required.

Whether cardioversion is achieved by electrical or pharmacological means, it is associated with an increased risk of thromboembolism, especially in patients whose AF has persisted for >48 hours. Adequate anticoagulation with warfarin (international normalized rate of 2-3) should be achieved 3 weeks prior to cardioversion and continued for 4 weeks thereafter. Alternatively, excluding atrial thrombus by TEE paves the way for early cardioversion, using IV heparin or low-molecular-weight heparin for anticoagulation.

TABLE 2
Pharmacological cardioversion: Typical drugs and doses

Maintaining sinus rhythm: Choosing the right drug

Without chronic antiarrhythmic therapy, only about 30% of patients with AF will remain in normal sinus rhythm after a year.²⁰ Of the drugs that can be used to maintain sinus rhythm—amiodarone, disopyramide, flecainide, propafenone, and sotalol—amiodarone is the most effective. In the Canadian Trial of Atrial Fibrillation,²¹ 403 patients treated with amiodarone, sotalol, or propafenone were followed for 16 months. The recurrence rate for the amiodarone group was 35%, compared with 63% for those being treated with sotalol or propafenone.

Adverse effects to consider

Amiodarone is less proarrhythmic than the other antiarrhythmic agents, but it is associated with serious noncardiac toxicities, including pulmonary, thyroid, neurologic, hepatic, optic, and dermatologic adverse effects. In addition, amiodarone can increase plasma levels of several drugs, including digoxin and warfarin, and periodic monitoring of the doses of these medications is essential. Adding enalapril, an angiotensin-converting enzyme inhibitor, or irbesartan, an angiotensin receptor blocker, can enhance the efficacy of amiodarone in maintaining normal sinus rhythm after cardioversion.

Thus, the choice of medication to maintain sinus rhythm should be individualized, based on the patient’s underlying cardiac condition and the safety profile of the antiarrhythmics being considered. (TABLE 3). The ACC/AHA/ESC guidelines recommend class 1C agents flecainide and propafenone as first-line therapy for maintaining sinus rhythm in patients with structurally normal hearts.¹ But because of their proarrhythmic and negative ionotropic effects, class 1C agents should not be given to patients who have heart failure or ischemia. Amiodarone and dofetilide are the preferred agents for maintaining sinus rhythm in patients with heart failure and severe left ventricular hypertrophy, and dofetilide, amiodarone, and sotalol are best suited for patients with ischemic heart disease.

Pill-in-the-pocket. For selected patients with paroxysmal AF and a structurally normal heart, a “pill-in-the-pocket” strategy is an option—provided it has been tried in the hospital and proven to be safe. A patient using this strategy would self-administer a single dose of a class 1C antiarrhythmic agent—eg, 600 mg propafenone or 300 mg flecainide—at the onset of an acute episode of AF. Concomitant administration of a beta-blocker or calcium channel blocker is recommended to prevent development of atrial flutter with rapid AV conduction.

TABLE 3
Maintaining sinus rhythm in patients with AF

Using anticoagulation as prophylaxis

Judicious use of antithrombotic prophylaxis can significantly reduce the incidence of strokes associated with AF, regardless of whether you pursue a rate-control or rhythm-control strategy. Despite clear evidence of the efficacy of warfarin and aspirin in this patient population, anticoagulation remains underused in clinical practice.

If AF recurs or the patient develops chronic AF, the AFFIRM trial suggests the need for long-term anticoagulation for patients with thromboembolic risk factors.⁹

Adjusted-dose warfarin gets best results. A meta-analysis of 29 randomized trials from 1996 to 2007 involving 28,044 patients (mean age, 71 years; mean follow-up, 1.5 years) assessed the benefits of antithrombotic therapy for patients with AF.²² Compared with the controls, adjusted-dose warfarin (6 trials, 2900 participants) and antiplatelet agents (8 trials, 4876 participants) reduced stroke by 64% (95% confidence interval [CI], 49%-74%) and 22% (95% CI, 6%-35%), respectively.

Adjusted-dose warfarin was substantially more effective than antiplatelet therapy (12 trials, 12,963 participants; relative risk reduction, 39% [95% CI, 22%-52%]). The absolute risk reduction (ARR) with adjusted-dose warfarin in all strokes was 2.7% per year (number needed to treat [NNT] for 1 year to prevent 1 stroke was 37) for primary prevention and 8.4% per year (NNT, 12) for secondary prevention. Aspirin showed an ARR of 0.8% per year (NNT, 125) for primary prevention trials and 2.5% per year (NNT, 40) for secondary prevention trials. The absolute increase in major extracranial hemorrhage was small (≤0.3% per year).²²

A recent Cochrane review of 8 randomized trials with a total of 9598 patients concluded that adjusted-dose warfarin reduces stroke and other major vascular events in patients with nonvalvular AF by about one third, compared with antiplatelet therapy alone.²³

Warfarin or aspirin? Tools to help you decide

The risk of stroke varies considerably among patients with AF, depending on age and history of thromboembolic events, among other risk factors. What’s more, anticoagulation therapy carries an inherent risk of increased bleeding, making its use a complicated decision. A validated stroke risk stratification scheme like the CHADS₂ can help.²⁴ (See “Warfarin or aspirin? An anticoagulation risk tool”.)

The ACC/AHA/ESC guidelines recommend an alternate means of determining when anticoagulation is needed. The recommended risk stratification scheme divides risk factors for stroke into 3 categories:

• weak/less validated (female gender, age 65-74 years, coronary artery disease, thyrotoxicosis)
• moderate (≥75 years of age, hypertension, heart failure, LV ejection fraction ≤35%, diabetes mellitus)
• high (previous stroke, TIA, or embolism; mitral stenosis, prosthetic heart valve).

The guidelines recommend warfarin therapy for any patient with any high-risk factor or 2 or more moderate-risk factors; aspirin therapy for patients with no moderate- or high-risk factors; and aspirin or warfarin for patients with 1 moderate-risk factor.¹

When conventional therapy fails

For patients who do not respond to conventional therapy, other options, including radiofrequency catheter ablation and pacemakers, may be effective in controlling symptoms and improving quality of life. In a recent RCT of 70 patients 18 to 75 years of age who experienced monthly symptomatic episodes of AF, the recurrence rate at the end of the 12-month follow-up was 13% after pulmonary vein isolation with radiofrequency ablation compared with 63% after treatment with antiarrhythmic drugs (P<.001). The rate of hospitalization was also significantly lower in the radiofrequency ablation group: 9% compared with 54% in the antiarrhythmia group (P<.001).²⁵ Another option to consider for patients who require cardiac surgery for other reasons is left atrial appendage (LAA) occlusion or ligation at the time of surgery. This may prevent cardiac embolization, because the vast majority of thrombi in nonvalvular AF involve the LAA.

Correspondence
Shobha Rao, MD, University of Texas Southwestern Family Medicine Residency Program, 6263 Harry Hines Blvd., Clinical 1 Building, Dallas, TX 75390; [email protected].

Atrial fibrillation (AF), the most common arrhythmia seen in clinical practice, affects an estimated 2.2 million American adults.¹ The condition is associated with a 1.5- to 1.9-fold mortality risk independent of other risk factors² and about a 4- to 5-fold increase in the risk of strokes.³ Achieving rate control; restoring or maintaining sinus rhythm, when it’s feasible; and preventing stroke are the primary goals in treating patients with AF. Yet many physicians are not always sure about the best ways to achieve them.

Failure to provide adequate anticoagulation therapy—despite clear evidence that anticoagulation significantly reduces the risk of thromboembolic complications—may be the most common misstep physicians make in treating AF.⁴ But anticoagulation is not the only trouble spot. Choosing between a rate-control and rhythm-control strategy also has its share of challenges, as does deciding which drugs are best for which patients.

AF is an age-related condition, with the prevalence increasing from 0.5% among individuals <60 years old to 9% of those >80.⁵ An aging population will make your ability to manage AF even more critical in the years ahead. The text and tables that follow will help you refine your care. But first, a quick review.

Classification, causes, and clinical features

AF is classified primarily on the basis of duration:

Paroxysmal AF is the term for brief episodes (lasting <24 hours) and episodes that last up to 7 days but terminate spontaneously. Cardioversion is not needed for this self-limiting condition.

Persistent AF lasts longer than 7 days, and often requires electrical or pharmacological cardioversion.

Permanent AF is used to describe instances in which cardioversion has failed (or has not been attempted) and the arrhythmia is continuous.

These categories are not mutually exclusive—a patient may primarily have paroxysmal AF, with an occasional episode of persistent AF. The term recurrent AF is used when 2 or more episodes of paroxysmal or persistent AF occur.

Warfarin or aspirin? An anticoagulation risk tool

CHADS₂ is a validated risk stratification scheme that offers help in making decisions about anticoagulation therapy. Each of the letters in this acronym represents a risk factor, and carries a certain number of points:

Congestive heart failure (1 point)
Hypertension (1 point)
Age >75 years (1 point)
Diabetes (1 point)
Stroke (2 points)

Patients with a score of ≥3 are at high risk and need to be treated with warfarin; those with a score of 0 are at low risk and can be managed with aspirin. For patients with a score of 1 or 2, the choice of warfarin or aspirin should be based on clinician assessment and patient preference.

Source: Gage BF, et al. JAMA. 2001.²⁴

AF typically linked to heart conditions—but not always

Chronic cardiac conditions commonly associated with AF include ischemic heart disease, congestive heart failure (CHF), hypertension, and rheumatic mitral valve disease. Recurrent AF may also be associated with atrial flutter, Wolff-Parkinson-White (WPW) syndrome, or atrioventricular (AV) nodal reentrant tachycardia. It is essential to recognize the presence of such conditions, because treatment of the primary arrhythmia may reduce or eliminate the incidence of recurrent AF. ⁶

There are also noncardiac causes of AF—eg, excessive alcohol intake (“holiday heart syndrome”), pulmonary embolism and other pulmonary diseases, and hyperthyroidism and other metabolic disorders. Lone AF, a term used when the patient is younger than 60 years of age and has neither clinical nor echocardiographic evidence of cardiopulmonary disease, is a diagnosis of exclusion. About 30% to 45% of cases of paroxysmal AF and 20% to 25% of persistent AF are considered to be lone AF.¹

EKG, x-ray, and echo: The role of each

Although some patients are asymptomatic, AF patients typically present with palpitations, dyspnea, fatigue, chest pain, or dizziness. A stroke may also be the first indication that a patient has AF.

