3 Management of Newly Diagnosed Atrial Fibrillation

3 Management of Newly Diagnosed Atrial Fibrillation

A Clinical Practice Guideline

From the American Academy of Family Physicians and the American College of Physicians

Jaya Udayasankar,

and Doron Schneider,

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INTRODUCTION

Atrial fibrillation (AF) is a common cardiac arrhythmia. The prevalence of AF increases progressively with age, ranging from about 1% for those under 60 yr

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From: Current Clinical Practice: Essential Practice Guidelines in Primary Care Edited by: N. S. Skolnik © Humana Press, Totowa, NJ

of age and increases to more than 8% for those over 80 yr of age. AF is more common in males, with the age-adjusted incidence for women being about half that of men. AF can occur in both the normal heart and the structurally abnormal heart. The cardiac conditions most commonly associated with AF are rheumatic mitral valve disease, ischemic heart disease, congestive cardiomyopathy, and hypertension. Other causes include hyperthyroidism, hypoxic conditions, and alcohol intoxication. The most widely accepted theory in the pathogenesis of AF is believed to be multiple re-entry wavelet mechanism. Patients with AF may be asymptomatic or have symptoms such as palpitations, light-headedness, short- ness of breath, and poor exercise tolerance. Some symptoms are related to reduc- tion of cardiac output. Patients with AF are at increased risk for systemic thromboembolism. The absolute risk for stroke is dependent on comorbidities and can range from 1 to 15% per year. The goals in the treatment of AF are to reduce the risk of stroke or other systemic embolus, control the symptoms of pal- pitations, and improve exercise tolerance.

The American College of Cardiology (ACC)/American Heart Association (AHA)/European Society of Cardiology Task Force on Clinical Guidelines for the Management of classified AF into four types: first detected episode, paroxysmal (terminates spontaneously), persistent (electrical or pharmacological termination necessary), and permanent (resistant to electrical or pharmacological conversion or accepted by the physician). The ACC/AHA has recommended using the term

“first detected atrial fibrillation” depending on when it was first clinically detected, either by the first onset of symptoms or electrocardiographic evidence of AF. For instances in which the patient is not able to recall symptoms at the onset of the arrhythmia, there can be uncertainty about the duration of the episode and about previous undetected episodes (1).

Guideline

This guideline reflects recommendations on the management strategy for adults with first-detected AF. These recommendations do not apply to patients with class 4 heart failure already taking antiarrhythmic medication, postoperative or postmyocardial infarction AF, or AF in patients with valvular heart disease.

The main objective of this guideline is to provide evidence-based guidelines for the practicing internist or family physician for the management of newly detected AF in the adult patient.

A joint American Academy of Family Physicians/American College of

Physicians panel (using the Guyatt Approach to Grading Recommendations; see

Table 1) made recommendations in the following areas: rate vs rhythm control,

stroke prevention and anticoagulation, electrical cardioversion vs pharmacological

cardioversion, and the role of transesophageal echocardiography (TEE) in guiding

therapy and maintenance therapy.

RATE CONTROL VS RHYTHM CONTROL

An initial question faced by practitioners is the choice of maintaining rate or attempting to re-establish normal rhythm. This decision must weigh morbidity and mortality data as well as quality-of-life data that are now available from recent clinical trials.

The Atrial Fibrillation Follow-Up Investigation of Rhythm Management Trial (AFFIRM) compared rhythm vs rate control. More than 4000 patients with AF

Table 1

Guyatt Approach to Grading Recommendations

Strength of Strength of Clarity of supporting recommendation/

Grade risk/benefit evidence implication

1A Clear Randomized trials without Strong; applies to most important limitation patients in most

circumstances 1B Clear Randomized trials without Strong; likely to apply

important limitation to most patients 1C Clear No randomized controlled Strong; can apply to

trial pertaining to this patient most patients in most but results from randomized circumstances controlled trial including

different patients, extrapolated to the patient, under consideration.

