Credits: Wilbert S. Aronow, MD, FACC, FAHA
and Maciej Banach, MD, FESC, FASA
Department of Medicine, New York Medical College, Valhalla, New York and the
Department of Molecular Cardionephrology and Hypertension, Medical University of Lodz, Lodz, Poland
Address for correspondence : Wilbert S. Aronow, MD, Cardiology Division, New York Medical College,
Macy Pavilion, Room 138, Valhalla, NY 10595.
The prevalence of atrial fibrillation (AF) increases
with age. As the population ages, the burden of AF increases. AF is associated
with an increased incidence of mortality, stroke, and coronary events compared
to sinus rhythm. AF with a rapid ventricular rate may cause a
tachycardia-related cardiomyopathy. Immediate direct-current (DC) cardioversion
should be performed in patients with AF and acute myocardial infarction, chest
pain due to myocardial ischemia, hypotension, severe heart failure, or syncope.
Intravenous beta blockers, diltiazem, or verapamil may be administered to
reduce immediately a very rapid ventricular rate in AF. An oral beta blocker,
verapamil, or diltiazem should be used in persons with AF if a fast ventricular
rate occurs at rest or during exercise despite digoxin. Amiodarone may be used
in selected patients with symptomatic life-threatening AF refractory to other
drugs. Digoxin should not be used to treat patients with paroxysmal AF.
Nondrug therapies should be performed in patients with symptomatic AF in whom a
rapid ventricular rate cannot be slowed by drugs. Paroxysmal AF associated with
the tachycardia-bradycardia syndrome should be treated with a permanent
pacemaker in combination with drugs. A permanent pacemaker should be implanted
in patients with AF and symptoms such as dizziness or syncope associated with
ventricular pauses greater than 3 seconds which are not drug-induced. Elective
DC cardioversion has a higher success rate and a lower incidence of cardiac
adverse effects than does medical cardioversion in converting AF to sinus
rhythm. Unless transesophageal echocardiography has shown no thrombus in the
left atrial appendage before cardioversion, oral warfarin should be given for 3
weeks before elective DC or drug cardioversion of AF and continued for at least
4 weeks after maintenance of sinus rhythm. Many cardiologists prefer,
especially in elderly patients , ventricular rate control plus warfarin rather
than maintaining sinus rhythm with antiarrhythmic drugs. Patients with chronic
or paroxysmal AF at high risk for stroke should be treated with long-term
warfarin to achieve an International Normalized Ratio of 2.0 to 3.0. Patients
with AF at low risk for stroke or with contraindications to warfarin should be
treated with aspirin 325 mg daily.
atrial fibrillation; beta blockers; stroke; cardiovascular disease;
cardioversion; digoxin; radiofrequency catheter ablation; pacemakers;
antiarrhythmic drugs; warfarin; aspirin
fibrillation (AF) is a cardiac rhythm which has irregular undulations of the
baseline electrocardiogram (ECG) of varying amplitude, contour, and spacing
known as fibrillation waves, with the atrial rate between 350 and 600 beats per
minute. The fibrillatory waves are seen best in leads V1, II, III,
and aVF. The fibrillation waves may be large and coarse, or they may be fine
with an almost flat ECG baseline. The ventricular rate in AF is irregular
unless complete atrioventricular (AV) block or dissociation is present. The
contour of the QRS complex in AF is normal unless there is prior bundle branch
block, an intraventricular conduction defect, or aberrant ventricular
AF is associated with a slow regular ventricular response, there is complete AV
block with an AV junctional escape rhythm or idioventricular escape rhythm.
Myocardial infarction, degenerative changes in the conduction system, and drug
toxicity such as digitalis toxicity are major causes of complete AV block. If
AF is associated with a regular ventricular response between 60 to 130 beats
per minute, there may be complete AV dissociation with an accelerated AV
junctional rhythm caused by an acute inferior myocardial infarction, digitalis
toxicity, open heart surgery, or myocarditis, usually rheumatic. Regularization
of the ventricular response in AF may also occur in patients with complete AV
dissociation due to ventricular tachycardia or a ventricular paced rhythm.
AF is the most
common sustained cardiac arrhythmia. The prevalence of AF increases with age [1-5]. In the Framingham Study, the prevalence
of chronic AF was 2% in persons aged 60 to 69 years, 5% in persons aged 70 to
79 years, and 9% in persons aged 80 to 89 years . In a
study of 2,101 persons, mean age 81 years, the prevalence of chronic AF was 5%
in persons aged 60 to 70 years, 13% in persons aged 71 to 90 years, and 22% in
persons aged 91 to 103 years . Chronic AF was present in
16% of 1,160 men, mean age 80 years, and in 13% of 2,464 women, mean age 81
years . In 5,201 persons aged 65 years and
older in the Cardiovascular Health Study, the prevalence of AF was 6% in men
and 5% in women . In 1,563 persons, mean age 80 years,
living in the community, the prevalence of chronic AF was 9% .
In the Cardiovascular Health Study, the incidence of AF was 19.2 per 1,000
person-years . As the population ages, the burden of AF in
the United States and worldwide will increase. In fact, AF has been described
as an epidemic due to its increasing prevalence in the ageing population .
may be paroxysmal or chronic. Episodes of paroxysmal AF may last from a few
seconds to several weeks. Sixty-eight percent of persons presenting with AF of
less than 72 hours duration spontaneously converted to sinus rhythm . Episodes of persistent AF last longer than 7 days but less
than 1 year. AF in which cardioversion has failed or lasts longer than 1 year
is usually termed permanent.
reentrant circuits arising in the atria, exhibiting variable wave lengths,
colliding, being extinguished, and arising again usually cause AF .
Rapidly firing foci are commonly located in or near the pulmonary veins and
may also cause AF . Factors responsible for onset of AF
include triggers that induce the arrhythmia and the substrate that sustains it.
Atrial inflammation or fibrosis acts as a substrate for the development of AF.
Triggers of AF include acute atrial stretch, accessory AV pathways, premature
atrial beats or atrial tachycardia, sympathetic or parasympathetic stimulation,
and ectopic foci <>occurring in sleeves
of atrial tissue within the pulmonary veins or vena caval junctions . Predisposing factors for AF include age, alcohol, aortic
regurgitation and stenosis, atrial septal defect, autonomic dysfunction,
cardiac or thoracic surgery, cardiomyopathies, chronic lung disease, cocaine,
congenital heart disease, coronary artery disease (CAD), congestive heart
failure (CHF), diabetes mellitus, drugs (especially sympathomimetics),
emotional stress, excess coffee, hypertension, hyperthyroidism, hypoglycemia,
hypokalemia, hypovolemia, hypoxia, left atrial enlargement, left ventricular
(LV) dysfunction, LV hypertrophy, male gender, mitral annular calcium (MAC),
mitral stenosis and regurgitation, myocardial infarction (MI), myocarditis, neoplastic disease, obesity,
pericarditis, pneumonia, pulmonary embolism, rheumatic heart disease, sick
sinus syndrome, smoking, systemic infection, and the Wolff-Parkinson-White
(WPW) syndrome. Obesity has been reported to increase the risk of developing AF
by 49% in the general population . This study was
commented on by Banach et al. . Signal-averaged P-wave
duration may independently predict postoperative AF at long-term follow-up
after surgical correction of atrial septal defect type II .
The Framingham Study
demonstrated that the 20-year incidence of AF was 5.6% in persons with a pulse
pressure of 40 mm Hg or less and 23.3% for a pulse pressure greater than 61 mm
Hg . Persons with lone AF have a normal C-reactive
protein suggesting that this marker of systemic inflammation is associated not
with AF but with the underlying cardiovascular conditions associated with AF . Left atrial volume is a strong and independent predictor
of postoperative AF after cardiac surgery .