A normal pulse rules out AF,⁷ and an irregular pulse should be an indication for an electrocardiogram (EKG). In most cases, a diagnosis can be made from the results of a 12-lead EKG. However, when diagnosis is uncertain or symptoms are paroxysmal, a Holter monitor or event recorder may be required.

Thyroid, renal, and hepatic function tests, serum electrolytes, and hemograms may help to rule out reversible causes of AF. Chest x-ray is valuable in diagnosing CHF, as well as lung pathology. Recent guidelines recommend that all patients who present with AF undergo echocardiography to evaluate for valvular heart disease, left and right atrial size, left ventricular size and function, left ventricular hypertrophy, and pericardial disease.¹ Transesophageal echocardiogram (TEE) should be used to detect intracardiac clots in patients who have had an embolic event or when AF has lasted for more than 48 hours and cardioversion is being considered.

Rate vs rhythm control: What the research reveals

For hemodynamically unstable patients who present with AF and a rapid rate associated with cardiogenic shock, pulmonary edema, acute myocardial infarction, or unstable angina, urgent direct-current cardioversion is indicated. In less urgent cases, treatment is not so clear cut. Spontaneous conversion to sinus rhythm occurs in up to 60% of patients within 24 hours, and in about 80% of patients within 48 hours.⁸

Intuitively, restoring normal sinus rhythm seems superior to rate control, but several randomized trials^9-12 and one meta-analysis¹³ found no support for that belief when researchers looked at mortality, thromboembolic events, and major hemorrhage.

One of the largest studies was the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM), which involved more than 4000 patients with paroxysmal and persistent AF who were randomized to either rate control or rhythm control.⁹ The research revealed a nonsignificant trend toward an increased death rate with the rhythm-control strategy—a 5-year mortality rate of 24% vs 21% for patients in the rate-control group. A trend toward higher risk of ischemic stroke, particularly associated with the lack of anticoagulation therapy, was also found in the rhythm-control group. That finding emphasizes the need for indefinite anticoagulation, independent of the use of a rate-control or rhythm-control approach.

A retrospective subanalysis of the AFFIRM trial that evaluated patients on the basis of a number of independent treatment variables found that sinus rhythm, in and of itself, was actually associated with a lower risk of death. But the antiarrhythmic agents that are often needed to achieve sinus rhythm are not associated with higher rates of survival. According to the researchers, this finding suggests that the drugs’ beneficial antiarrhythmic effects are offset by their adverse effects.¹⁴

Age is another confounding factor. Most of the AFFIRM subjects were relatively older, with a mean age of 69.7 years. In another study, rhythm control was found to be beneficial in young patients (mean age of 38.6 years) with AF and rheumatic valvular heart disease, in terms of morbidity and mortality.¹⁵

With no single treatment strategy emerging as the best approach, guidelines offer help in determining whether to pursue a rate-control or rhythm-control strategy for a particular patient. The recommendations of the British National Institute for Health and Clinical Excellence (NICE) guideline for AF,¹⁶ developed on the basis of a systematic literature review as well as expert consensus, are summarized here.

When should you opt for rate control?

The NICE guideline recommends rate control as the initial choice for patients who have persistent AF and:

• are >65 years of age
• have coronary artery disease
• do not have CHF
• are not candidates for cardioversion
• have contraindications to antiarrhythmic drugs.¹⁶

The American College of Cardiology (ACC), American Heart Association (AHA), and European Society of Cardiology (ESC) guidelines recommend maintaining a ventricular rate during AF of 60 to 80 beats per minute at rest and 90 to 115 beats per minute during exercise.¹

Which drug for which patient?

Beta-blockers and nondihydropyridine calcium channel blockers (verapamil and diltiazem) and digoxin slow conduction through the AV node. Compared with placebo, beta-blockers and calcium channel blockers are effective for controlling the ventricular rate in patients with AF, both at rest and during exercise.¹⁷ In the AFFIRM trial, rate control was achieved in 70% of patients treated with beta-blockers vs 54% of patients taking calcium channel blockers.⁹

That said, the type of drug you use to achieve rate control should be an individual decision based on characteristics of your particular patient. In general, beta-blockers are preferable for patients with myocardial infarction or ischemia, and for any patient in a high adrenergic state, whereas calcium channel blockers should be used for patients with severe asthma or chronic obstructive pulmonary disease. Consider using digoxin for patients with CHF or hypotension, because both beta-blockers and calcium channel blockers can precipitate hemodynamic deterioration in these patients.

Digoxin has a relatively slow onset of action, however, and is less effective than beta-blockers or calcium channel blockers for rate control. What’s more, digoxin is ineffective for slowing the heart rate during exercise or in hyperadrenergic states. Thus, combination therapy will be needed to achieve adequate rate control in many cases.

Agents that predominantly block AV conduction, such as beta-blockers, calcium channel blockers, and digoxin, are contraindicated in patients with WPW syndrome and wide-complex ventricular response related to the preexcitation syndrome. That’s because these drugs can trigger an antegrade conduction along the accessory pathway.¹⁸ In this subset of patients, use a Class 1 antiarrhythmic such as flecainide or procainamide, or amiodarone for rate control¹ (TABLE 1).

TABLE 1
Rate-control agents: A review of the options

When should you consider cardioversion?

The NICE guidelines recommend rhythm control as the initial choice for patients who:

• are symptomatic
• are <65 years old
• are presenting for the first time with lone AF or AF secondary to a condition that has been treated or corrected
• have CHF.¹⁶

While the guidelines recommend restoring sinus rhythm in patients with heart failure, a recent study suggests that rhythm control is no more effective for reducing the rate of death from cardiovascular causes compared to a rate-control strategy in this patient population.¹⁹ As with other aspects of AF management for which there is no definitive approach, individualized factors—including patient preference—should be your guide.

Electrical vs pharmacological cardioversion. Sinus rhythm can be established with electrical or pharmacological cardioversion. Electrical cardioversion, in which an external defibrillator delivers an electric shock that’s synchronized with the QRS complex, is usually well tolerated; embolization, pulmonary edema, and other arrhythmias are infrequent complications. Cardioversion with biphasic waveform defibrillation typically uses less energy and may have greater efficacy than monophasic waveforms.

The success rate of electrical cardioversion is higher than that of pharmacological cardioversion.⁸ But the use of electrical cardioversion is limited by the need for general anesthesia or conscious sedation for pain control. Pharmacological cardioversion is more effective for patients who have had AF for <48 hours; after that, the conversion rate drops considerably, and electrical cardioversion is often needed to restore sinus rhythm in a patient whose AF has lasted more than 7 days. A variety of antiarrhythmic drugs (TABLE 2), including propafenone, flecainide, ibutilide, and amiodarone, can be used to restore sinus rhythm. But because of the proarrhythmic potential of most of these agents, patients should be monitored in the hospital while drug therapy is initiated. After sinus rhythm is restored, maintenance therapy may be required.

Whether cardioversion is achieved by electrical or pharmacological means, it is associated with an increased risk of thromboembolism, especially in patients whose AF has persisted for >48 hours. Adequate anticoagulation with warfarin (international normalized rate of 2-3) should be achieved 3 weeks prior to cardioversion and continued for 4 weeks thereafter. Alternatively, excluding atrial thrombus by TEE paves the way for early cardioversion, using IV heparin or low-molecular-weight heparin for anticoagulation.

TABLE 2
Pharmacological cardioversion: Typical drugs and doses

Maintaining sinus rhythm: Choosing the right drug

Without chronic antiarrhythmic therapy, only about 30% of patients with AF will remain in normal sinus rhythm after a year.²⁰ Of the drugs that can be used to maintain sinus rhythm—amiodarone, disopyramide, flecainide, propafenone, and sotalol—amiodarone is the most effective. In the Canadian Trial of Atrial Fibrillation,²¹ 403 patients treated with amiodarone, sotalol, or propafenone were followed for 16 months. The recurrence rate for the amiodarone group was 35%, compared with 63% for those being treated with sotalol or propafenone.

Adverse effects to consider

Amiodarone is less proarrhythmic than the other antiarrhythmic agents, but it is associated with serious noncardiac toxicities, including pulmonary, thyroid, neurologic, hepatic, optic, and dermatologic adverse effects. In addition, amiodarone can increase plasma levels of several drugs, including digoxin and warfarin, and periodic monitoring of the doses of these medications is essential. Adding enalapril, an angiotensin-converting enzyme inhibitor, or irbesartan, an angiotensin receptor blocker, can enhance the efficacy of amiodarone in maintaining normal sinus rhythm after cardioversion.

Thus, the choice of medication to maintain sinus rhythm should be individualized, based on the patient’s underlying cardiac condition and the safety profile of the antiarrhythmics being considered. (TABLE 3). The ACC/AHA/ESC guidelines recommend class 1C agents flecainide and propafenone as first-line therapy for maintaining sinus rhythm in patients with structurally normal hearts.¹ But because of their proarrhythmic and negative ionotropic effects, class 1C agents should not be given to patients who have heart failure or ischemia. Amiodarone and dofetilide are the preferred agents for maintaining sinus rhythm in patients with heart failure and severe left ventricular hypertrophy, and dofetilide, amiodarone, and sotalol are best suited for patients with ischemic heart disease.

Pill-in-the-pocket. For selected patients with paroxysmal AF and a structurally normal heart, a “pill-in-the-pocket” strategy is an option—provided it has been tried in the hospital and proven to be safe. A patient using this strategy would self-administer a single dose of a class 1C antiarrhythmic agent—eg, 600 mg propafenone or 300 mg flecainide—at the onset of an acute episode of AF. Concomitant administration of a beta-blocker or calcium channel blocker is recommended to prevent development of atrial flutter with rapid AV conduction.

TABLE 3
Maintaining sinus rhythm in patients with AF

Using anticoagulation as prophylaxis

Judicious use of antithrombotic prophylaxis can significantly reduce the incidence of strokes associated with AF, regardless of whether you pursue a rate-control or rhythm-control strategy. Despite clear evidence of the efficacy of warfarin and aspirin in this patient population, anticoagulation remains underused in clinical practice.