Overwhelming evidence from observational studies

1C + Clear Observational studies Intermediate; may change when stronger evidence becomes available

2A Unclear Randomized trials without Intermediate; best action important limitations may differ depending

on social, patient’s value, or circumstances 2B Unclear Randomized trials without Weak; alternative;

important limitations approaches may be better for some patients under some

circumstances 2C Unclear Observational studies Very weak; other

alternatives may be

reasonable

who were at least 65 yr of age or who had risk factors for stroke or death, such as diabetes, coronary artery disease (CAD), hypertension, poor ventricular func- tion, or previous stroke were studied for a mean of 3.5 yr. Anticoagulation was recommended in both arms (although discontinuation was permitted in the cardio- version arm after 4 wk of antiarrhythmic therapy). Physicians were allowed to select pharmacological or nonpharmacological therapies to achieve sinus rhythm. The prevalence of the sinus rhythm in the rhythm-control group was 82, 73, and 63% at 1, 3, and 5 yr, whereas sinus rhythm in the rate-control group was 34.6% at 5 yr. Overall mortality, the Primary End Point of the AFFIRM trial was not different between the two groups. A higher risk of death as noted in the rhythm-control group for patients with CAD, congestive heart failure (CHF), and in the elderly. Although stroke rates did not differ between the two groups, 70% of all strokes occurred in patients who had stopped receiving anticoagula- tion or who had subtherapeutic international normalized ratio (INR <2). More hospitalizations were reported in the rhythm-control group (p < 0.001).

A smaller study conducted in Europe called the Rate Control vs Electrical Cardioversion study, randomly assigned 522 patients to either aggressive rhythm control or rate control. About 64% patients were men, 49% had hyper- tension, and 27% had CAD. Eligibility criteria consisted of persistent AF last- ing less than 1 yr and failure of at least one previous electrical cardioversion.

There was no difference between the two groups in the primary end point, which was a composite of cardiovascular mortality, heart failure, thromboem- bolic complications, bleeding, pacemaker implantation, and severe side effects of antiarrhythmic drugs. In post hoc analysis, rate control was superior for patients with hypertension and women.

Another small study, the Pharmacological Intervention in Atrial Fibrillation trial randomly assigned 252 patients aged between 18 and 75 yr with new-onset or permanent symptomatic AF to rate control with diltiazem or conversion to sinus rhythm and its maintenance with amiodarone. The primary end point was symptomatic improvement. The study outcomes were similar in both groups including symptom relief and quality-of-life measures. Hospital admissions were more frequent in the rhythm-control group.

In the Strategies of Treatment of Atrial Fibrillation trial, patients were randomly

assigned into two groups: those with short-term anticoagulation after attempted

conversion with antiarrhythmic therapy to prevent AF recurrence or a rate-control

group with long-term anticoagulation. After 19.6 mo, the annual incidence of the

primary end points of death, stroke, transient ischemic attacks, and thromboem-

bolism was similar in the two groups. Only 40% of patients in the rhythm-control

group were in sinus rhythm at the end of 1 yr, despite aggressive attempts. In the

rhythm-control group, all the thromboembolic end points occurred in patients

while they were in AF. It also highlights the fact that a substantial number of

patients cannot maintain sinus rhythm despite aggressive conversion methods.

All the trials consistently showed no improvement in mortality or morbidity by aggressively controlling rhythm as opposed to rate control. Moreover, patients randomly assigned to aggressive rhythm control with brief anticoagulation post- cardioversion consistently have more hospitalizations, adverse drug events, and frequently do not maintain sinus rhythm. The population studied in the earlier trials did have sufficient representation in certain subgroups of patients, such as younger patients with healthy hearts, therefore, it is not certain whether these groups may benefit from more aggressive rhythm or rate control.