254 elderly persons with AF compared to 1,445 elderly persons with sinus
rhythm, mean age 81 years, 2-dimensional and Doppler echocardiography
demonstrated that the prevalence of AF was increased 17.1 times by rheumatic
mitral stenosis, 2.9 times by left atrial enlargement, 2.5 times by abnormal LV
ejection fraction, 2.3 times by aortic stenosis, 2.2 times by MAC and by ≥1+ mitral regurgitation, 2.1 times by
≥1+ aortic regurgitation, and 2.0 times by
LV hypertrophy . The Framingham Study showed that low
serum thyrotropin levels were independently associated with a 3.1 times
increase in the development of new AF in older patients .
drugs can induce AF . A meta-analysis of 11 studies
including 56, 308 patients showed that angiotensin-converting enzyme inhibitors
and angiotensin receptor blockers significantly reduced the risk of AF by 28%,
with a 44% significant reduction in AF in patients with CHF .
This benefit was limited to patients with reduced LV ejection fraction or LV hypertrophy .
many authors have reported the important role of statins in the prevention and
treatment of AF since inflammation, is one of the hypotheses of AF, and the
most popular hypothesis of postoperative AF [22-27]. For that reason, many authors suggested that
preoperative use of statins, due to their anti-inflammatory characteristics,
might decrease the risk of postoperative AF.
important study on this subject was the ARMYDA-3 Study (Atorvastatin for
Reduction of MYocardial Dysrhythmia After cardiac surgery) .
The authors included 200 patients undergoing elective cardiac surgery with
cardiopulmonary bypass without previous statin treatment or history of AF.
Patients were randomized to atorvastatin 40 mg daily or placebo starting 7 days
before operation. The primary end point was incidence of postoperative AF;
secondary end points were length of stay, 30-day major adverse cardiac and
cerebrovascular events, and postoperative C-reactive protein variations. They
showed that atorvastatin significantly reduced the incidence of AF versus
placebo (35% versus 57%, p=0.003). Accordingly, length of stay was longer in
the placebo versus atorvastatin arm (6.9±1.4 vs. 6.3±1.2 days, p=0.001). Peak
C-reactive protein levels were significantly lower in patients without AF,
irrespective of randomization assignment. Multivariable analysis showed that
atorvastatin treatment conferred a 61% reduction in risk of AF, whereas high
postoperative C-reactive protein levels were associated with increased risk.
The authors concluded that preoperative treatment with atorvastatin at a dose
of 40 mg daily significantly reduced the incidence of postoperative AF after
elective cardiac surgery with cardiopulmonary bypass and shortened the
results might influence practice patterns with regard to adjuvant
pharmacological therapy before cardiac surgery. These results were also
confirmed, among others, in the study by Mariscalco et al. ,
where the authors assessed the efficacy of preoperative statins in prevention
of AF in patients after coronary artery bypass grafting (CABG). Four hundred
and five consecutive patients who underwent isolated CABG procedures were
included in the study. Postoperative AF occurred in 29.5% of the patients with
preoperative statin therapy compared with 40.9% patients without such treatment
(p=0.021) . These investigators observed that
preoperative statins were associated with a 42% reduction in risk of AF
development after CABG . This study confirmed the result of the ARMYDA-3
study and showed that preoperative statins could significantly reduce
postoperative AF after CABG.
meta-analysis of 9 studies with 28,786 patients undergoing isolated surgical
revascularization showed that 7,019 patients (24.4%) developed postoperative AF
[28,29]. Important factors predicting postoperative AF were advanced age,
preoperative LV ejection fraction, history of AF, hypertension, CHF, peripheral
vascular disease, chronic obstructive pulmonary disease, neurological event,
significant stenosis of the left main coronary artery before surgery, and
postoperative use of inotropic therapy [28, 29].
diabetes mellitus undergoing coronary angiography with AF have a higher
prevalence of obstructive CAD and of 3-vessel obstructive CAD than those with
sinus rhythm . In the Framingham Study, the incidence of
death from cardiovascular causes was 2.7 times higher in women and 2.0 times
higher in men with chronic AF than in women and men with sinus rhythm . The Framingham Study also showed that after adjustment for
preexisting cardiovascular conditions, the odds ratio for mortality in persons
with AF was 1.9 in women and 1.5 in men . At 42-month
follow-up of 1,359 elderly persons with heart disease, mean age 81 years,
patients with chronic AF had a 2.2 times increased risk of having new coronary
events than patients with sinus rhythm after controlling for other prognostic
variables . In the Copenhagen City Heart Study, the
effect of AF on the risk of cardiovascular death was significantly increased
4.4 times in women and 2.2 times in men . In the Euro
Heart Survey on Atrial Fibrillation, women with AF had a 1.83 times
significantly increased risk of stroke than men with AF .
AF after isolated coronary artery surgery significantly increased mortality at
51-month median follow-up (adjusted hazard ratio = 2.13) .
occurred in 22% of 106,780 persons aged ≥65 years with acute MI in the
Cooperative Cardiovascular Project . Compared with sinus
rhythm, patients with AF had a higher in-hospital mortality (25% versus 16%),
30-day mortality (29% versus 19%), and 1-year mortality (48% versus 33%) . AF was an independent predictor of in-hospital mortality
(odds ratio = 1.2), 30-day mortality (odds ratio = 1.2), and 1-year mortality
(odds ratio = 1.3). Elderly patients developing AF during hospitalization had
a worse prognosis than elderly patients presenting with AF .
In the Global Use of Strategies To Open Occluded Coronary Arteries (GUSTO-III)
study, 906 of 13,858 patients (7%) developed AF during hospitalization . After adjusting for baseline differences, AF increased the
30-day mortality (odds ratio = 1.6) and the 1-year mortality (odds ratio = 1.6)
the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptors Suppression
Using Integrilin Therapy (PURSUIT) trial, AF developed in 6.4% of 9,432
patients with acute coronary syndromes without ST-segment elevation . After adjustment for other variables, patients with AF had
a higher 30-day mortality (hazard ratio = 4.0) and 6-month mortality (hazard
ratio = 3.0) than patients without AF .
is also an independent risk factor for stroke, especially in elderly persons [1, 2]. In the Framingham Study, the relative
risk of stroke in patients with nonvalvular AF compared with patients with
sinus rhythm was increased 2.6 times in patients aged 60 to 69 years, increased
3.3 times in patients aged 70 to 79 years, and increased 4.5 times in patients
aged 80 to 89 years . Chronic AF was an independent risk
factor for thromboembolic (TE) stroke with a relative risk of 3.3 in 2,101
older persons, mean age 81 years . The 3-year incidence
of TE stroke was 38% in older persons with chronic AF and 11% in older persons
with sinus rhythm . The 5-year incidence of TE stroke was
72% in older persons with AF and 24% in older persons with sinus rhythm . At 37-month follow-up of 1,476 patients who had 24-hour
ambulatory ECGs (AECGs), the incidence of TE stroke was 43% for 201 patients
with AF (relative risk = 3.3), 17% for 493 patients with paroxysmal
supraventricular tachycardia, and 18% for 782 patients with sinus rhythm .
the Copenhagen City Heart Study, the effect of AF on the risk of stroke was
significantly increased 7.6 times in women and 1.7 times in men .
AF is also a risk factor for impaired cognitive function .
2,384 older persons, mean age 81 years, AF was present in 17% of older persons
with LV hypertrophy and in 8% of persons without LV hypertrophy .