If AF recurs or the patient develops chronic AF, the AFFIRM trial suggests the need for long-term anticoagulation for patients with thromboembolic risk factors.⁹

Adjusted-dose warfarin gets best results. A meta-analysis of 29 randomized trials from 1996 to 2007 involving 28,044 patients (mean age, 71 years; mean follow-up, 1.5 years) assessed the benefits of antithrombotic therapy for patients with AF.²² Compared with the controls, adjusted-dose warfarin (6 trials, 2900 participants) and antiplatelet agents (8 trials, 4876 participants) reduced stroke by 64% (95% confidence interval [CI], 49%-74%) and 22% (95% CI, 6%-35%), respectively.

Adjusted-dose warfarin was substantially more effective than antiplatelet therapy (12 trials, 12,963 participants; relative risk reduction, 39% [95% CI, 22%-52%]). The absolute risk reduction (ARR) with adjusted-dose warfarin in all strokes was 2.7% per year (number needed to treat [NNT] for 1 year to prevent 1 stroke was 37) for primary prevention and 8.4% per year (NNT, 12) for secondary prevention. Aspirin showed an ARR of 0.8% per year (NNT, 125) for primary prevention trials and 2.5% per year (NNT, 40) for secondary prevention trials. The absolute increase in major extracranial hemorrhage was small (≤0.3% per year).²²

A recent Cochrane review of 8 randomized trials with a total of 9598 patients concluded that adjusted-dose warfarin reduces stroke and other major vascular events in patients with nonvalvular AF by about one third, compared with antiplatelet therapy alone.²³

Warfarin or aspirin? Tools to help you decide

The risk of stroke varies considerably among patients with AF, depending on age and history of thromboembolic events, among other risk factors. What’s more, anticoagulation therapy carries an inherent risk of increased bleeding, making its use a complicated decision. A validated stroke risk stratification scheme like the CHADS₂ can help.²⁴ (See “Warfarin or aspirin? An anticoagulation risk tool”.)

The ACC/AHA/ESC guidelines recommend an alternate means of determining when anticoagulation is needed. The recommended risk stratification scheme divides risk factors for stroke into 3 categories:

• weak/less validated (female gender, age 65-74 years, coronary artery disease, thyrotoxicosis)
• moderate (≥75 years of age, hypertension, heart failure, LV ejection fraction ≤35%, diabetes mellitus)
• high (previous stroke, TIA, or embolism; mitral stenosis, prosthetic heart valve).

The guidelines recommend warfarin therapy for any patient with any high-risk factor or 2 or more moderate-risk factors; aspirin therapy for patients with no moderate- or high-risk factors; and aspirin or warfarin for patients with 1 moderate-risk factor.¹

When conventional therapy fails

For patients who do not respond to conventional therapy, other options, including radiofrequency catheter ablation and pacemakers, may be effective in controlling symptoms and improving quality of life. In a recent RCT of 70 patients 18 to 75 years of age who experienced monthly symptomatic episodes of AF, the recurrence rate at the end of the 12-month follow-up was 13% after pulmonary vein isolation with radiofrequency ablation compared with 63% after treatment with antiarrhythmic drugs (P<.001). The rate of hospitalization was also significantly lower in the radiofrequency ablation group: 9% compared with 54% in the antiarrhythmia group (P<.001).²⁵ Another option to consider for patients who require cardiac surgery for other reasons is left atrial appendage (LAA) occlusion or ligation at the time of surgery. This may prevent cardiac embolization, because the vast majority of thrombi in nonvalvular AF involve the LAA.

Correspondence
Shobha Rao, MD, University of Texas Southwestern Family Medicine Residency Program, 6263 Harry Hines Blvd., Clinical 1 Building, Dallas, TX 75390; [email protected].

Evidence summary

As many as 25% of patients with GAS pharyngitis remain culture-positive after an adequate regimen of antibiotic therapy and are deemed GAS carriers.¹ Appropriate screening and management of asymptomatic carriers continues to cause confusion.

Routine treatment is usually unnecessary

The Infectious Diseases Society of America (IDSA) considers GAS carriers at low risk for developing complications and spreading infection to close contacts.² The 2002 IDSA practice guidelines recommend against routine screening for and treatment of GAS carriage except under the circumstances (2 through 7) outlined in the evidence-based answer.² It may be reasonable to treat patients whose carrier status is unknown when they have a second case of pharyngitis. For known GAS-positive patients, however, repeated episodes of pharyngitis over months or years should raise suspicion of intercurrent viral pharyngitis rather than true GAS pharyngitis.

When you should consider routine treatment

Some experts practicing in areas with a high prevalence of acute rheumatic fever take a different position: They favor routine treatment of patients with active pharyngitis and a positive throat culture, even if the patient is a known GAS carrier.³

No clear consensus on prophylaxis

In 1995, the Centers for Disease Control and Prevention convened a consensus group to address the issue of prophylaxis for people exposed to GAS-positive carriers, but the consensus group failed to reach a definitive conclusion.⁴

Clindamycin works; penicillin + rifampin is also effective

Most RCTs investigating effective antibiotic treatment of GAS target cases of acute pharyngitis. A wide variety of antibiotics have been studied, including cefadroxil, amoxicillin, amoxicillin/clavulanate, cefuroxime, azithromycin, cefprozil, and cephalexin. We evaluated 41 of 43 studies of treatment of acute GAS. Only 2 RCTs specifically address effective antibiotic regimens for treating GAS carriers.

The most recent study demonstrated a significantly greater eradication rate with oral clindamycin than penicillin plus rifampin (P<.025).⁵ Compared with penicillin plus rifampin after 3 weeks of therapy, the number needed to treat (NNT) for clindamycin was 4.⁵

An older study found intramuscular penicillin plus 4 days of oral rifampin superior to intramuscular penicillin alone (P<.005) or no treatment at all (P<.0005) for eradicating GAS in carriers.¹ Compared with placebo after 3 weeks of therapy, the NNT for penicillin plus rifampin was 2.¹

The IDSA recommends a 10-day course of amoxicillin/clavulanate as an alternative treatment option.²

Recommendations

The 2006 Red Book: Report of the Committee on Infectious Diseases notes 6 possible indications for treating GAS carriers; they’re nearly identical to circumstances 2 through 7 in the evidence-based answer.⁶ The Red Book also acknowledges several treatment options, including clindamycin, amoxicillin, azithromycin, and penicillin plus rifampin. A 10-day course of oral clindamycin, however, is the therapy of choice.⁶

Evidence summary

As many as 25% of patients with GAS pharyngitis remain culture-positive after an adequate regimen of antibiotic therapy and are deemed GAS carriers.¹ Appropriate screening and management of asymptomatic carriers continues to cause confusion.

Routine treatment is usually unnecessary

The Infectious Diseases Society of America (IDSA) considers GAS carriers at low risk for developing complications and spreading infection to close contacts.² The 2002 IDSA practice guidelines recommend against routine screening for and treatment of GAS carriage except under the circumstances (2 through 7) outlined in the evidence-based answer.² It may be reasonable to treat patients whose carrier status is unknown when they have a second case of pharyngitis. For known GAS-positive patients, however, repeated episodes of pharyngitis over months or years should raise suspicion of intercurrent viral pharyngitis rather than true GAS pharyngitis.

When you should consider routine treatment

Some experts practicing in areas with a high prevalence of acute rheumatic fever take a different position: They favor routine treatment of patients with active pharyngitis and a positive throat culture, even if the patient is a known GAS carrier.³

No clear consensus on prophylaxis

In 1995, the Centers for Disease Control and Prevention convened a consensus group to address the issue of prophylaxis for people exposed to GAS-positive carriers, but the consensus group failed to reach a definitive conclusion.⁴

Clindamycin works; penicillin + rifampin is also effective

Most RCTs investigating effective antibiotic treatment of GAS target cases of acute pharyngitis. A wide variety of antibiotics have been studied, including cefadroxil, amoxicillin, amoxicillin/clavulanate, cefuroxime, azithromycin, cefprozil, and cephalexin. We evaluated 41 of 43 studies of treatment of acute GAS. Only 2 RCTs specifically address effective antibiotic regimens for treating GAS carriers.

The most recent study demonstrated a significantly greater eradication rate with oral clindamycin than penicillin plus rifampin (P<.025).⁵ Compared with penicillin plus rifampin after 3 weeks of therapy, the number needed to treat (NNT) for clindamycin was 4.⁵

An older study found intramuscular penicillin plus 4 days of oral rifampin superior to intramuscular penicillin alone (P<.005) or no treatment at all (P<.0005) for eradicating GAS in carriers.¹ Compared with placebo after 3 weeks of therapy, the NNT for penicillin plus rifampin was 2.¹

The IDSA recommends a 10-day course of amoxicillin/clavulanate as an alternative treatment option.²

Recommendations

The 2006 Red Book: Report of the Committee on Infectious Diseases notes 6 possible indications for treating GAS carriers; they’re nearly identical to circumstances 2 through 7 in the evidence-based answer.⁶ The Red Book also acknowledges several treatment options, including clindamycin, amoxicillin, azithromycin, and penicillin plus rifampin. A 10-day course of oral clindamycin, however, is the therapy of choice.⁶

Evidence summary

As many as 25% of patients with GAS pharyngitis remain culture-positive after an adequate regimen of antibiotic therapy and are deemed GAS carriers.¹ Appropriate screening and management of asymptomatic carriers continues to cause confusion.

Routine treatment is usually unnecessary

The Infectious Diseases Society of America (IDSA) considers GAS carriers at low risk for developing complications and spreading infection to close contacts.² The 2002 IDSA practice guidelines recommend against routine screening for and treatment of GAS carriage except under the circumstances (2 through 7) outlined in the evidence-based answer.² It may be reasonable to treat patients whose carrier status is unknown when they have a second case of pharyngitis. For known GAS-positive patients, however, repeated episodes of pharyngitis over months or years should raise suspicion of intercurrent viral pharyngitis rather than true GAS pharyngitis.

When you should consider routine treatment

Some experts practicing in areas with a high prevalence of acute rheumatic fever take a different position: They favor routine treatment of patients with active pharyngitis and a positive throat culture, even if the patient is a known GAS carrier.³

No clear consensus on prophylaxis

In 1995, the Centers for Disease Control and Prevention convened a consensus group to address the issue of prophylaxis for people exposed to GAS-positive carriers, but the consensus group failed to reach a definitive conclusion.⁴

Clindamycin works; penicillin + rifampin is also effective

Most RCTs investigating effective antibiotic treatment of GAS target cases of acute pharyngitis. A wide variety of antibiotics have been studied, including cefadroxil, amoxicillin, amoxicillin/clavulanate, cefuroxime, azithromycin, cefprozil, and cephalexin. We evaluated 41 of 43 studies of treatment of acute GAS. Only 2 RCTs specifically address effective antibiotic regimens for treating GAS carriers.

