The medical letter on drugs and therapeutics july 7 2014

The Medical Letter

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on Drugs and Therapeutics
Objective Drug Reviews Since 1959

Volume 56

ISSUE
ISSUE
No.

July 7, 2014

IN THIS ISSUE

1433
1446 Treatment of Atrial Fibrillation
Volume 56

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The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959

Volume 56

July 7, 2014

A Note to Our Readers
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reviews of new drugs like those traditionally found in The Medical Letter, reviews of drug classes like those
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ISSUE

ISSUE No.

IN THIS ISSUE

1433
1446 Treatment of Atrial Fibrillation
Volume 56
Related article(s) since publication

The treatment of atrial fibrillation includes anticoagulation, rate control, and rhythm control. New US
guidelines for the management of atrial fibrillation
have recently been published.1
ANTICOAGULATION
Atrial fibrillation increases the risk of thromboembolic
stroke. Anticoagulant therapy reduces this risk, but it
can cause intracranial and other serious bleeding. The
risk of bleeding must be weighed against the benefit of
thromboembolic risk reduction.
A new scoring system, the CHA2DS2-VASc score, has been
designed to aid in this assessment for patients with nonvalvular atrial fibrillation. An algorithm from the recent US
guidelines recommends oral anticoagulant treatment for
patients who have a CHA2DS2-VASc score ≥2. For patients
with a CHA2DS2-VASc score of 0, who have a very low risk of
thromboemboli, it would be reasonable to omit antithrombotic therapy. For patients with a CHA2DS2-VASc score
Table 1. CHA2DS2-VASc Scoring
Condition
C
H

A
D
S
V
A
Sc

Points

Congestive heart failure
Hypertension
Age ≥75 years
Diabetes mellitus
Stroke, TIA, or thromboembolism
Vascular disease
Age 65-74 years
Sex category (Female)

1
1
2
1
2
1
1
1

of 1, the US guidelines recommend no antithrombotic
therapy or use of either aspirin or an oral anticoagulant,
but evidence supporting use of aspirin for this indication

is limited. European guidelines recommend use of an oral
anticoagulant for patients with a CHA2DS2-VASc score of 1,
except for women with no other risk factor, for whom no
antithrombotic therapy is recommended.2
Patients with atrial fibrillation associated with a mechanical valve, a bioprosthetic valve, prior mitral valve
repair, or mitral stenosis should take warfarin.
WARFARIN — When anticoagulation is indicated, the
benefits of long-term warfarin therapy in preventing
ischemic stroke in patients with atrial fibrillation
outweigh the risk of major bleeding.
Dosing – The main drawback of warfarin has been the
need for close monitoring and dosage adjustment to
keep the international normalized ratio (INR) between 2
and 3. The usual starting dosage range is 2-5 mg once
daily, varying with the weight and age of the patient.
Algorithms are available at www.warfarindosing.org.
Drug Interactions – Maintaining the INR in the desired
range is made more difficult by warfarin’s numerous
interactions with food and with other drugs (see Table 2).
In patients with atrial fibrillation, the most important of
these is with amiodarone, which decreases the warfarin
dose requirement by one-third to one-half. Another interaction is with the widely used analgesic acetaminophen;
53

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The Medical Letter

®

Table 2. Some Drugs that Interact with Warfarin
Possible Increased
Anticoagulant Effect

Possible Decreased
Anticoagulant Effect

Acetaminophen (Tylenol)
Barbiturates
Amiodarone (Cordarone)
Carbamazepine (Tegretol)
Cefazolin
Cholestyramine (Questran)
Cefotetan
Colestipol (Colestid)
Ceftriaxone (Rocephin)
Dicloxacillin
Clarithromycin (Biaxin)
Nafcillin
Erythromycin
Phenytoin (Dilantin)
Fluconazole (Diflucan)
Rifampin (Rifadin)
Fluoroquinolones
St. John’s wort
Fluorouracil
Sucralfate (Carafate)
Fluoxetine (Prozac)
Fluvastatin (Lescol)