Both AF (risk ratio = 3.2) and LV hypertrophy (risk ratio = 2.8) were independent
risk factors for new TE stroke at 44-month follow-up .
The higher prevalence of LV hypertrophy in older patients with chronic AF
contributes to the increased incidence of TE stroke in elderly patients with
AF (risk ratio = 3.3) and 40% to 100% extracranial carotid arterial disease
(ECAD) (risk ratio = 2.5) were independent risk factors for new TE stroke at
45-month follow-up of 1,846 older persons, mean age 81 years .
Elderly persons with both chronic AF and 40% to 100% ECAD had a 6.9 times
higher probability of developing new TE stroke than elderly persons with sinus
rhythm and no significant ECAD .
infarctions were documented in 22% of 54 autopsied patients aged ≥70
years with paroxysmal AF . Symptomatic cerebral
infarction was 2.4 times more common in elderly patients with paroxysmal AF
than in elderly patients with sinus rhythm . AF also
causes silent cerebral infarction .
predisposes to CHF in elderly patients. As much as 30% to 40% of LV end-diastolic volume may be attributable to left atrial contraction in older persons.
Absence of a coordinated left atrial contraction reduces late diastolic filling
of the LV because of loss of the atrial kick. In addition, a rapid ventricular
rate in AF shortens the LV diastolic filling period, further reducing LV filling and stroke volume.
A retrospective analysis
of the Studies of Left Ventricular Dysfunction Prevention and Treatment Trials
demonstrated that AF was an independent risk factor for all-cause mortality
(relative risk = 1.3), progressive pump failure (relative risk = 1.4), and
death or hospitalization for CHF (relative risk = 1.3) .
AF was present in 37% of 355 patients, mean age 80 years, with prior MI, CHF,
and abnormal LV ejection fraction and in 33% of 296 patients, mean age 82
years, with prior MI, CHF, and normal LV ejection fraction .
In this study, AF was an independent risk factor for mortality with a risk
ratio of 1.5 .
A CHADS2 score in persons with AF gives 1 point for CHF, 1
point for hypertension, 1 point for age older than 75 years, 1 point for
diabetes mellitus, and 2 points for previous stroke or transient ischemic
attack and estimates the risk of stroke . At 31-month
follow-up of 521 persons with AF, a CHADS2 score of 5 or 6 had a 52
times significantly increased risk for stroke than a CHADS2 score of
A very fast ventricular rate associated with chronic or paroxysmal AF
may cause a tachycardia-related cardiomyopathy which may be an unrecognized
curable cause of CHF [50, 51]. Reducing
the rapid ventricular rate by radiofrequency ablation of the AV node with
permanent pacing caused an improvement in LV ejection fraction in patients with
medically refractory AF . In a substudy of the Ablate
and Pace Trial, 63 of 161 patients [39%) with AF referred for AV junction
ablation and right ventricular pacing had an abnormal LV ejection fraction . Forty-eight of the 63 patients had follow-up
echocardiograms. Sixteen of the 48 patients [33%) had a marked improvement in LV ejection fraction to a value >45% after ventricular rate control by AV junction
AF may be symptomatic or asymptomatic with their arrhythmia diagnosed by
physical examination or by an ECG. Examination of a patient after a stroke may
lead to the diagnosis of AF. Symptoms caused by AF may include palpitations,
skips in heartbeat, exercise intolerance, fatigue on exertion, cough, chest
pain, dizziness, and syncope. A very fast ventricular rate and loss of atrial
contraction decrease cardiac output and may lead to angina pectoris, CHF,
hypotension, acute pulmonary edema, and syncope, especially in patients with
aortic stenosis, mitral stenosis, or hypertrophic cardiomyopathy.
When AF is
suspected, a 12-lead ECG with a 1-minute rhythm strip should be obtained to
confirm the diagnosis. If paroxysmal AF is suspected, a 24-hour AECG should be
obtained. All patients with AF should have an M-mode, 2-dimensional, and
Doppler echocardiogram to determine the presence and severity of the cardiac
abnormalities causing AF and to identify risk factors for stroke. Appropriate
tests for noncardiac causes of AF should be obtained when clinically indicated.
Thyroid function tests should be obtained as AF or CHF may be the only clinical
manifestations of apathetic hyperthyroidism in elderly patients. Transthoracic
echocardiographic predictors of left atrial appendage thrombus are mitral
stenosis, AF, tricuspid tregurgitation, valvular prosthesis, LV dysfunction,
and right ventricular dysfunction .
Management of AF should include treatment of the
underlying disease (such as hyperthyroidism, pneumonia, or pulmonary embolism)
when possible. Surgical candidates for mitral valve replacement should have
mitral valve surgery if it is clinically indicated. If mitral valve surgery is
not performed in patients with significant mitral valve disease, elective
cardioversion should not be attempted in patients with AF since early frequent
relapses are common if AF converts to sinus rhythm. Precipitating factors such
as CHF, infection, hypoglycemia, hypokalemia, hypovolemia, and hypoxia should
be treated immediately. Alcohol, coffee, and drugs (especially
sympathomimetics) that precipitate AF should be avoided. Paroxysmal AF
associated with the tachycardia-bradycardia (sick sinus syndrome) should be
treated with permanent pacing in combination with drugs to decrease a very
fast ventricular rate associated with AF .
(DC) cardioversion should be performed immediately in patients who have
paroxysmal AF with a very rapid ventricular rate associated with an acute MI,
chest pain caused by myocardial ischemia, hypotension, severe CHF, syncope, or
preexcitation syndromes. Intravenous beta blockers [56-59], diltiazem [60 ], or verapamil  may be administered to slow immediately a very rapid
ventricular rate associated with AF except in patients with preexcitation
should be administered intravenously in a dose of 1.0 mg over a 5-minute
period and then given intravenously at a rate of 0.5 mg/minute to a maximum
dose of 0.1 mg/kg. Esmolol administered intravenously in a dose of 0.5 mg/kg
over 1 minute followed by 0.05 to 0.1 mg/kg per minute may also be used to
slow a very rapid ventricular rate in AF. After the very rapid ventricular
rate is slowed, oral propranolol should be started with an initial dose of 10
mg given every 6 hours. This dose may be increased progressively to a maximum
dose of 80 mg every 6 hours if necessary. Other beta blockers can be used with
appropriate doses administered.
The initial dose of diltiazem administered
intravenously to slow a very rapid ventricular rate in AF is 0.25 mg/kg given
over 2 minutes. If this dose does not reduce the very fast ventricular rate or
cause adverse effects, a second dose of 0.35 mg/kg administered intravenously
over 2 minutes should be given 15 minutes after the first dose. After slowing
the very rapid ventricular rate, oral diltiazem should be started with an
initial dose of 60 mg given every 6 hours. If necessary, this dose may be
increased to a maximum dose of 90 mg every 6 hours.
initial dose of verapamil administered intravenously is 0.075 mg/kg (to a
maximum dose of 5 mg). If this dose does not slow the very rapid ventricular
rate or cause adverse effects, a second dose of 0.075 mg/kg (to a maximum dose
of 5 mg) should be given intravenously 10 minutes after the first dose. If
the second dose of intravenous verapamil does not decrease the very rapid
ventricular rate or cause adverse effects, a dose of 0.15 mg/kg (to a maximum
dose of 10 mg) should be given intravenously 30 minutes after the second dose.
After slowing the very rapid ventricular rate, oral verapamil should be started
with an initial dose of 80 mg every 6 to 8 hours. This dose may be increased to
120 mg every 6 hours over the next 2 to 3 days.
glycosides are ineffective in converting AF to sinus rhythm .