The most recent study demonstrated a significantly greater eradication rate with oral clindamycin than penicillin plus rifampin (P<.025).⁵ Compared with penicillin plus rifampin after 3 weeks of therapy, the number needed to treat (NNT) for clindamycin was 4.⁵

An older study found intramuscular penicillin plus 4 days of oral rifampin superior to intramuscular penicillin alone (P<.005) or no treatment at all (P<.0005) for eradicating GAS in carriers.¹ Compared with placebo after 3 weeks of therapy, the NNT for penicillin plus rifampin was 2.¹

The IDSA recommends a 10-day course of amoxicillin/clavulanate as an alternative treatment option.²

Recommendations

The 2006 Red Book: Report of the Committee on Infectious Diseases notes 6 possible indications for treating GAS carriers; they’re nearly identical to circumstances 2 through 7 in the evidence-based answer.⁶ The Red Book also acknowledges several treatment options, including clindamycin, amoxicillin, azithromycin, and penicillin plus rifampin. A 10-day course of oral clindamycin, however, is the therapy of choice.⁶

Evidence summary

Brief counseling works

Good evidence suggests that physician-administered smoking cessation counseling lasting less than 3 minutes improves quit rates.¹ A Cochrane analysis of pooled data from 17 randomized trials that compared brief advice to no advice or usual care showed a small but significant increase in the odds of smoking cessation (odds ratio [OR]=1.74; 95% confidence interval [CI], 1.48-2.05).² The absolute difference in cessation rate was about 2.5% (number needed to treat [NNT]=40).

Another systematic review of 188 RCTs concluded that an estimated 2% (95% CI, 1%-3%; P<.001) of all smokers stopped smoking and did not relapse for as long as a year after receiving advice and encouragement to quit smoking from their physician in a single routine consultation.³

NRT is effective and safe for heart patients

NRT reduces withdrawal symptoms associated with stopping smoking by partially replacing nicotine in the blood. Abstinence rates are superior to placebo based on a Cochrane review (OR=1.77; 95% CI, 1.66-1.88; NNT=20; 95% CI, 17-23).⁴ The Cochrane review also concluded that all commercially available forms of NRT are effective for smoking cessation. Also, recent studies have established no association between NRT and further cardiac events.¹

Antidepressants are good treatment options

Bupropion acts by increasing brain levels of dopamine and norepinephrine and is a nicotine antagonist. A large double-blind, placebo controlled trial compared the relative efficacy of sustained-release bupropion (n=244), nicotine patch (n=244), bupropion plus nicotine patch (n=245), and placebo (n=160).⁵ At 1 year, the bupropion groups had higher self-reported point-prevalence abstinence rates (abstinence during the previous 7 days) than the placebo and nicotine-patch-alone groups (bupropion 30%, placebo 16%, nicotine-patch-alone 16%; absolute risk reduction [ARR]=0.14, NNT=7, P<.001).

Continuous abstinence (abstinence from quit date) was also higher for the bupropion groups compared with placebo (bupropion 18%, placebo 6%; ARR=0.12; NNT=8; P<.001). Adding nicotine replacement to bupropion therapy increased 1-year smoking cessation rates by 5% over bupropion alone but was not statistically significant.

A Cochrane review assessing the efficacy of antidepressants for smoking cessation showed that, when used as monotherapy, bupropion (31 trials; OR=1.94; 95% CI, 1.72-2.19) and nortriptyline (4 trials; OR=2.34; 95% CI, 1.61-3.41) both doubled the odds of smoking cessation.⁶

Another option: Varenicline

Varenicline, a partial agonist at the α4β2 nicotinic acetylcholine receptor, aids smoking cessation by relieving nicotine withdrawal symptoms. A Cochrane meta-analysis concluded that varenicline resulted in significantly greater continuous abstinence at 12 months than placebo (OR=3.22; 95% CI, 2.43-4.27; NNT=8; 95% CI, 5-11).⁷

Recommendations

The US Preventive Service Task Force (USPSTF) strongly recommends that clinicians screen all adults for tobacco use and provide tobacco cessation interventions as needed.⁸ The USPSTF’s Clinical Practice Guideline for treating tobacco dependence recommends following a 5-step (5 A’s) intervention for smoking cessation in patients willing to quit.¹

1. Ask the patient about smoking status at every visit.
2. Advise the patient to stop smoking.
3. Assess the patient’s willingness to quit.
4. Assist the patient by setting a date to quit smoking, providing self-help materials, and recommending the use of pharmacologic agents.
5. Arrange for follow-up visits.

Evidence summary

Brief counseling works

Good evidence suggests that physician-administered smoking cessation counseling lasting less than 3 minutes improves quit rates.¹ A Cochrane analysis of pooled data from 17 randomized trials that compared brief advice to no advice or usual care showed a small but significant increase in the odds of smoking cessation (odds ratio [OR]=1.74; 95% confidence interval [CI], 1.48-2.05).² The absolute difference in cessation rate was about 2.5% (number needed to treat [NNT]=40).

Another systematic review of 188 RCTs concluded that an estimated 2% (95% CI, 1%-3%; P<.001) of all smokers stopped smoking and did not relapse for as long as a year after receiving advice and encouragement to quit smoking from their physician in a single routine consultation.³

NRT is effective and safe for heart patients

NRT reduces withdrawal symptoms associated with stopping smoking by partially replacing nicotine in the blood. Abstinence rates are superior to placebo based on a Cochrane review (OR=1.77; 95% CI, 1.66-1.88; NNT=20; 95% CI, 17-23).⁴ The Cochrane review also concluded that all commercially available forms of NRT are effective for smoking cessation. Also, recent studies have established no association between NRT and further cardiac events.¹

Antidepressants are good treatment options

Bupropion acts by increasing brain levels of dopamine and norepinephrine and is a nicotine antagonist. A large double-blind, placebo controlled trial compared the relative efficacy of sustained-release bupropion (n=244), nicotine patch (n=244), bupropion plus nicotine patch (n=245), and placebo (n=160).⁵ At 1 year, the bupropion groups had higher self-reported point-prevalence abstinence rates (abstinence during the previous 7 days) than the placebo and nicotine-patch-alone groups (bupropion 30%, placebo 16%, nicotine-patch-alone 16%; absolute risk reduction [ARR]=0.14, NNT=7, P<.001).

Continuous abstinence (abstinence from quit date) was also higher for the bupropion groups compared with placebo (bupropion 18%, placebo 6%; ARR=0.12; NNT=8; P<.001). Adding nicotine replacement to bupropion therapy increased 1-year smoking cessation rates by 5% over bupropion alone but was not statistically significant.

A Cochrane review assessing the efficacy of antidepressants for smoking cessation showed that, when used as monotherapy, bupropion (31 trials; OR=1.94; 95% CI, 1.72-2.19) and nortriptyline (4 trials; OR=2.34; 95% CI, 1.61-3.41) both doubled the odds of smoking cessation.⁶

Another option: Varenicline

Varenicline, a partial agonist at the α4β2 nicotinic acetylcholine receptor, aids smoking cessation by relieving nicotine withdrawal symptoms. A Cochrane meta-analysis concluded that varenicline resulted in significantly greater continuous abstinence at 12 months than placebo (OR=3.22; 95% CI, 2.43-4.27; NNT=8; 95% CI, 5-11).⁷

Recommendations

The US Preventive Service Task Force (USPSTF) strongly recommends that clinicians screen all adults for tobacco use and provide tobacco cessation interventions as needed.⁸ The USPSTF’s Clinical Practice Guideline for treating tobacco dependence recommends following a 5-step (5 A’s) intervention for smoking cessation in patients willing to quit.¹

1. Ask the patient about smoking status at every visit.
2. Advise the patient to stop smoking.
3. Assess the patient’s willingness to quit.
4. Assist the patient by setting a date to quit smoking, providing self-help materials, and recommending the use of pharmacologic agents.
5. Arrange for follow-up visits.

Evidence summary

Brief counseling works

Good evidence suggests that physician-administered smoking cessation counseling lasting less than 3 minutes improves quit rates.¹ A Cochrane analysis of pooled data from 17 randomized trials that compared brief advice to no advice or usual care showed a small but significant increase in the odds of smoking cessation (odds ratio [OR]=1.74; 95% confidence interval [CI], 1.48-2.05).² The absolute difference in cessation rate was about 2.5% (number needed to treat [NNT]=40).

Another systematic review of 188 RCTs concluded that an estimated 2% (95% CI, 1%-3%; P<.001) of all smokers stopped smoking and did not relapse for as long as a year after receiving advice and encouragement to quit smoking from their physician in a single routine consultation.³

NRT is effective and safe for heart patients

NRT reduces withdrawal symptoms associated with stopping smoking by partially replacing nicotine in the blood. Abstinence rates are superior to placebo based on a Cochrane review (OR=1.77; 95% CI, 1.66-1.88; NNT=20; 95% CI, 17-23).⁴ The Cochrane review also concluded that all commercially available forms of NRT are effective for smoking cessation. Also, recent studies have established no association between NRT and further cardiac events.¹

Antidepressants are good treatment options

Bupropion acts by increasing brain levels of dopamine and norepinephrine and is a nicotine antagonist. A large double-blind, placebo controlled trial compared the relative efficacy of sustained-release bupropion (n=244), nicotine patch (n=244), bupropion plus nicotine patch (n=245), and placebo (n=160).⁵ At 1 year, the bupropion groups had higher self-reported point-prevalence abstinence rates (abstinence during the previous 7 days) than the placebo and nicotine-patch-alone groups (bupropion 30%, placebo 16%, nicotine-patch-alone 16%; absolute risk reduction [ARR]=0.14, NNT=7, P<.001).

Continuous abstinence (abstinence from quit date) was also higher for the bupropion groups compared with placebo (bupropion 18%, placebo 6%; ARR=0.12; NNT=8; P<.001). Adding nicotine replacement to bupropion therapy increased 1-year smoking cessation rates by 5% over bupropion alone but was not statistically significant.