Fluvoxamine (Luvox)
Metronidazole (Flagyl)
Phenytoin (initial; Dilantin)
Rosuvastatin (Crestor)
Trimethoprim-sulfamethoxazole (Bactrim)
Voriconazole (Vfend)

occasional use of acetaminophen generally has little
or no effect on the INR in patients on chronic warfarin therapy, but in some patients even a few grams of
acetaminophen can cause a dramatic increase in INR.
Patients on chronic warfarin therapy who take more
than 2 g/day of acetaminophen for more than a few days
should be monitored closely for INR changes.
NEWER ORAL ANTICOAGULANTS — In patients with
nonvalvular atrial fibrillation, dabigatran etexilate, rivaroxaban, and apixaban all appear to be at least as effective as warfarin in preventing stroke, and in clinical
trials all caused less intracranial bleeding than warfarin.3-5 Patients with atrial fibrillation associated with
a mechanical valve, a bioprosthetic valve, prior mitral
valve repair, or mitral stenosis should take warfarin.
The three new oral anticoagulants do not require routine INR-type monitoring, have no dietary restrictions,
and may have fewer interactions with other drugs
compared to warfarin, but they have no established
method for determining the extent of anticoagulation,
have no specific antidote to reverse their anticoagulant effect, and are not recommended for use in patients with end-stage kidney disease.
DABIGATRAN – The oral direct thrombin inhibitor
dabigatran etexilate is FDA-approved for prevention
of thromboembolic stroke in patients with nonvalvular
atrial fibrillation.6
Bleeding Risk – Because of multiple spontaneous
reports of severe, sometimes fatal, bleeding with
dabigatran, the FDA conducted a post-marketing

study in >134,000 Medicare patients ≥65 years old
which found that the risks of intracranial bleeding and
ischemic and thromboembolic stroke were lower with
dabigatran than with warfarin, but the risk of major
gastrointestinal bleeding was higher with dabigatran.7,8
54

Vol. 56 (1446)

July 7, 2014

Drug Interactions – Dabigatran etexilate is a substrate
of the efflux transporter P-glycoprotein (P-gp). Coadministration with P-gp inducers such as rifampin
reduces serum concentrations of dabigatran and may
decrease its effectiveness. P-gp inhibitors such as
amiodarone may increase serum concentrations of
dabigatran.9
Reversibility – Unlike warfarin, which can be reversed by vitamin K, there is no specific antidote for
dabigatran-induced bleeding. Its anticoagulant effect
is not reversible except by hemodialysis.
RIVAROXABAN – The factor Xa inhibitor rivaroxaban
is also FDA-approved for prevention of stroke and
systemic embolism in patients with nonvalvular atrial
fibrillation.10 It should not be used in patients with
moderate or severe hepatic impairment.
Reversibility – Due to the high percentage of drug
bound to protein in plasma, rivaroxaban is not expected
to be dialyzable. Preliminary studies suggest that its
anticoagulant effect may be reversed by prothrombin
complex concentrate.11

Drug Interactions – Rivaroxaban is a substrate of
CYP3A4 and P-gp. Coadministration of drugs that inhibit
CYP3A4 and P-gp may increase serum concentrations
of rivaroxaban, leading to an increased risk of bleeding.
Coadministration of drugs that are inhibitors of P-gp
and strong inhibitors of CYP3A4, such as ketoconazole,
are contraindicated. Coadministration of P-gp inducers
and strong inducers of CYP3A4, such as rifampin,
should also be avoided.9
APIXABAN – The factor Xa inhibitor apixaban is the
third new oral anticoagulant to be approved by the FDA
for use in patients with nonvalvular atrial fibrillation.
In clinical trials, apixaban was the only one of the new
oral anticoagulants to cause less overall bleeding than
warfarin, but the trials were conducted in somewhat
different populations and used slightly different definitions of major bleeding.12 Apixaban should not be used
in patients with severe hepatic impairment.
Reversibility – There is no established antidote to
reverse the anticoagulant effect of apixaban, which persists for about 24 hours after the last dose, and the drug
is not dialyzable. Preliminary studies suggest that it may
be reversible with prothrombin complex concentrate.11
Drug Interactions – Apixaban is a substrate of CYP3A4
and P-gp. The dose should be reduced to 2.5 mg twice
daily if it is used concurrently with drugs that inhibit
both CYP3A4 and P-gp, such as itraconazole, ritonavir,