Digoxin is also ineffective in slowing a rapid ventricular rate in AF if
there is associated fever, hyperthyroidism, acute blood loss, hypoxia or any
condition involving increased sympathetic tone .
However, digoxin should be used to decrease a rapid ventricular rate in AF
unassociated with increased sympathetic tone, hypertrophic cardiomyopathy, or
the WPW syndrome, especially if there is LV systolic dysfunction.
usual initial dose of digoxin given to undigitalized patients with AF is 0.5
mg orally. Depending on the clinical response, a second oral dose of 0.25 mg
may be given in 6 to 8 hours, and a third oral dose of 0.25 mg may be
administered in another 6 to 8 hours to slow a rapid ventricular rate. The
usual maintenance oral dose of digoxin given to patients with AF is 0.25 mg to
0.5 mg daily, with the dose reduced to 0.125 mg to 0.25 mg daily for older patients
who are more susceptible to digitalis toxicity .
beta blockers , diltiazem , or
verapamil  should be added to the therapeutic
regimen if a rapid ventricular rate in AF occurs at rest or during exercise
despite digoxin. These drugs act synergistically with digoxin to depress
conduction through the AV junction. In a study of atenolol 50 mg daily, digoxin
0.25 mg daily, diltiazem-CD 240 mg daily, digoxin 0.25 mg plus atenolol 50 mg
daily, and digoxin 0.25 mg plus diltiazem-CD 240 mg daily, digoxin and
diltiazem as single drugs were least effective and digoxin plus atenolol was
most effective in controlling the ventricular rate in AF during daily
is the most effective drug for slowing a rapid ventricular rate in AF [69, 70]. The noncompetitive beta receptor
inhibition and calcium channel blockade are powerful AV nodal conduction
depressants. However, the adverse side effect profile of amiodarone limits its
use in the treatment of AF. Oral doses of 200 mg to 400 mg of amiodarone daily
may be used in selected patients with symptomatic life-threatening AF
refractory to other drugs.
is a new antiarrhythmic drug with an electropharmacologic profile related to
amiodarone but with modifications intended to eliminate thyroid adverse effects
. In 2 double-blind, randomized trials in patients in
sinus rhythm with a history of AF in the preceding 3 months and no CHF, 828
patients were treated with dronedarone 400 mg twice daily and 409 patients with
placebo . At 1-year follow-up, 67% of patients
randomized to dronedarone and 78% of patients randomized to placebo had
recurrence of AF . The serum creatinine significantly
increased in patients treated with dronedarone (2.4%) compared to patients treated
with placebo (0.2%) .
the Antiarrhythmic Trial with Dronedarone in Moderate-to-Severe Congestive
Heart Failure Evaluating Morbidity Decrease (ANDROMEDA), 627 persons were
randomized to dronedarone or placebo . This
study was prematurely stopped because of an excess risk of death in the
persons treated with dromedarone .
concentrations of digoxin do not lower the frequency of episodes of paroxysmal
AF or the duration of episodes of paroxysmal AF diagnosed by 24-hour AECGS [73,74]. Digoxin has been found to increase
the duration of episodes of paroxysmal AF, a result consistent with its action
in reducing the atrial refractory period . Therapeutic
concentrations of digoxin also do not prevent a rapid ventricular rate from
occurring in patients with paroxysmal AF [73-75].
After a brief episode of AF, digoxin increases the shortening that occurs in
atrial refactoriness and predisposes to the reinduction of AF .
Therefore, digoxin should be avoided in patients with sinus rhythm with a history
of paroxysmal AF.
catheter modification of AV conduction could be performed in patients with
symptomatic AF in whom a rapid ventricular rate cannot be slowed by drugs [77, 78]. If this procedure does not slow the
rapid ventricular rate associated with AF, complete AV block produced by
radiofrequency catheter ablation followed by permanent pacemaker implantation
should be performed . In a randomized controlled study
of 66 persons with CHF and chronic AF, AV junction ablation with implantation
of a VVIR pacemaker was superior to drug treatment in controlling symptoms . Long-term survival is similar for patients with AF whether
they receive radiofrequency ablation of the AV node and implantation of a
permanent pacemaker or drug therapy . In 44 patients,
mean age 78±5 years, radiofrequency catheter ablation followed by pacemaker
implantation was successful in ablating the AV junction in 43 of 44 patients
(98%) with AF and a rapid ventricular rate not controlled by drug therapy .
techniques have been developed for use in patients with AF in whom the ventricular
rate cannot be slowed by drug treatment [83, 84]. The maze procedure is a surgical dissection of the right
and left atrium creating a maze through which the electrical activation is
compartamentalized, preventing the formation and perpetuation of the multiple
wavelets needed for maintenance of AF. This procedure is typically performed in
association with mitral valve surgery or CABG. At 2 to 3 years follow-up, 74%
of 39 patients and 90% of 100 patients undergoing the maze procedure remained
in sinus rhythm [85, 86]. Thirty-five of
43 patients [85%) with drug-refractory, lone paroxysmal AF were arrhythmia free
after maze surgery . At 29-month follow-up, 18 of 28
patients (64%), mean age 71 years, who had an intraoperative radiofrequency
maze procedure for treating AF at the time of valve surgery or CABS were in
sinus rhythm .
intraoperative approach for treating AF in patients undergoing mitral valve
surgery is cryoablation limited to the posterior left atrium. Sinus rhythm was
restored in 20 of 29 patients [69%) with chronic AF undergoing this procedure .
of pulmonary vein foci that cause AF is a developing area in the treatment of
AF. However, recurrent AF develops in 40% to 60% of patients despite initial
efficacy with this procedure . Another problem with this
approach is a 3% incidence of pulmonary vein stenosis occurring after this
randomized studies documented that circumferential pulmonary vein
radiofrequency ablation was significantly more effective than antiarrhythmic
drug therapy in preventing recurrence of AF (93% versus 35%) in 198 patients at
1 year  and (87% versus 37%) in 67 patients at 1 year . At 15-month follow-up, 27 of 55 persons with AF (49%)
with isolation of each individual pulmonary vein and 37 of 55 persons with AF
(67%) with isolation of large areas around both ipsilateral pulmonary veins had
no AF or atrial flutter (AFL) after a single radiofrequency ablation . There are no long-term follow-up data showing a reduction
in stroke risk in patients apparently cured of AF with radiofrequency catheter
of the substrate responsible for AF can be accomplished in the right and/or
left atrium with linear lesions. This catheter maze-ablation approach is
effective in a small percentage of patients .
Atrioverter, an implantable defibrillator connected to right atrial and right
coronary sinus defibrillation leads, causes restoration of sinus rhythm by
low-energy shock and has an 80% efficacy in terminating AF .
Further efforts are needed to improve patient tolerability and to prevent
earlier recurrence of AF after successful transvenous atrial defibrillation.