A Cochrane review assessing the efficacy of antidepressants for smoking cessation showed that, when used as monotherapy, bupropion (31 trials; OR=1.94; 95% CI, 1.72-2.19) and nortriptyline (4 trials; OR=2.34; 95% CI, 1.61-3.41) both doubled the odds of smoking cessation.⁶

Another option: Varenicline

Varenicline, a partial agonist at the α4β2 nicotinic acetylcholine receptor, aids smoking cessation by relieving nicotine withdrawal symptoms. A Cochrane meta-analysis concluded that varenicline resulted in significantly greater continuous abstinence at 12 months than placebo (OR=3.22; 95% CI, 2.43-4.27; NNT=8; 95% CI, 5-11).⁷

Recommendations

The US Preventive Service Task Force (USPSTF) strongly recommends that clinicians screen all adults for tobacco use and provide tobacco cessation interventions as needed.⁸ The USPSTF’s Clinical Practice Guideline for treating tobacco dependence recommends following a 5-step (5 A’s) intervention for smoking cessation in patients willing to quit.¹

1. Ask the patient about smoking status at every visit.
2. Advise the patient to stop smoking.
3. Assess the patient’s willingness to quit.
4. Assist the patient by setting a date to quit smoking, providing self-help materials, and recommending the use of pharmacologic agents.
5. Arrange for follow-up visits.

Evidence summary

Three large cohort studies determined that African Americans have a higher prevalence of hypertension and worse cardiovascular and renal outcomes when compared with white Americans. For African American patients, the standard blood pressure goals apply: below 140/90 mm Hg with uncomplicated hypertension and below 130/80 with diabetes or renal disease.¹

Dietary interventions

An RCT compared the effects of consuming the DASH diet (consisting of 4–5 servings of fruit, 4–5 servings of vegetables, 2–3 servings of low-fat dairy per day, and <25% fat) with a typical high-fat control diet among 459 adults with normal or elevated blood pressure.² Among 133 patients with hypertension, the DASH diet reduced systolic and diastolic blood pressure by 11.4 mm Hg (97.5% confidence interval [CI], –15.9 to –6.9) and 5.5 mm Hg (97.5% CI, –8.2 to –2.7) respectively when compared with the control diet. Among African Americans with hypertension, the DASH diet was even more beneficial, reducing their systolic and diastolic blood pressure by 13.2 mm Hg and 6.1 mm Hg respectively.¹

Another RCT studied the effect of different levels of dietary sodium in conjunction with the DASH diet.³ A total of 412 participants were randomly assigned to eat either a control diet or the DASH diet. Within the assigned diet, participants ate foods with high (150 mmol/d), intermediate (100 mmol/d), and low (50 mmol/d) levels of sodium in random order. In this study, low-sodium DASH diet was associated with additional lowering of blood pressure, an effect that was also found to be stronger for African Americans patients than others.³ When compared with the combination of the control diet and a high level of sodium, the DASH diet and a low level of sodium lowered systolic blood pressure by 11.5 mm Hg for participants with hypertension (12.6 mm Hg for blacks; 9.5 mm Hg for others), and by 7.1 mm Hg for participants without hypertension (7.2 mm Hg for blacks; 6.9 mm Hg for others).³

Medical interventions

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial⁴ (ALLHAT) and African American Study of Kidney Disease and Hypertension⁵ (AASK) have demonstrated the benefit of blood pressure reduction using specific classes of antihypertensive agents.

The ALLHAT trial, a double-blind RCT of 42,448 high-risk hypertensive patients aged >55 years, compared chlorthalidone (a thiazide-type diuretic) with amlodipine (Norvasc), lisinopril (Prinivil, Zestril), or doxazosin (Cardura). In this study, which included 36% African Americans, chlorthalidone, lisinopril, and amlodipine did not differ in preventing major cardiovascular events. However, lisinopril was associated with an increased risk for heart failure (relative risk [RR] for African Americans=1.32; 95% CI, 1.11–1.58) and stroke (RR for African Americans=1.4; 95% CI, 1.17–1.68), and amlodipine was associated with a higher risk of heart failure (RR in African Americans=1.47; 95% CI, 1.24–1.74). Additionally, ACE inhibitor–induced angioedema or cough occurred more frequently among African American patients than white patients.⁴

Although a randomized controlled trial⁵ and a review of multiple studies⁶ demonstrated that African Americans may be less responsive to monotherapy with ACE inhibitors, the AASK trial confirmed that ACE inhibitors can provide significant clinical benefits for African Americans with hypertensive renal disease. AASK, a double-blind RCT of 1094 African American patients with renal insufficiency, compared the effects of an ACE inhibitor (ramipril [Altace]), a dihydropyridine calcium channel blocker (amlodipine), or a beta blocker (metoprolol [Lopressor]) on the progression of hypertensive renal disease.

The study showed a 44% relative risk reduction (95% CI, 13%–65%; number needed to treat [NNT]=25) in progression to end-stage renal disease, and a significant decrease in the combined endpoints of glomerular filtration rate events (decrease >50%), end-stage renal disease, and death (decreased by 38%) in the ramipril group compared with the amlodipine group (95% CI, 13%–56%; NNT=56 per patient-year).^5,7 Metoprolol appeared to have intermediate outcomes.⁸

Recommendations from others

Both the International Society on Hypertension in Blacks (ISHIB) guidelines¹ and the JNC 7⁹ recommend therapeutic lifestyle modification that includes DASH diet, dietary sodium restriction, and weight reduction. Both guidelines recognize the importance of thiazide diuretics and recommend its use as first-line therapy or as a part of combination therapy for hypertension among African Americans. They also recommend initiating therapy with 2 agents for blood pressure significantly above target level (20/10 mm Hg above target per JNC 7, 15/10 mm Hg above target per ISHIB).

The ISHIB report emphasizes the need for not overlooking renal protection with an ACE inhibitor for African Americans with renal disease. The American Diabetes Association recommends that all patients with diabetes and hypertension be treated with a regimen that includes either an ACE inhibitor or an ARB.¹⁰

Evidence summary

Three large cohort studies determined that African Americans have a higher prevalence of hypertension and worse cardiovascular and renal outcomes when compared with white Americans. For African American patients, the standard blood pressure goals apply: below 140/90 mm Hg with uncomplicated hypertension and below 130/80 with diabetes or renal disease.¹

Dietary interventions

An RCT compared the effects of consuming the DASH diet (consisting of 4–5 servings of fruit, 4–5 servings of vegetables, 2–3 servings of low-fat dairy per day, and <25% fat) with a typical high-fat control diet among 459 adults with normal or elevated blood pressure.² Among 133 patients with hypertension, the DASH diet reduced systolic and diastolic blood pressure by 11.4 mm Hg (97.5% confidence interval [CI], –15.9 to –6.9) and 5.5 mm Hg (97.5% CI, –8.2 to –2.7) respectively when compared with the control diet. Among African Americans with hypertension, the DASH diet was even more beneficial, reducing their systolic and diastolic blood pressure by 13.2 mm Hg and 6.1 mm Hg respectively.¹

Another RCT studied the effect of different levels of dietary sodium in conjunction with the DASH diet.³ A total of 412 participants were randomly assigned to eat either a control diet or the DASH diet. Within the assigned diet, participants ate foods with high (150 mmol/d), intermediate (100 mmol/d), and low (50 mmol/d) levels of sodium in random order. In this study, low-sodium DASH diet was associated with additional lowering of blood pressure, an effect that was also found to be stronger for African Americans patients than others.³ When compared with the combination of the control diet and a high level of sodium, the DASH diet and a low level of sodium lowered systolic blood pressure by 11.5 mm Hg for participants with hypertension (12.6 mm Hg for blacks; 9.5 mm Hg for others), and by 7.1 mm Hg for participants without hypertension (7.2 mm Hg for blacks; 6.9 mm Hg for others).³

Medical interventions

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial⁴ (ALLHAT) and African American Study of Kidney Disease and Hypertension⁵ (AASK) have demonstrated the benefit of blood pressure reduction using specific classes of antihypertensive agents.

The ALLHAT trial, a double-blind RCT of 42,448 high-risk hypertensive patients aged >55 years, compared chlorthalidone (a thiazide-type diuretic) with amlodipine (Norvasc), lisinopril (Prinivil, Zestril), or doxazosin (Cardura). In this study, which included 36% African Americans, chlorthalidone, lisinopril, and amlodipine did not differ in preventing major cardiovascular events. However, lisinopril was associated with an increased risk for heart failure (relative risk [RR] for African Americans=1.32; 95% CI, 1.11–1.58) and stroke (RR for African Americans=1.4; 95% CI, 1.17–1.68), and amlodipine was associated with a higher risk of heart failure (RR in African Americans=1.47; 95% CI, 1.24–1.74). Additionally, ACE inhibitor–induced angioedema or cough occurred more frequently among African American patients than white patients.⁴

Although a randomized controlled trial⁵ and a review of multiple studies⁶ demonstrated that African Americans may be less responsive to monotherapy with ACE inhibitors, the AASK trial confirmed that ACE inhibitors can provide significant clinical benefits for African Americans with hypertensive renal disease. AASK, a double-blind RCT of 1094 African American patients with renal insufficiency, compared the effects of an ACE inhibitor (ramipril [Altace]), a dihydropyridine calcium channel blocker (amlodipine), or a beta blocker (metoprolol [Lopressor]) on the progression of hypertensive renal disease.

The study showed a 44% relative risk reduction (95% CI, 13%–65%; number needed to treat [NNT]=25) in progression to end-stage renal disease, and a significant decrease in the combined endpoints of glomerular filtration rate events (decrease >50%), end-stage renal disease, and death (decreased by 38%) in the ramipril group compared with the amlodipine group (95% CI, 13%–56%; NNT=56 per patient-year).^5,7 Metoprolol appeared to have intermediate outcomes.⁸

Recommendations from others

Both the International Society on Hypertension in Blacks (ISHIB) guidelines¹ and the JNC 7⁹ recommend therapeutic lifestyle modification that includes DASH diet, dietary sodium restriction, and weight reduction. Both guidelines recognize the importance of thiazide diuretics and recommend its use as first-line therapy or as a part of combination therapy for hypertension among African Americans. They also recommend initiating therapy with 2 agents for blood pressure significantly above target level (20/10 mm Hg above target per JNC 7, 15/10 mm Hg above target per ISHIB).