Recommendation 1

For the majority of patients with AF, rate control with chronic anticoag- ulation is the preferred treatment modality. Rhythm control has not been shown to be superior to rate control with anticoagulation in reducing mor- bidity and mortality and may be inferior to rate control in certain patient subgroups. Rhythm control is appropriate when based on other consider- ations, such as patients’ preference, symptom, and exercise tolerance (grade 2A).

PREVENTION OF SYSTEMIC EMBOLIZATION: ROLE OF ANTICOAGULATION IN ATRIAL FIBRILLATION Meta-analysis of the primary prevention studies reported on the pooled effi- cacy (prevention of stroke and peripheral embolism) and safety (major and minor bleeding events) of warfarin vs placebo, aspirin vs placebo, and warfarin vs aspirin.

Warfarin is more efficacious than placebo for primary stroke prevention (odds ratio [OR] 0.3 [95% confidence interval {CI}, 0.19–0.48]). There is a concurrent increase in warfarin-related risk of major bleeding (OR, 1.90 [CI, 0.89–4]).

Aspirin performs better than placebo in the prevention of primary stroke (OR, 0.68 [CI 0.46–1.02]), with an inconclusive difference for bleeding risk (OR, 0.82 [CI, 0.37–1.78]). Warfarin has been found to be more efficacious than aspirin for stroke prevention (OR, 0.66 [CI, 0.45–0.99]), with inconclusive evidence for difference in major bleeding (OR, 1.6 [CI, 0.75–3.44]).

Adjusted-dose warfarin is more superior for stroke prevention than low- dose warfarin (OR, 0.52 [CI, 0.25–1.08]) or low-dose warfarin combined with aspirin (OR, 0.44 [CI, 0.14–1.39]) but it increased major bleeding (OR, 1.4 [CI, 0.72–2.7]).

Two trials of secondary prevention evaluated warfarin or aspirin. In one

trial, it was found that among the warfarin-eligible patients, warfarin was

more efficacious for stroke prevention (OR, 0.38 [CI, 0.22–0.66]) but led

to more episodes of major bleeding (OR, 4.1 [CI, 1.2–14]; p = 0.029) than

did placebo.

The absolute reduction in stroke rate with warfarin as opposed to aspirin was greater in older than in younger patients (15/1000 person-years vs 5.5/1000 person-years, respectively). The evidence suggests that aspirin may be useful for persons with a low risk for stroke. Regarding the use of other antithrom- botic agents, there is insufficient evidence in the literature. There is insufficient evidence for the use of low-molecular-weight, low-dose warfarin, or newer antiplatelet agents. Depending on the individual’s risk for stroke and bleed- ing, evidence is sufficient to support the use of warfarin or aspirin. Aspirin may be useful for patients with AF who are at low risk for stroke.

When anticoagulation is appropriate, continuation is generally recommended regardless of return to normal sinus.

Recommendation 2

Patients with AF should receive chronic anticoagulation with adjusted- dose warfarin (INR 2:3), unless they are at low risk of stroke or have a spe- cific contraindication for warfarin (thrombocytopenia, recent surgery or trauma, alcoholism) (grade 1A).

Clinical prediction rules for estimating stroke risk based on existing litera- ture have been designed and validated. One such tool called CHADS2 uses the conventional risk factors for stroke, including “C” for CHF (active within the past 100 d or documented by echocardiography); “H” for hypertension (systolic or diastolic); “A” for old age (at least 75 yr); “D” for diabetes mellitus, “S” for history of stroke or transient ischemic attack. Each risk factor is assigned one point except stroke or transient ischemic attack, which is assigned two points.

Risk of stroke is stratified by total score and reflected in the Table 2.