The implanted atrial defibrillator is currently available only in combination
with a ventricular defibrillator. The Atrioverter may also convert atrial
tachycardia to sinus rhythm using an atrial pacing overdrive algorhythm before
such tachycardias induce AF.
associated with the tachycardia-bradycardia (sick sinus) syndrome should be
treated with a permanent pacemaker combined with drugs to slow a rapid
ventricular rate associated with AF . Ventricular pacing
is an independent risk factor for the development of chronic AF in patients
with paroxysmal AF associated with the tachycardia-bradycardia syndrome . Patients with paroxysmal AF associated with the tachycardia-bradycardia
syndrome and no signs of AV conduction abnormalities should be treated with
atrial pacing or dual-chamber pacing rather than with ventricular pacing
because atrial pacing is associated with less AF, fewer TE complications, and a
lower risk of AV block than is ventricular pacing .
elderly persons are able to tolerate AF without the need for therapy because
the ventricular rate is slow due to concomitant AV nodal disease. These persons
should not be treated with drugs that depress AV conduction. A permanent
pacemaker should be implanted in patients with AF who develop cerebral symptoms
such as dizziness or syncope associated with ventricular pauses longer than 3
seconds which are not drug-induced, as documented by a 24-hour AECG . If patients with AF have drug-induced symptomatic
bradycardia, and the causative drug cannot be discontinued, a permanent
pacemaker must be implanted.
pacing is effective in treating vagotonic AF 
and may be considered if treatment with a vagolytic antiarrhythmic drug such as
disopyramide is ineffective. Atrial pacing is also effective in treating
patients with the sick sinus syndrome . However, when
bradycardia is not an indication for pacing, atrial-based pacing may not
prevent episodes of AF . Dual-site atrial pacing is
more efficacious than single-site pacing for preventing AF .
However, the patients in this study had a bradycardia indication for pacing and
continued to need antiarrhythmic drugs .
atrial pacing with continued sinus overdrive for AF in patients with
bradycardia prolonged time to AF recurrence and decreased AF burden in
patients with paroxysmal AF . However, there was no
difference in AF checklist symptom scores or overall quality-of-life scores . The absence of an effect on symptom control suggests
that pacing should be used as adjunctive therapy with other treatment
modalities for AF .
pacing after CABS has also been shown to decrease the incidence of AF . All ECGs in patients with paced rhythm should be
examined closely for underlying AF to prevent under-recognition of AF and
under-treatment with anticoagulants . Permanent pacing
to prevent AF is not indicated .
In 2 prospective multicenter trials, percutaneous left
atrial appendage occlusion using the PLAATO system was attempted in 111
patients, mean age 71 years, with a contraindication to anticoagulant therapy
and at least 1 additional risk factor for stroke .
Implantation was successful in 108 of 111 patients (97%). At 9.8-month
follow-up, 2 patients (2%) developed stroke . Long-term studies are
necessary to confirm the long-term safety of the device and a reduction in TE
The WATCHMAN Left Atrial Appendage System is
another left atrial appendage occlusion device . At
45-day follow-up, 54 of 58 persons (93%) treated with this device had
successful sealing of the left atrial appendage . Two
patients (4%) developed transient ischemic attack at 24-month follow-up. Anticoagulation
is required for 45 days to 6 months until endothelialization of this device is
should be performed if a rapid ventricular rate in patients with paroxysmal AF
associated with the WPW syndrome is life-threatening or fails to respond to
drug therapy. Drug treatment for paroxysmal AF associated with the WPW
syndrome includes propranolol plus procainamide, disopyramide, or quinidine . Digoxin, diltiazem, and verapamil are contraindicated in
patients with AF with the WPW syndrome because these drugs shorten the
refractory period of the accessory AV pathway, resulting in more rapid
conduction down the accessory pathway. This results in a marked increase in
ventricular rate. Radiofrequency catheter ablation or surgical ablation of the
accessory conduction pathway should be considered in patients with AF and rapid
AV conduction over the accessory pathway . In 500
patients with an accessory pathway, radiofrequency catheter ablation of the
accessory pathway was successful in treating 93% of patients .
cardioversion has a higher success rate than does medical cardioversion in
converting AF to sinus rhythm . Table
1 shows favorable and unfavorable conditions for elective cardioversion of
Table 1: Conditions Favorable and Unfavorable for Cardioversion of Atrial Fibrillation
American College of Cardiology (ACC)/American Heart Association (AHA)/European
Society for Cardiology (ESC) guidelines state that Class I indications for
cardioversion of AF to sinus rhythm include 1) immediate DC cardioversion in
patients with paroxysmal AF and a rapid ventricular rate who have ECG evidence
of acute MI or symptomatic hypotension, angina, or CHF that does not respond
promptly to pharmacological measures and 2) DC or drug cardioversion in
patients with chronic AF without hemodynamic instability when symptoms of AF
are unacceptable .
cardioversion of AF either by DC or by antiarrhythmic drugs should not be
performed in asymptomatic older patients with chronic AF. Rectilinear,
biphasic shocks have been found to have greater efficacy and need less energy
than the traditional damped sine wave monophasic shocks .
Therefore, biphasic shocks to cardiovert AF should become the clinical
drugs that have been used to convert AF to sinus rhythm include amiodarone,
disopyramide, dofetilide, encainide, flecainide, ibutilide, procainamide,
propafenone, quinidine, and sotalol. None of these drugs is as successful as DC
cardioversion, which has a success rate of 80% to 90% in converting AF to sinus
rhythm. All of these drugs are proarrhythmic and may aggravate or cause cardiac
and flecainide caused atrial proarrhythmic effects in 6 of 60 patients (10%) . The atrial proarrhythmic effects included conversion of
AF to atrial flutter with a 1-to-1 AV conduction response and a very fast
ventricular rate . Flecainide has caused ventricular
tachycardia (VT) and ventricular fibrillation (VF) in patients with chronic AF
. Antiarrhythmic drugs including amiodarone,
disopyramide, flecainide, procainamide, propafenone, quinidine, and sotalol
caused cardiac adverse effects in 73 of 417 patients (18%) hospitalized for AF
. Class IC drugs such as encainide, flecainide, and
propafenone should not be used in patients with prior MI or abnormal LV ejection fraction because these drugs may cause life-threatening ventricular
tachyarrhythmias in these patients .
and ibutilide are Class III antiarrhythmic drugs that have been used for the
conversion of AF to sinus rhythm. Eleven of 75 patients (15%) with AF treated
with intravenous dofetilide converted to sinus rhythm .
Torsade de pointes occurred in 3% of patients treated with intravenous
dofetilide . After 1-month, 22 of 190 patients (12%)
with AF and CHF had sinus rhythm restored with dofetilide compared to 3 of 201
patients (1%) treated with placebo . Torsade de
pointes developed in 25 of 762 patients (3%) treated with dofetilide and in
none of 756 patients (0%) treated with placebo .
Dofetilide has also been reported to be useful for the prevention of AF after
CABG . This study was commented on by Mariscalco et al.
of 79 patients (29%) with AF treated with intravenous ibutilide converted to
sinus rhythm . Polymorphic VT developed in 4% of
patients who received intravenous ibutilide in this study .
Baseline bradycardia with AF may predispose to ibutilide-induced polymorphic
is a relatively atrium-selective , early-activating K+, and frequency-dependent
Na+ channel blocker with a half-life of 2 to 3 hours .
In patients with an AF duration of 3 hours to 7 days, 75 of 145 patients (52%)
randomized to vernakalant and 3 of 75 patients randomized to placebo (4%)
converted to sinus rhythm . In patients with an AF
duration of 8 to 45 days, 8 of 76 patients (11%) randomized to vernakalant
and 0 of 40 patients (0%) randomized to placebo converted to sinus rhythm . In the 221 patients treated with vernakalant,
hypotension developed in 2 patients, cardiogenic shock in 1 patient, and
complete AV block in 1 patient .
cardioversion of AF has a higher success rate in converting AF to sinus rhythm
and a lower incidence of cardiac adverse effects than treatment with any
antiarrhythmic drug. However, pretreatment with ibutilide has been found to
facilitate transthoracic cardioversion of AF .
transesophageal echocardiography has demonstrated no thrombus in the left
atrial appendage before cardioversion , oral warfarin
should be administered for 3 weeks before elective DC or drug conversion of patients
with AF to sinus rhythm . Anticoagulant therapy should
also be administered at the time of cardioversion and continued until sinus
rhythm has been maintained for 4 weeks . After DC or
drug cardioversion of AF to sinus rhythm, the left atrium becomes stunned and
contracts poorly for 3 to 4 weeks, predisposing to TE stroke unless the patient
is maintained on oral warfarin [127, 128].