The ISHIB report emphasizes the need for not overlooking renal protection with an ACE inhibitor for African Americans with renal disease. The American Diabetes Association recommends that all patients with diabetes and hypertension be treated with a regimen that includes either an ACE inhibitor or an ARB.¹⁰

Evidence summary

Three large cohort studies determined that African Americans have a higher prevalence of hypertension and worse cardiovascular and renal outcomes when compared with white Americans. For African American patients, the standard blood pressure goals apply: below 140/90 mm Hg with uncomplicated hypertension and below 130/80 with diabetes or renal disease.¹

Dietary interventions

An RCT compared the effects of consuming the DASH diet (consisting of 4–5 servings of fruit, 4–5 servings of vegetables, 2–3 servings of low-fat dairy per day, and <25% fat) with a typical high-fat control diet among 459 adults with normal or elevated blood pressure.² Among 133 patients with hypertension, the DASH diet reduced systolic and diastolic blood pressure by 11.4 mm Hg (97.5% confidence interval [CI], –15.9 to –6.9) and 5.5 mm Hg (97.5% CI, –8.2 to –2.7) respectively when compared with the control diet. Among African Americans with hypertension, the DASH diet was even more beneficial, reducing their systolic and diastolic blood pressure by 13.2 mm Hg and 6.1 mm Hg respectively.¹

Another RCT studied the effect of different levels of dietary sodium in conjunction with the DASH diet.³ A total of 412 participants were randomly assigned to eat either a control diet or the DASH diet. Within the assigned diet, participants ate foods with high (150 mmol/d), intermediate (100 mmol/d), and low (50 mmol/d) levels of sodium in random order. In this study, low-sodium DASH diet was associated with additional lowering of blood pressure, an effect that was also found to be stronger for African Americans patients than others.³ When compared with the combination of the control diet and a high level of sodium, the DASH diet and a low level of sodium lowered systolic blood pressure by 11.5 mm Hg for participants with hypertension (12.6 mm Hg for blacks; 9.5 mm Hg for others), and by 7.1 mm Hg for participants without hypertension (7.2 mm Hg for blacks; 6.9 mm Hg for others).³

Medical interventions

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial⁴ (ALLHAT) and African American Study of Kidney Disease and Hypertension⁵ (AASK) have demonstrated the benefit of blood pressure reduction using specific classes of antihypertensive agents.

The ALLHAT trial, a double-blind RCT of 42,448 high-risk hypertensive patients aged >55 years, compared chlorthalidone (a thiazide-type diuretic) with amlodipine (Norvasc), lisinopril (Prinivil, Zestril), or doxazosin (Cardura). In this study, which included 36% African Americans, chlorthalidone, lisinopril, and amlodipine did not differ in preventing major cardiovascular events. However, lisinopril was associated with an increased risk for heart failure (relative risk [RR] for African Americans=1.32; 95% CI, 1.11–1.58) and stroke (RR for African Americans=1.4; 95% CI, 1.17–1.68), and amlodipine was associated with a higher risk of heart failure (RR in African Americans=1.47; 95% CI, 1.24–1.74). Additionally, ACE inhibitor–induced angioedema or cough occurred more frequently among African American patients than white patients.⁴

Although a randomized controlled trial⁵ and a review of multiple studies⁶ demonstrated that African Americans may be less responsive to monotherapy with ACE inhibitors, the AASK trial confirmed that ACE inhibitors can provide significant clinical benefits for African Americans with hypertensive renal disease. AASK, a double-blind RCT of 1094 African American patients with renal insufficiency, compared the effects of an ACE inhibitor (ramipril [Altace]), a dihydropyridine calcium channel blocker (amlodipine), or a beta blocker (metoprolol [Lopressor]) on the progression of hypertensive renal disease.

The study showed a 44% relative risk reduction (95% CI, 13%–65%; number needed to treat [NNT]=25) in progression to end-stage renal disease, and a significant decrease in the combined endpoints of glomerular filtration rate events (decrease >50%), end-stage renal disease, and death (decreased by 38%) in the ramipril group compared with the amlodipine group (95% CI, 13%–56%; NNT=56 per patient-year).^5,7 Metoprolol appeared to have intermediate outcomes.⁸

Recommendations from others

Both the International Society on Hypertension in Blacks (ISHIB) guidelines¹ and the JNC 7⁹ recommend therapeutic lifestyle modification that includes DASH diet, dietary sodium restriction, and weight reduction. Both guidelines recognize the importance of thiazide diuretics and recommend its use as first-line therapy or as a part of combination therapy for hypertension among African Americans. They also recommend initiating therapy with 2 agents for blood pressure significantly above target level (20/10 mm Hg above target per JNC 7, 15/10 mm Hg above target per ISHIB).

The ISHIB report emphasizes the need for not overlooking renal protection with an ACE inhibitor for African Americans with renal disease. The American Diabetes Association recommends that all patients with diabetes and hypertension be treated with a regimen that includes either an ACE inhibitor or an ARB.¹⁰

Evidence summary

Acne vulgaris is the most common cutaneous disorder, affecting about 45 million people in the United States. Five to 6 million acne-related visits are made to physicians in outpatient offices each year.¹

For mild noninflammatory (come-donal) acne, the preferred option is monotherapy with topical retinoids. Randomized controlled trials (RCTs) have proven the efficacy of tretinoin, an older retinoid for comedonal acne.² In one RCT, patients were randomly assigned to 1 of 3 treatment groups, each having 33 enrollees: patients in the first group received 0.1% tazarotene gel as twice daily application; the second group received 0.1% tazarotene gel in the evening and vehicle gel in the morning; the third group received vehicle gel twice daily. By 12 weeks, the first and second groups achieved significantly greater improvement in acne than the third group, based on mean percentage reduction in noninflammatory lesions (46% and 41% vs 2%; P=.002) and inflammatory lesions (38% and 34% vs 9%; P=.01).³ Another 12-week RCT of 237 patients with mild to moderate acne demonstrated superior efficacy with 0.1% adapalene cream over placebo (P<.05).⁴ While most studies did not compare the use of one retinoid vs another, a recent meta-analysis of placebo-controlled trials concluded that topical tazarotene is more effective in treating mild comedonal acne than adapalene or tretinoin, although it may be more likely to cause skin irritation.^6,7

A systematic review evaluating the evidence for treatment of acne found that combining topical antibiotics with topical retinoids or benzoyl peroxide is effective for moderate noninflammatory (come-donal) and mild to moderate inflammatory (papulopustular) acne.⁷ Because of its antibacterial and anti-comedogenic properties, benzoyl peroxide is preferred to retinoids for inflammatory acne. Another benefit of using benzoyl peroxide with antibiotic cream is its potential to reduce antibiotic-associated resistance to Propionibacterium acnes.^7,8

No comparative trials or meta-analyses compare efficacy of different combination therapies. A recent narrative review of clinical trials concluded that clindamycin plus benzoyl peroxide was more effective in reducing inflammatory lesions than monotherapy with either agent alone, and was similar in efficacy to benzoyl peroxide/erythromycin combination.⁸ Similarly, combination therapy with clindamycin and adapalene was superior to clindamycin alone in improving mild to moderate acne.⁹ Both 1% clindamycin and 2% erythromycin were comparable in reducing inflammatory and noninflammatory lesions for patients with moderate acne.¹⁰

Studies are ongoing for topical tetracycline, topical isotretinoin, and light and laser therapy in treatment of mild to moderate acne.

Recommendations from others

An expert review stated that treatment of acne should be individualized for best results.⁷ A report from the Global Alliance to Improve Outcomes in Acne states that topical retinoids are appropriate first-line therapy for all forms of acne and should be combined with topical antimicrobial therapy when inflammatory lesions are present.¹¹

Evidence summary

Acne vulgaris is the most common cutaneous disorder, affecting about 45 million people in the United States. Five to 6 million acne-related visits are made to physicians in outpatient offices each year.¹

For mild noninflammatory (come-donal) acne, the preferred option is monotherapy with topical retinoids. Randomized controlled trials (RCTs) have proven the efficacy of tretinoin, an older retinoid for comedonal acne.² In one RCT, patients were randomly assigned to 1 of 3 treatment groups, each having 33 enrollees: patients in the first group received 0.1% tazarotene gel as twice daily application; the second group received 0.1% tazarotene gel in the evening and vehicle gel in the morning; the third group received vehicle gel twice daily. By 12 weeks, the first and second groups achieved significantly greater improvement in acne than the third group, based on mean percentage reduction in noninflammatory lesions (46% and 41% vs 2%; P=.002) and inflammatory lesions (38% and 34% vs 9%; P=.01).³ Another 12-week RCT of 237 patients with mild to moderate acne demonstrated superior efficacy with 0.1% adapalene cream over placebo (P<.05).⁴ While most studies did not compare the use of one retinoid vs another, a recent meta-analysis of placebo-controlled trials concluded that topical tazarotene is more effective in treating mild comedonal acne than adapalene or tretinoin, although it may be more likely to cause skin irritation.^6,7

A systematic review evaluating the evidence for treatment of acne found that combining topical antibiotics with topical retinoids or benzoyl peroxide is effective for moderate noninflammatory (come-donal) and mild to moderate inflammatory (papulopustular) acne.⁷ Because of its antibacterial and anti-comedogenic properties, benzoyl peroxide is preferred to retinoids for inflammatory acne. Another benefit of using benzoyl peroxide with antibiotic cream is its potential to reduce antibiotic-associated resistance to Propionibacterium acnes.^7,8

No comparative trials or meta-analyses compare efficacy of different combination therapies. A recent narrative review of clinical trials concluded that clindamycin plus benzoyl peroxide was more effective in reducing inflammatory lesions than monotherapy with either agent alone, and was similar in efficacy to benzoyl peroxide/erythromycin combination.⁸ Similarly, combination therapy with clindamycin and adapalene was superior to clindamycin alone in improving mild to moderate acne.⁹ Both 1% clindamycin and 2% erythromycin were comparable in reducing inflammatory and noninflammatory lesions for patients with moderate acne.¹⁰

Studies are ongoing for topical tetracycline, topical isotretinoin, and light and laser therapy in treatment of mild to moderate acne.