EFFICACY OF DIFFERENT AGENTS IN THE CONTROL

OF VENTRICULAR RATE IN ATRIAL FIBRILLATION

The most commonly used drugs for rate control are β-blockers, digoxin, and

calcium channel blockers. Evidence-based reports assessing 17 different agents

from 48 trials were reviewed. Main outcome measures consist of mean heart rate

at rest, maximum heart rate with exercise, and distance or time walked on the

exercise test. Comparisons of digoxin with placebo were inconsistent, particu-

larly during exercise. Diltiazem and verapamil are more effective than placebo

or digoxin in reducing the ventricular rate at rest and during exercise. Although

atenolol and metoprolol were found effective in controlling rest and exercise

heart rate, results with other β-blockers were less consistent. Studies of combi-

nations found that digoxin plus diltiazem, digoxin plus atenolol, and digoxin

plus betaxolol were effective both at rest and with exercise. Combination ther-

apy should only be employed when single-agent regimens have failed. Labetalol

combined with digoxin was effective only with exertion. Side-effect profile should be considered when selecting agents for rate control.

Recommendation 3

For patients with AF, the following drugs are recommended for their demonstrated efficacy in rate control during exercise and rest: atenolol, metoprolol, diltiazem, and verapamil. Digoxin is only effective for rate con- trol at rest and could be used as a second-line agent for rate control in AF (grade 1B).

ACUTE CONVERSION TO SINUS RHYTHM: EFFICACY OF ELECTRICAL VS PHARMACOLOGICAL CARDIOVERSION

In studies, rates of spontaneous conversion to sinus rhythm have ranged from 0 to 76%. In many active pharmacological conversion trials, the rate of mainte- nance of sinus rhythm is often less than 50%. The contributing characteristics for the wide variation in the rate of spontaneous conversion and reversion may be resulting from age, enlarged left atrial size, ischemic heart disease, hyperten- sion, valvular disease, and differing durations of AF. However, it is still unclear as to which patient characteristic would be the most reliable predictor for spon- taneous conversion to sinus rhythm or reversion to AF.

Electrical Conversion

The efficacy of cardioversion of AF with modern biphasic external defibrilla- tors is consistently about 80–85%. Percutaneous catheter-based cardioversion efficacy is about 90%. Risk of a thromboembolic event is equal in both electrical and pharmacological conversion. Patient preference should drive decision mak- ing around the modality of cardioversion. Of all antiarrythmics, only pretreatment

Table 2

Risk for Stroke Stratified by CHADS2 Score

CHADS2 Adjusted stroke CHADS2

Score rate (95% CI) Risk level

0 1.9 (1.2–3) Low

1 2.8 (2–3.8) Low

2 4 (3.1–5.1) Moderate

3 5.9 (4.6–7.3) Moderate

4 8.5 (6.3–11.1) High

5 12.5 (8.2–17.5) High

6 18.2 (10.5–27.4) High

with ibutilide provides added efficacy but carries a higher risk for inducing ven- tricular arrhythmia.

Pharmacological Conversion

In meta-analysis of 54 randomized trials, drugs with strong evidence for effi- cacy for acute conversion were ibutilide, flecainide, dofetilide, propafenone, and amiodarone. Quinidine demonstrated moderate evidence for efficacy. Evidence for the efficacy of sotalol and disopyramide was insufficient. Small sample size, limited follow-up period, and variable duration of AF limit the quality of the reviewed studies.

Induction of torsades de pointes through prolongation of the QT interval is the most important side effect of antiarrhythmic therapy. Risk is greatest in the first 24–72 h of treatment. Meaningful comparison of risk between agents is limited by heterogeneity of reporting in reviewed studies. No reports of ventric- ular arrhythmia were seen with amiodarone and procainamide. Rates were about 2% for flecainide, propafenone, and sotalol. Rates of up to 9% for ibu- tilide, 12% for quinidine and dofetilide have been reported. Consideration of the risk of torsades de pointes is important when deciding where to start therapy (inpatient or outpatient setting).

There is no reliable way to predict which patients are at risk for arrhythmia.

Adverse outcomes from arrhythmias related to acute cardioversion are more common with pharmacological conversion than with electrical cardioversion.