The maintenance dose of oral warfarin should be titrated by serial prothrombin
times so that the International Normalized Ratio (INR) is 2.0 to 3.0 .
multicenter, randomized, prospective study, 1,222 patients with AF of >2 days
duration were randomized to either treatment guided by the findings on
transesophageal echocardiography or to management with conventional therapy . The primary endpoint was cerebrovascular accident,
transient ischemic attack, and peripheral embolism within 8 weeks. The
incidence of embolic events at 8 weeks was 0.8% in the transesophageal
echocardiography treatment group and 0.5% in the conventional treatment group . At 8 weeks, there were also no significant differences
between the 2 groups in the rates of death, maintenance of sinus rhythm, or
functional status . However, there was a trend toward
a higher rate of death from any cause in the transesophageal echocardiography
treatment group (2.4%) than in the conventional treatment group (1.0%) (p=0.06)
showed the importance of maintaining therapeutic anticoagulation in the period
after cardioversion even if there is no transesophageal echocardiographic
evidence of thrombus [128,130]. The
best management strategy for patients with evidence of an atrial thrombus on
initial transesophageal echocardiography remains controversial .
In the absence of data from a randomized trial, patients probably should have
follow-up transesophageal echocardiography after 1 month of warfarin therapy to
demonstrate resolution of the atrial thrombus [131,132].
The efficacy and
safety of antiarrhythmic drugs after cardioversion of AF to maintain sinus
rhythm has been questioned. A meta-analysis of 6 double-blind,
placebo-controlled studies of quinidine involving 808 patients who had
direct-current cardioversion of chronic AF to sinus rhythm showed that 50% of
patients treated with quinidine and 25% of patients treated with placebo
remained in sinus rhythm at 1 year follow-up .
However, the mortality was significantly higher in patients treated with
quinidine (2.9%) than in patients treated with placebo (0.8%) .
In a study of 406 elderly patients, mean age 82 years, with heart disease and
complex ventricular arrhythmias, the incidence of adverse effects causing drug
cessation was 48% for quinidine and 55% for procainamide .
The incidence of total mortality at 2-year follow-up was insignificantly higher
in elderly patients treated with quinidine or procainamide compared with
elderly patients not receiving an antiarrhythmic drug .
another study, 85 patients were randomized to quinidine and 98 patients to
sotalol after DC cardioversion of AF to sinus rhythm .
At 6-month follow-up, 48% of quinidine-treated patients and 52% of
sotalol-treated patients remained in sinus rhythm . At
1-year follow-up of 100 patients with AF cardioverted to sinus rhythm, 37% of
50 patients randomized to sotalol and 30% of 50 patients randomized to
propafenone remained in sinus rhythm .
a study of 403 patients with at least 1 episode of AF in the prior 6 months,
201 patients were treated with amiodarone and 202 patients were treated with
sotalol or propafenone . At 16-month follow-up, AF
recurred in 35% of patients treated with amiodarone and in 63% of patients
treated with sotalol or propafenone . Adverse effects
causing cessation of drug occurred in 18% of patients treated with amiodarone
and in 11% of patients treated with sotalol or propafenone .
cardioversion of 394 patients with AF to sinus rhythm, 197 patients were
randomized to metoprolol CR/XL and 197 patients to placebo .
At 6-month follow-up, the percent of patients in sinus rhythm was significantly
higher on metoprolol CR/XL (51%) than on placebo (40%) .
The heart rate in patients who relapsed into AF was also significantly lower in
pts treated with metoprolol CR/XL than in patients treated with placebo .
In a study of 384 patients with a history of AF or atrial flutter,
azimilide lengthened the median time to first symptomatic arrhythmia recurrence
from 17 days in the placebo group to 60 days in the azimilide group . However, additional data on both efficacy and
safety of azimilide are needed before knowing its role in clinical practice.
Of the 1,330 patients in
the Stroke Prevention in Atrial Fibrillation (SPAF) Study, 127 persons were
taking quinidine, 57 procainamide, 34 flecainide, 20 encainide, 15
disopyramide, and 7 amiodarone . Patients who were
taking an antiarrhythmic drug had a 2.7 times higher adjusted relative risk of
cardiac mortality and a 2.3 times higher adjusted relative risk of arrhythmic
death compared with patients not taking an antiarrhythmic drug .
Patients with a history of CHF who were taking an antiarrhythmic drug had a 4.7
times increased risk of cardiac death and a 3.7 times increased risk of
arrhythmic death than patients with a history of CHF not taking an
antiarrhythmic drug .
A meta-analysis of 59 randomized, controlled trials comprising 23,229
patients that investigated the use of aprindine, disopyramide, encainide,
flecainide, imipramine, lidocaine, mexiletine, moricizine, phenytoin,
procainamide, quinidine, and tocainide after MI also demonstrated that
mortality was significantly higher in patients receiving Class I antiarhythmic
drugs (odds ratio = 1.14) than in patients not receiving an antiarrhythmic drug
. None of the 59 studies showed a decrease in
mortality by antiarrhythmic drugs .
Amiodarone is the antiarrhythmic drug with the
highest success rate in maintenance of sinus rhythm after cardioversion of AF . However, in the Cardiac Arrest in Seattle: Conventional
Versus Amiodarone Drug Evaluation Study, the incidence of pulmonary toxicity
was 10% at 2 years in patients receiving amiodarone in a mean dose of 158 mg
daily . The incidence of adverse effects from
amiodarone also approaches 90% after 5 years of therapy .
maintenance of sinus rhythm with antiarrhythmic drugs may require serial
cardioversions, exposes patients to the risks of proarrhythmia, sudden cardiac
death, and other adverse effects, and requires the use of anticoagulants in
patients in sinus rhythm who have a high risk of recurrence of AF, many
cardiologists prefer the management strategy of ventricular rate control plus
use of anticoagulants in patients with AF, especially in older patients with
AF. Beta blockers such as propranolol 10 mg to 30 mg given 3 to 4 times daily
can be administered to control ventricular arrhythmias  and after conversion of AF to sinus rhythm. Should AF
recur, beta blockers have the added advantage of slowing the ventricular rate.
Beta blockers are also the most effective drugs in preventing and treating AF
after CABS . Logistic regression analysis showed that
postoperative treatment with carvedilol prevented postoperative paroxysmal AF
after CABG (p = 0.0159) . This study was commented on
by Banach et al. .
The Pharmacological Intervention in Atrial
Fibrillation trial was a randomized trial of 252 patients with AF of between 7
days and 360 days duration which compared ventricular rate control (125
patients) with rhythm control (127 patients) .