Recommendations from others

An expert review stated that treatment of acne should be individualized for best results.⁷ A report from the Global Alliance to Improve Outcomes in Acne states that topical retinoids are appropriate first-line therapy for all forms of acne and should be combined with topical antimicrobial therapy when inflammatory lesions are present.¹¹

Evidence summary

Acne vulgaris is the most common cutaneous disorder, affecting about 45 million people in the United States. Five to 6 million acne-related visits are made to physicians in outpatient offices each year.¹

For mild noninflammatory (come-donal) acne, the preferred option is monotherapy with topical retinoids. Randomized controlled trials (RCTs) have proven the efficacy of tretinoin, an older retinoid for comedonal acne.² In one RCT, patients were randomly assigned to 1 of 3 treatment groups, each having 33 enrollees: patients in the first group received 0.1% tazarotene gel as twice daily application; the second group received 0.1% tazarotene gel in the evening and vehicle gel in the morning; the third group received vehicle gel twice daily. By 12 weeks, the first and second groups achieved significantly greater improvement in acne than the third group, based on mean percentage reduction in noninflammatory lesions (46% and 41% vs 2%; P=.002) and inflammatory lesions (38% and 34% vs 9%; P=.01).³ Another 12-week RCT of 237 patients with mild to moderate acne demonstrated superior efficacy with 0.1% adapalene cream over placebo (P<.05).⁴ While most studies did not compare the use of one retinoid vs another, a recent meta-analysis of placebo-controlled trials concluded that topical tazarotene is more effective in treating mild comedonal acne than adapalene or tretinoin, although it may be more likely to cause skin irritation.^6,7

A systematic review evaluating the evidence for treatment of acne found that combining topical antibiotics with topical retinoids or benzoyl peroxide is effective for moderate noninflammatory (come-donal) and mild to moderate inflammatory (papulopustular) acne.⁷ Because of its antibacterial and anti-comedogenic properties, benzoyl peroxide is preferred to retinoids for inflammatory acne. Another benefit of using benzoyl peroxide with antibiotic cream is its potential to reduce antibiotic-associated resistance to Propionibacterium acnes.^7,8

No comparative trials or meta-analyses compare efficacy of different combination therapies. A recent narrative review of clinical trials concluded that clindamycin plus benzoyl peroxide was more effective in reducing inflammatory lesions than monotherapy with either agent alone, and was similar in efficacy to benzoyl peroxide/erythromycin combination.⁸ Similarly, combination therapy with clindamycin and adapalene was superior to clindamycin alone in improving mild to moderate acne.⁹ Both 1% clindamycin and 2% erythromycin were comparable in reducing inflammatory and noninflammatory lesions for patients with moderate acne.¹⁰

Studies are ongoing for topical tetracycline, topical isotretinoin, and light and laser therapy in treatment of mild to moderate acne.

Recommendations from others

An expert review stated that treatment of acne should be individualized for best results.⁷ A report from the Global Alliance to Improve Outcomes in Acne states that topical retinoids are appropriate first-line therapy for all forms of acne and should be combined with topical antimicrobial therapy when inflammatory lesions are present.¹¹

Evidence Summary

Both IGT and IFG are associated with a significant risk of developing diabetes and its associated cardiovascular comorbidities; thus, the primary goal for treatment is to prevent or delay the onset of diabetes. Recent well-designed studies have demonstrated benefits of lifestyle interventions for patients with IGT.

In the US Diabetes Prevention Program (DPP), 3234 patients with IGT and a body-mass index (BMI) of at least 24 kg/m² were randomly assigned to one of the following groups: placebo, metformin, or intensive lifestyle modification. After an average follow-up of 2.8 years, there was a 14% absolute risk reduction in the progression to diabetes in the lifestyle intervention group compared with placebo (number needed to treat [NNT]=7).¹ In the Finnish Diabetes Prevention Study, the lifestyle intervention group had a 12.5% absolute risk reduction compared with the control group (NNT=8).² Successful lifestyle interventions in these studies included weight loss of 5% to 7%, decreased fat intake, increased fiber intake, and 150 minutes of exercise per week.^1-2

Drug therapy with metformin, acarbose, and troglitazone has also been successful in preventing or delaying diabetes in people with IGT.^1,3,4 In the placebo-controlled DPP trial, metformin use was associated with a reduction in progression to diabetes mellitus (NNT=14).¹ In the STOP-NIDDM trial of 1429 persons over 3.3 years of follow-up, acarbose 100 mg 3 times daily resulted in a 9% reduction of progression to diabetes, compared with placebo (NNT=11).³

In the TRIPOD study, troglitazone use was associated with a 17% absolute risk reduction in the incidence of diabetes in high-risk Hispanic women (NNT=6 over an average of 30 months).⁴ The preventive effect of the drug was maintained more than 8 months after troglitazone therapy was discontinued (due to withdrawal from the US market). Current trials with other thiazolidinediones are underway.

TABLE
Comparison of major lifestyle and pharmacologic trials in IGT and IFG

Recommendations from others

The American Diabetes Association (ADA) recommends counseling on weight loss and instructing on increased physical activity in people with IGT.⁵ The United States Preventive Services Task Force recommends intensive programs of lifestyle modification (diet, exercise, and behavior) for patients who have pre-diabetes.⁶

The ADA recommends regular monitoring (every 1 to 2 years) for the development of diabetes in people with prediabetes, and prefers FPG to screen for diabetes since it is faster, cost-effective, and more reproducible than the more sensitive 2-hour oral glucose tolerance test.^5,7 The ADA also recommends that if the FPG is <126 mg/dL and there is a high suspicion for diabetes, a 2-hour oral glucose tolerance test should be performed.

Glycosylated hemoglobin (HbA_1C) is not recommended as a screening tool, because individuals with IFG or IGT may have normal or near-normal HbA_1C levels; these individuals often manifest hyperglycemia only when challenged with the oral glucose load use in the standardized oral glucose tolerance test.⁸

Evidence Summary

Both IGT and IFG are associated with a significant risk of developing diabetes and its associated cardiovascular comorbidities; thus, the primary goal for treatment is to prevent or delay the onset of diabetes. Recent well-designed studies have demonstrated benefits of lifestyle interventions for patients with IGT.

In the US Diabetes Prevention Program (DPP), 3234 patients with IGT and a body-mass index (BMI) of at least 24 kg/m² were randomly assigned to one of the following groups: placebo, metformin, or intensive lifestyle modification. After an average follow-up of 2.8 years, there was a 14% absolute risk reduction in the progression to diabetes in the lifestyle intervention group compared with placebo (number needed to treat [NNT]=7).¹ In the Finnish Diabetes Prevention Study, the lifestyle intervention group had a 12.5% absolute risk reduction compared with the control group (NNT=8).² Successful lifestyle interventions in these studies included weight loss of 5% to 7%, decreased fat intake, increased fiber intake, and 150 minutes of exercise per week.^1-2

Drug therapy with metformin, acarbose, and troglitazone has also been successful in preventing or delaying diabetes in people with IGT.^1,3,4 In the placebo-controlled DPP trial, metformin use was associated with a reduction in progression to diabetes mellitus (NNT=14).¹ In the STOP-NIDDM trial of 1429 persons over 3.3 years of follow-up, acarbose 100 mg 3 times daily resulted in a 9% reduction of progression to diabetes, compared with placebo (NNT=11).³

In the TRIPOD study, troglitazone use was associated with a 17% absolute risk reduction in the incidence of diabetes in high-risk Hispanic women (NNT=6 over an average of 30 months).⁴ The preventive effect of the drug was maintained more than 8 months after troglitazone therapy was discontinued (due to withdrawal from the US market). Current trials with other thiazolidinediones are underway.

TABLE
Comparison of major lifestyle and pharmacologic trials in IGT and IFG

Recommendations from others

The American Diabetes Association (ADA) recommends counseling on weight loss and instructing on increased physical activity in people with IGT.⁵ The United States Preventive Services Task Force recommends intensive programs of lifestyle modification (diet, exercise, and behavior) for patients who have pre-diabetes.⁶

The ADA recommends regular monitoring (every 1 to 2 years) for the development of diabetes in people with prediabetes, and prefers FPG to screen for diabetes since it is faster, cost-effective, and more reproducible than the more sensitive 2-hour oral glucose tolerance test.^5,7 The ADA also recommends that if the FPG is <126 mg/dL and there is a high suspicion for diabetes, a 2-hour oral glucose tolerance test should be performed.

Glycosylated hemoglobin (HbA_1C) is not recommended as a screening tool, because individuals with IFG or IGT may have normal or near-normal HbA_1C levels; these individuals often manifest hyperglycemia only when challenged with the oral glucose load use in the standardized oral glucose tolerance test.⁸

Evidence Summary

Both IGT and IFG are associated with a significant risk of developing diabetes and its associated cardiovascular comorbidities; thus, the primary goal for treatment is to prevent or delay the onset of diabetes. Recent well-designed studies have demonstrated benefits of lifestyle interventions for patients with IGT.

In the US Diabetes Prevention Program (DPP), 3234 patients with IGT and a body-mass index (BMI) of at least 24 kg/m² were randomly assigned to one of the following groups: placebo, metformin, or intensive lifestyle modification. After an average follow-up of 2.8 years, there was a 14% absolute risk reduction in the progression to diabetes in the lifestyle intervention group compared with placebo (number needed to treat [NNT]=7).¹ In the Finnish Diabetes Prevention Study, the lifestyle intervention group had a 12.5% absolute risk reduction compared with the control group (NNT=8).² Successful lifestyle interventions in these studies included weight loss of 5% to 7%, decreased fat intake, increased fiber intake, and 150 minutes of exercise per week.^1-2

Drug therapy with metformin, acarbose, and troglitazone has also been successful in preventing or delaying diabetes in people with IGT.^1,3,4 In the placebo-controlled DPP trial, metformin use was associated with a reduction in progression to diabetes mellitus (NNT=14).¹ In the STOP-NIDDM trial of 1429 persons over 3.3 years of follow-up, acarbose 100 mg 3 times daily resulted in a 9% reduction of progression to diabetes, compared with placebo (NNT=11).³

In the TRIPOD study, troglitazone use was associated with a 17% absolute risk reduction in the incidence of diabetes in high-risk Hispanic women (NNT=6 over an average of 30 months).⁴ The preventive effect of the drug was maintained more than 8 months after troglitazone therapy was discontinued (due to withdrawal from the US market). Current trials with other thiazolidinediones are underway.