Recommendation 4

For those patients who choose to undergo acute cardioversion to achieve sinus rhythm in AF, both direct-current cardioversion (grade 1C+) and pharmacological conversion (grade 2A) are appropriate options.

No head-to-head trials are available to demonstrate superiority of either modality of cardioversion. Long-term effectiveness in maintaining sinus rhythm is moderate to low for both methods.

THE ROLE OF ECHOCARDIOGRAPHY IN THE ACUTE CONVERSION OF ATRIAL FIBRILLATION

Role of Transesophageal Echocardiography

Risk of thromboembolism during cardioversion is related to intra-atrial clot

burden slow return of mechanical contraction. TEE, because of high sensitivity

and specificity, is an excellent modality to risk-stratify patients by ruling out

pre-existing clot.

The Assessment of Cardioversion Using Transesophageal Echocardiography trial randomized patients with AF of more than 48 h duration to either TEE and anticoagulation 4 wk postcardioversion against 3 wk precardioversion anticoag- ulation followed by 4 wk postcardioversion anticoagulation. Rates of stroke, transient ischemic attack, or peripheral embolism did not differ between groups.

The TEE-guided approach was more cost effective. Rates of maintenance of sinus rhythm at 8 wk were similar in both groups. The rates for major and minor bleeding were higher in the conventional group.

Role of Measurement of Left Atrial Size

An inverse relationship between left atrial size and the success rate for cardioversion exists. Although this qualitative relationship exists, evidence- based recommendation to support the routine measurement of the left atrial size for predicting success cannot be made. However, transesophageal echocardio- graphy can still be useful in evaluating left ventricular function or hypertrophy.

Recommendation 5

For those patients with new-onset AF, the conventional approach would be delayed cardioversion with 4 wk of anticoagulation pre- and postconver- sion. However, if TEE does not reveal intracardiac thrombus, short-term precardioversion anticoagulation followed by early acute cardioversion with postcardioversion anticoagulation is an appropriate strategy for those patients who elect early cardioversion (grade 2A).

EFFICACY FOR EACH ANTIARRHYTHMIC AGENT FOR THE MAINTENANCE OF NORMAL SINUS RHYTHM

AFTER SUCCESSFUL CARDIOVERSION Maintenance Therapy

Amiodarone, disopyramide, propafenone, and sotalol all been have found efficacious in the maintenance of sinus rhythm. Moderate evidence exists for flecainide, quinidine, and azimilide. Comparison trials show amiodarone to be more efficacious than propafenone and sotalol.

Torsades de points and other ventricular arrhythmias are the most significant

antiarrhythmic side effect. However, only 18 out of 35 clinical trials of mainte-

nance therapy reported incidence of ventricular arrhythmia. No ventricular

arrhythmia were reported with amiodarone or disopyramide, but it was reported

in 0–3% of patients treated with propafenone, 0–5% of those treated with

sotalol, and 0–12% of those treated with quinidine. Cessation or dose changes

were reported in 50–60% of patients treated with quinidine or disopyramide and

10–25% of patients treated with propafenone, flecainide, amiodarone, or sotalol.

Recommendation 6

Most patients with AF, who were successfully converted to sinus rhythm, should not be placed on rhythm maintenance therapy because the risks outweigh the benefits. However, should AF reoccur in some patients whose quality of life is compromised by the AF, the recommended medications for rhythm maintenance are amiodarone, disopyramide, propafenone, and sotalol. The choice of the agent depends on the risk of side effects based on individual patient characteristics (grade 2A).

Amiodarone, despite more noncardiac side effects than other agents, is con- sidered safer in patients with CHF and left ventricular hypertrophy. Sotalol and amiodarone should be considered in patients with CAD. Flecainide is contra- indicated in patients with CAD. For carefully selected patients whose quality of life is substantially compromised by AF, the benefits of maintenance therapy may offset the risks.

SOURCES

1. Annals of Internal Medicine, 16 December, 2003, Volume 139 Issue 12.