Diltiazem was used as first-line therapy in patients randomized to ventricular
rate control. Amiodarone was used as first-line therapy in patients randomized
to rhythm control. Amiodarone administration resulted in conversion of 23% of
patients to sinus rhythm . Symptomatic improvement was
reported in a similar percentage of patients in both groups. Assessment of
quality of life showed no significant difference between the 2 treatment
groups. The incidence of hospital admission was significantly higher in
patients treated with rhythm control (69%) than in patients treated with
ventricular rate control (24%) . Adverse drug effects
caused a change in drug therapy in significantly more patients treated with
rhythm control (25%) than in patients treated with ventricular rate control
The Atrial Fibrillation Follow-Up
Investigation of Rhythm Management (AFFIRM) Study randomized 4, 060 patients,
mean age 70 years (39% women), with paroxysmal or chronic AF of less than 6
months duration at high risk for stroke to either maintenance of AF with
ventricular rate control or to an attempt to maintain sinus rhythm with
antiarrhythmic drugs after cardioversion . Patients in
both arms of this study were treated with warfarin. All-cause mortality at 5
years was insignificantly increased 15% in the maintenance of sinus rhythm
group compared to the ventricular rate control group (24% versus 21 %, p =
0.08) . TE stroke was insignificantly decreased in
the ventricular rate control group (5.5% versus 7.1%), and all-cause
hospitalization was significantly decreased in the ventricular rate control
group (73% versus 80%, p < 0.001) . In both
groups, the majority of strokes developed after warfarin was stopped or when
the INR was subtherapeutic. There was no significant difference in quality of
life or functional status between the 2 treatment groups .
Rhythm control did not improve mortality, hospitalization, or New York
Heart Association class in patients with LV ejection fractions of 40% to 49%,
30% to 39%, or less than 30% .
Rate Control Versus Electrical Cardioversion for Persistent Atrial Fibrillation
Study Group randomized 522 patients with persistent AF after a previous
electrical cardioversion to receive treatment aimed at ventricular rate control
or rhythm control . Both groups were treated with oral
anticoagulants. At 2.3-year follow-up, the composite end point of death from
cardiovascular causes, heart failure, TE complications, bleeding, implantation
of a pacemaker, and severe adverse effects of drugs was 17.2% in the
ventricular rate control group versus 22.6% in the rhythm control group . In this study, women randomized to rhythm control had a
3.1 times significant increase in cardiovascular morbidity or mortality than
women randomized to ventricular rate control (p=0.002) .
The 2-year mortality was similar in 1,009
patients with AF and CHF treated with rate control or rhythm control . At 37-month follow-up of 1,376 patients, mean age 67
years with AF and CHF, cardiovascular mortality was 27% in patients treated
with rhythm control versus 25% in patients treated with ventricular rate
control . The secondary outcomes of all-cause
mortality, stroke, worsening CHF, and composite of cardiovascular death,
stroke, or worsening CHF were also similar in both groups .
During 19-month follow-up of 110 patients
with a history of AF treated with antiarrhythmic drug therapy, recurrent AF was
diagnosed by ECG recordings in 46% of the patients and by an implantable
monitoring device in 88% of the patients . AF lasting
longer than 48 hours was diagnosed by the monitoring device in 50 of the 110
patients (46%) . Nineteen of these 50 patients (38%)
were completely asymptomatic .
2 lists risk factors for TE stroke in patients with AF [1, 2, 42, 43, 156 - 167]. In the SPAF Study involving patients, mean age 67 years,
recent CHF (within 3 months), a history of hypertension, previous
thromboembolism, echocardiographic left atrial enlargement, and
echocardiographic LV systolic dysfunction were associated independently with
the development of new TE events [161,164].
The incidence of new TE events was 18.6% per year if 3 or more risk factors
were present, 6.0% per year if 1 or 2 risk factors were present, and 1.0% per
year if none of these risk factors was present .
Table 2: Risk Factors for Stroke in Elderly Patients With Atrial Fibrillation
In the SPAF Study III
involving patients, mean age 72 years, patients were considered at high risk
for developing TE stroke if they had either CHF or abnormal LV systolic
function, prior thromboembolism, a systolic blood pressure of >160 mm Hg,
or the patient was a woman older than age 75 years .
In a study of 312 elderly patients with chronic AF, mean age 84 years,
independent risk factors for the development of new TE stroke were prior stroke
(risk ratio = 1.6), rheumatic mitral stenosis (risk ratio = 2.0), LVH (risk
ratio = 2.8), abnormal LVEF (risk ratio = 1.8), serum total cholesterol (risk
ratio = 1.01 per 1 mg/dL increase), serum high-density lipoprotein cholesterol
(risk ratio = 1.04 per 1 mg/dL decrease), and age (risk ratio = 1.03 per 1 year
randomized trials [157, 158, 162, 165, 168-174] and prospective, nonrandomized observational data from
elderly patients, mean age 83 years , and mean age 84
years , have shown that warfarin is effective in
lowering the incidence of TE stroke in patients with nonvalvular AF. Analysis
of pooled data from 5 randomized, placebo-controlled studies showed that
warfarin significantly lowered the incidence of new TE stroke by 68% and was
significantly more effective than aspirin in reducing the incidence of new TE
stroke . In the Veterans Affairs Cooperative study,
the incidence of new TE events was 4.3% per year in patients on placebo versus
0.9% per year in patients on warfarin in patients with no prior stroke, 9.3%
per year in patients on placebo versus 6.1% per year in patients on warfarin in
patients with prior stroke, and 4.8% per year in patients on placebo versus
0.9% per year in patients on warfarin in patients older than age 70 years . In the European Atrial Fibrillation Trial involving
patients with recent transient cerebral ischemic attack or minor ischemic
stroke, at 2.3-year follow-up, the incidence of new TE events was 12% per year
in patients taking placebo, 10% per year in patients taking aspirin, and 4.0
per year in patients taking warfarin .
Nonrandomized observational data from
elderly patients with chronic AF, mean age 83 years, found that 141 patients
treated with oral warfarin to achieve an INR between 2.0 and 3.0 (mean INR was
2.4) had a 67% significant decrease in new TE stroke compared with 209 patients
treated with oral aspirin . Compared with aspirin,
warfarin caused a 40% significant reduction in new TE stroke in patients with
prior stroke, a 31% significant reduction in new TE stroke in patients with no
prior stroke, a 45% significant reduction in new TE stroke in patients with
abnormal LVEF, and a 36% significant reduction in new TE stroke in patients
with normal LVEF .
1.1-year follow-up in the SPAF Study III, patients with AF considered to be at
high risk for developing new TE stroke who were randomized totment with oral
warfarin to achieve an INR between 2.0 and 3.0 had a 72% significant decrease
in ischemic stroke or systemic embolism compared with patients randomized to
treatment with oral aspirin 325 mg daily plus oral warfarin to achieve an INR
between 1.2 and 1.5 . Adjusted-dose warfarin caused an
absolute reduction in ischemic stroke or systemic embolism of 6.0% per year . In the Second Copenhagen Atrial Fibrillation, Aspirin,
Anticoagulation (AFASK) Study, low-dose warfarin plus aspirin was also less
effective in decreasing stroke or systemic TE events in patients with AF (7.2%
after 1 year) than was adjusted-dose warfarin to achieve an INR between 2.0 and
3.0 (2.8% after 1 year) .
of pooled data from 5 randomized controlled studies demonstrated that the
annual incidence of major hemorrhage was 1.0% for the control group, 1.0% for
the aspirin group, and 1.3% for the warfarin group .
The incidence of major hemorrhage in patients, mean age 72 years, taking
adjusted-dose warfarin to achieve an INR of 2.0 to 3.0 in the SPAF III Study
was 2.1% . In the Second Copenhagen AFASK Study, the
incidence of major hemorrhage in patients, mean age 73 years, was 0.8% per year
for patients treated with adjusted-dose warfarin to achieve an INR between 2.0
and 3.0 and 1.0% per year for patients treated with aspirin 300 mg daily . The incidence of major hemorrhage in elderly patients
with chronic AF, mean age 83 years, was 4.3% (1.4% per year) in patients
treated with warfarin to maintain an INR between 2.0 and 3.0 and 2.9% (1.0% per
year) in patients treated with aspirin 325 mg daily .
the SPAF III Study, 892 patients, mean age 67 years, at low risk for developing
TE stroke were treated with oral aspirin 325 mg daily .