TABLE
Comparison of major lifestyle and pharmacologic trials in IGT and IFG

Recommendations from others

The American Diabetes Association (ADA) recommends counseling on weight loss and instructing on increased physical activity in people with IGT.⁵ The United States Preventive Services Task Force recommends intensive programs of lifestyle modification (diet, exercise, and behavior) for patients who have pre-diabetes.⁶

The ADA recommends regular monitoring (every 1 to 2 years) for the development of diabetes in people with prediabetes, and prefers FPG to screen for diabetes since it is faster, cost-effective, and more reproducible than the more sensitive 2-hour oral glucose tolerance test.^5,7 The ADA also recommends that if the FPG is <126 mg/dL and there is a high suspicion for diabetes, a 2-hour oral glucose tolerance test should be performed.

Glycosylated hemoglobin (HbA_1C) is not recommended as a screening tool, because individuals with IFG or IGT may have normal or near-normal HbA_1C levels; these individuals often manifest hyperglycemia only when challenged with the oral glucose load use in the standardized oral glucose tolerance test.⁸

Evidence summary

A prospective cohort study compared cardiovascular events among patients with white-coat hypertension vs those with sustained hypertension. The study evaluated 479 patients with persistently elevated clinic systolic blood pressures of 140 to 180 mm Hg. Using 24-hour intraarterial ambulatory blood pressure monitoring (ABPM), they found that 126 patients had ambulatory blood pressures below 140/90 mm Hg (white-coat hypertension) while 353 patients maintained pressures above 140/90 mm Hg (sustained hypertension). On average, white-coat hypertension patients were younger than sustained hypertension patients (44 vs 52 years) but were otherwise similar. Over the next 9 years, patients with white-coat hypertension had significantly fewer cardiovascular events than patients with sustained hypertension (Table).¹

Another prospective cohort study compared fatal and nonfatal cardiovascular event rates among patients who had white-coat hypertension, sustained hypertension, or were normotensive. Investigators performed 24-hour ABPM on 1187 patients who had clinic blood pressures over 140/90 on three visits. They found that 228 patients had white-coat hypertension, defined as mean ambulatory blood pressures below the 90th percentile of a normotensive population, and 959 patients had sustained hypertension. They followed these patients, along with 205 normotensive controls, for a mean of 3.2 years. Cardiovascular event rates did not differ significantly between normotensive and white-coat hypertension patients (P=.83; see Table), but the difference in event-free survival between the sustained hypertension group and both the white-coat hypertension and normotensive groups was highly significant (P=.002).²

In contrast, a recent 10-year longitudinal study of 146 normotensive people, 76 people with white-coat hypertension, and 344 with sustained hypertension showed that cardiovascular event rates were similar for patients with white-coat and sustained hypertension, and were significantly higher than in the normotensive group (P=.03 overall, P=.03 between white-coat hypertension and normotension and P=.01 between sustained hypertension and normotension).³

One randomized trial evaluated outcomes of antihypertensive therapy for white-coat hypertension for patients aged >60 years. Ninety-nine patients with white-coat hypertension were identified on the basis of systolic blood pressure greater than 160 mm Hg in clinic and normal 24-hour ABPM and were randomized to either place-bo or drug therapy. Active treatment did not significantly lower ambulatory blood pressure in white-coat hypertension, but it did reduce blood pressure measured in clinic. After a year, medication produced an absolute reduction in cardiovascular events of 8.6%, and in stroke of 4.2%. Neither result was statistically significant due to the small sample size.⁴

TABLE
Cohort studies of patients with white-coat hypertension

Recommendations from others

The American College of Cardiology and American Academy of Family Physicians have made no specific recommendations about white-coat hypertension. The Blood Pressure Monitoring Task Force V concluded that a significant number of white-coat hypertension patients become truly hypertensive over years of follow-up.⁵

Experts agree that patients with white-coat hypertension should be indefinitely monitored for the development of sustained hypertension.⁶ Treatment is not needed unless the patient has sustained hypertension, evidence of cardiovascular disease, or signs of target organ injury.^7,8 Typically, expert opinion recommends confirming the diagnosis of white-coat hypertension with home blood pressure records or ambulatory blood pressure monitoring.

Evidence summary

A prospective cohort study compared cardiovascular events among patients with white-coat hypertension vs those with sustained hypertension. The study evaluated 479 patients with persistently elevated clinic systolic blood pressures of 140 to 180 mm Hg. Using 24-hour intraarterial ambulatory blood pressure monitoring (ABPM), they found that 126 patients had ambulatory blood pressures below 140/90 mm Hg (white-coat hypertension) while 353 patients maintained pressures above 140/90 mm Hg (sustained hypertension). On average, white-coat hypertension patients were younger than sustained hypertension patients (44 vs 52 years) but were otherwise similar. Over the next 9 years, patients with white-coat hypertension had significantly fewer cardiovascular events than patients with sustained hypertension (Table).¹

Another prospective cohort study compared fatal and nonfatal cardiovascular event rates among patients who had white-coat hypertension, sustained hypertension, or were normotensive. Investigators performed 24-hour ABPM on 1187 patients who had clinic blood pressures over 140/90 on three visits. They found that 228 patients had white-coat hypertension, defined as mean ambulatory blood pressures below the 90th percentile of a normotensive population, and 959 patients had sustained hypertension. They followed these patients, along with 205 normotensive controls, for a mean of 3.2 years. Cardiovascular event rates did not differ significantly between normotensive and white-coat hypertension patients (P=.83; see Table), but the difference in event-free survival between the sustained hypertension group and both the white-coat hypertension and normotensive groups was highly significant (P=.002).²

In contrast, a recent 10-year longitudinal study of 146 normotensive people, 76 people with white-coat hypertension, and 344 with sustained hypertension showed that cardiovascular event rates were similar for patients with white-coat and sustained hypertension, and were significantly higher than in the normotensive group (P=.03 overall, P=.03 between white-coat hypertension and normotension and P=.01 between sustained hypertension and normotension).³

One randomized trial evaluated outcomes of antihypertensive therapy for white-coat hypertension for patients aged >60 years. Ninety-nine patients with white-coat hypertension were identified on the basis of systolic blood pressure greater than 160 mm Hg in clinic and normal 24-hour ABPM and were randomized to either place-bo or drug therapy. Active treatment did not significantly lower ambulatory blood pressure in white-coat hypertension, but it did reduce blood pressure measured in clinic. After a year, medication produced an absolute reduction in cardiovascular events of 8.6%, and in stroke of 4.2%. Neither result was statistically significant due to the small sample size.⁴

TABLE
Cohort studies of patients with white-coat hypertension

Recommendations from others

The American College of Cardiology and American Academy of Family Physicians have made no specific recommendations about white-coat hypertension. The Blood Pressure Monitoring Task Force V concluded that a significant number of white-coat hypertension patients become truly hypertensive over years of follow-up.⁵

Experts agree that patients with white-coat hypertension should be indefinitely monitored for the development of sustained hypertension.⁶ Treatment is not needed unless the patient has sustained hypertension, evidence of cardiovascular disease, or signs of target organ injury.^7,8 Typically, expert opinion recommends confirming the diagnosis of white-coat hypertension with home blood pressure records or ambulatory blood pressure monitoring.

Evidence summary

A prospective cohort study compared cardiovascular events among patients with white-coat hypertension vs those with sustained hypertension. The study evaluated 479 patients with persistently elevated clinic systolic blood pressures of 140 to 180 mm Hg. Using 24-hour intraarterial ambulatory blood pressure monitoring (ABPM), they found that 126 patients had ambulatory blood pressures below 140/90 mm Hg (white-coat hypertension) while 353 patients maintained pressures above 140/90 mm Hg (sustained hypertension). On average, white-coat hypertension patients were younger than sustained hypertension patients (44 vs 52 years) but were otherwise similar. Over the next 9 years, patients with white-coat hypertension had significantly fewer cardiovascular events than patients with sustained hypertension (Table).¹

Another prospective cohort study compared fatal and nonfatal cardiovascular event rates among patients who had white-coat hypertension, sustained hypertension, or were normotensive. Investigators performed 24-hour ABPM on 1187 patients who had clinic blood pressures over 140/90 on three visits. They found that 228 patients had white-coat hypertension, defined as mean ambulatory blood pressures below the 90th percentile of a normotensive population, and 959 patients had sustained hypertension. They followed these patients, along with 205 normotensive controls, for a mean of 3.2 years. Cardiovascular event rates did not differ significantly between normotensive and white-coat hypertension patients (P=.83; see Table), but the difference in event-free survival between the sustained hypertension group and both the white-coat hypertension and normotensive groups was highly significant (P=.002).²

In contrast, a recent 10-year longitudinal study of 146 normotensive people, 76 people with white-coat hypertension, and 344 with sustained hypertension showed that cardiovascular event rates were similar for patients with white-coat and sustained hypertension, and were significantly higher than in the normotensive group (P=.03 overall, P=.03 between white-coat hypertension and normotension and P=.01 between sustained hypertension and normotension).³

One randomized trial evaluated outcomes of antihypertensive therapy for white-coat hypertension for patients aged >60 years. Ninety-nine patients with white-coat hypertension were identified on the basis of systolic blood pressure greater than 160 mm Hg in clinic and normal 24-hour ABPM and were randomized to either place-bo or drug therapy. Active treatment did not significantly lower ambulatory blood pressure in white-coat hypertension, but it did reduce blood pressure measured in clinic. After a year, medication produced an absolute reduction in cardiovascular events of 8.6%, and in stroke of 4.2%. Neither result was statistically significant due to the small sample size.⁴

TABLE
Cohort studies of patients with white-coat hypertension

Recommendations from others

The American College of Cardiology and American Academy of Family Physicians have made no specific recommendations about white-coat hypertension. The Blood Pressure Monitoring Task Force V concluded that a significant number of white-coat hypertension patients become truly hypertensive over years of follow-up.⁵

Experts agree that patients with white-coat hypertension should be indefinitely monitored for the development of sustained hypertension.⁶ Treatment is not needed unless the patient has sustained hypertension, evidence of cardiovascular disease, or signs of target organ injury.^7,8 Typically, expert opinion recommends confirming the diagnosis of white-coat hypertension with home blood pressure records or ambulatory blood pressure monitoring.