The incidence of ischemic stroke or systemic embolism was 2.2% per year . The incidence of ischemic stroke or systemic embolism
was 3.6% per year in patients with a history of hypertension and 1.1% per year
in patients with no history of hypertension .
the Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) study, 973
patients aged 75 years and older with AF and a low prevalence of risk factors
for stroke were randomized to warfarin with a target INR of 2.0-3.0 or aspirin
75 mg daily . Warfarin was significantly
better than aspirin in reducing disabling strokes or clinically significant
arterial embolism (1.8% per year on warfarin versus 3.8% per year on aspirin)
. Major bleeding was 1.9% per year for warfarin versus
2.0% per year for warfarin.
a study of 13, 559 patients with nonvalvular AF hospitalized with an outpatient
stroke, compared to an INR of 2.0 or greater, an INR of <2.0 at hospital
admission significantly increased the odds of a severe stroke by 1.9 times and
the risk of death within 30 days by 3.4 times . The
30-day mortality was similar among patients who were taking aspirin or warfarin
with an INR of <2.0 . Elderly patients taking
warfarin should have an INR maintained between 2.0 and 3.0, not one <2.0 or
of paroxysmal AF in patients undergoing aortic valve replacement for aortic
stenosis were heart failure, age 70 years and older, low and high body mass
index, maximal transvalvular gradient, low LV ejection fraction, end-systolic
and end-diastolic intraventricular septum thickness, and insignificant mitral
regurgitation in the preoperative period; and LV ejection fraction and
end-systolic intraventricular septum thickness in the early postoperative
period . Predictors of paroxysmal AF in patients
undergoing aortic valve replacement for aortic regurgitation were hypertension,
diabetes, and history of heart failure in the preoperative period; LV ejection
fraction and left atrial dimension in the early postoperative period; and age,
LV ejection fraction, LV end-systolic diameter, end-systolic intraventricular
septum thickness, left atrial dimension, and insignificant mitral regurgitation
in the postoperative period . Prophylactic treatment
should be administered to patients undergoing aortic valve replacement at high
risk for developing postoperative AF .
3,000 patients undergoing isolated surgical revascularization, 174 (5.8%) had
preoperative AF . At 3-year follow-up, survival rates
were 90.6% in patients without preoperative AF versus 70.7% in those with
preoperative AF (p<0.01) .
physicians are reluctant to prescribe warfarin for AF in patients with chronic
kidney disease because of concern of bleeding complications. Because of the
high prevalence of AF and its association with an increased incidence of TE
events in patients with late stage chronic kidney disease, it is very important
to perform double-blind, placebo-controlled studies in these patients to
determine the efficacy of oral anticoagulant therapy in preventing TE events
and the incidence and type of bleeding complications .
Until these data are available, the authors favor treating patients with AF on
hemodialysis with warfarin on an individual basis taking into account both
the TE risk as well as the hemorrhagic risk .
the basis of the available data, patients with chronic or paroxysmal AF at high
risk for developing TE stroke or with a history of hypertension and who have no
contraindications to anticoagulation therapy should be treated with long-term
oral warfarin to achieve an INR between 2.0 and 3.0 [124,183]. Hypertension must be controlled. Whenever the patient
has a prothrombin time taken, the blood pressure should also be checked. The
physician prescribing warfarin should be aware of the numerous drugs which
potentiate the effect of warfarin causing an increased prothrombin time and
risk of bleeding . Patients with AF at low risk for
developing TE stroke or with contraindications to treatment with long-term oral
warfarin should be treated with aspirin 325 mg orally daily .
younger than age 60 years in Olmstead County, Minnesota with lone AF (no heart
disease) had a low risk of TE stroke at 15-year follow-up .
However, at 30-year follow-up in the Framingham Heart Study, the age-adjusted
percentage of patients with lone AF who developed a cerebrovascular event was
28% versus 7% in the control group . At 30-year
follow-up of 76 patients with lone AF in Olmstead County, Minnesota, risk for
stroke or transient ischemic attack was similar to the expected population risk
during the first 25 years of follow-up but significantly increased thereafter
(p = 0.004) . Age or hypertension increased the TE
Table 3 shows the ACC/AHA/ESC Class I indications for
antithrombotic therapy in the management of patients with AF .
Table 3: American College of Cardiology/American Heart Association/European Society for Cardiology Class I Indications for Treating Patients With Atrial Fibrillation With Antithrombotic Therapy
the data showing the efficacy of oral warfarin used in a dose to achieve an INR
between 2.0 and 3.0 in reducing the incidence of new TE events in patients with
paroxysmal or chronic AF, only about one-third of patients with AF who should
be taking warfarin receive it . In an academic
hospital-based geriatrics practice, only 61 of 124 patients (49%), mean age 80
years, with chronic AF at high risk for developing TE stroke and no
contraindications to warfarin were being treated with warfarin therapy . The Euro Heart Survey on Atrial Fibrillation found that
compared to guideline-adherent antithrombotic therapy, undertreatment of AF
with oral anticoagulants was associated with a 1.97 times significant increase
in thromboembolic events and a 1.54 times significant increase in
cardiovascular death, thromboembolism, or major bleeding .
Elderly patients have a higher prevalence and
incidence of AF than younger patients [1-6].
Elderly patients with AF are at higher risk for developing TE stroke than are
younger patients with AF [1,40, 42,154-158]. However,
physicians are more reluctant to treat elderly patients with AF with warfarin
therapy. Hopefully, intensive physician education will help solve this
important clinical problem.
In the Anticoagulation and Risk Factor in Atrial
Fibrillation Study, women off warfarin had significantly higher annual rates of
thromboembolism (3.5%) than men (1.8%) . Warfarin was
associated with significantly lower adjusted TE rates for both women (60%
reduction) and men (40% reduction) with similar annual rates of major bleeding
(1.0% and 1.1%, respectively) .
The Atrial Fibrillation Clopidogrel Trial
with Irbersartan for the Prevention of Vascular Events (ACTIVE W) demonstrated
in patients with AF that the annual risk of first occurrence of stroke,
non-central nervous system systemic embolus, MI, or vascular death was 3.93% in
3,371 patients randomized to warfarin to maintain an INR between 2.0 and 3.0
and 5.60% in 3,335 patients randomized to clopidogrel 75 mg daily plus aspirin
75-100 mg daily, with a 44% significant reduction in the primary outcome
attributed to warfarin . The incidence of major
bleeding was 10% insignificantly higher in patients treated with clopidogrel
plus aspirin than in persons treated with warfarin .
oral direct thrombin inhibitor ximelagatran was as effective as warfarin in
decreasing TE stroke and systemic embolism in 7,329 patients treated with
these 2 drugs in 2 combined studies (1.6% per year for both drugs) [193,194]. The incidence of
major bleeding in the 2 pooled studies was 1.9% per year on ximelagatran and
2.5% per year for warfarin. However, Ximelagatran increased serum transaminase
levels in 6% of patients and was not approved by the USA Food and Drug
Administration because of concerns of hepatotoxicity.
is another direct thrombin inhibitor which is being investigated versus
warfarin in a large phase III trial in patients with AF .
Rivaroxaban and apixaban are oral factor Xa inhibitors which are
being compared with warfarin in large phase III trials in patients with AF .
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Aronow WS, Ahn C, Gutstein H. Prevalence and incidence of cardiovascular disease in 1,160 older men and 2,464 older women in a long-term health care facility. J Gerontol: Med Sciences 2002;57A:M45-M46.
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