The Medical Letter

Vol. 56 (1446)

®

July 7, 2014

Table 3. Oral Anticoagulants for Atrial Fibrillation
Drug

Mechanism
of Action

Usual
Dosage

Warfarin
Vitamin K
generic
antagonist
(Coumadin)

2-10 mg
once/d2

Apixaban
(Eliquis)

Direct factor
Xa inhibitor

5 mg bid3

Dabigatran
etexilate
(Pradaxa)

Direct thrombin 150 mg bid4
inhibitor

Rivaroxaban Direct factor
(Xarelto)
Xa inhibitor

20 mg
once/d5

Some Advantages

Some Disadvantages

Long history of clinical experience
Once-daily dosing
Vitamin K can reverse the anticoagulant effect
Mortality benefit over warfarin in
one clinical trial
Causes less bleeding than warfarin
Lower rates of ischemic stroke
compared to warfarin
Does not require INR monitoring

Variability in dosage requirements

Dietary restrictions
INR monitoring required
Numerous drug interactions
No established method for determining
the extent of anticoagulation
No specific antidote for reversal
Not dialyzable
Dose adjustment for age, weight, or
renal impairment
Twice-daily dosing
No established method for determining
the extent of anticoagulation
No specific antidote for reversal
Dose adjustment for renal impairment
Twice-daily dosing
Must be dispensed and stored in original
container
No established method for determining
the extent of anticoagulation
No specific antidote for reversal
Not dialyzable
Dose adjustment for renal impairment

Lower rates of stroke and intracranial bleeding than warfarin in
one clinical trial
Does not require INR monitoring
Dialyzable

Less intracranial and fatal bleeding
than warfarin in one clinical trial

Does not require INR monitoring
Once-daily dosing

Cost1
$ 6.00
48.90
291.70

291.70

286.40

1. Wholesale acquisition cost (WAC) of 30 days’ treatment at the lowest usual dosage. Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) June 5,
2014. Reprinted with permission by FDB, Inc. All rights reserved. ©2014. www.fdbhealth.com/policies/drug-pricing-policy. Actual retail prices may be higher.
2. Monitor and maintain INR in therapeutic range (2-3).
3. Dose is 2.5 mg bid for patients with 2 or more of the following: age >80 years, body weight <60 kg, or serum creatinine >1.5 mg/dL.
4. Dose is 75 mg bid for CrCl 15-30 mL/min, according to the US label. The American College of Chest Physicians and Health Canada do not recommend use of
the drug in patients with a CrCl <30 mL/min.
5. Taken with the evening meal. Dose is 15 mg once daily for CrCl 15-50 mL/min.

or clarithromycin.9 Coadministration of drugs that induce both CYP3A4 and P-gp, such as rifampin, should
be avoided.
RATE CONTROL
Ventricular rate control is now widely used as first-line
therapy for management of chronic atrial fibrillation.
Antiarrhythmic drugs have not been shown to be
more effective in preventing serious complications
and have considerable toxicity.13 Lenient rate control
(resting heart rate <110 beats per minute), particularly
in patients with a structurally normal heart and no

heart failure, is easier to achieve and appears to be
as effective as strict rate control (resting heart rate
<80 beats per minute).14 The drugs most commonly
used for rate control in atrial fibrillation are listed in
Table 4.
BETA-ADRENERGIC BLOCKERS — A beta-blocker
such as propranolol, metoprolol, or esmolol given
intravenously can acutely control the ventricular rate
in atrial fibrillation or flutter. Oral beta-blockers are
used for long-term rate control. Beta-blockers are
preferred over calcium channel blockers for patients
with coronary disease or systolic dysfunction. They
should be used cautiously in patients with decompensated heart failure.

CALCIUM CHANNEL BLOCKERS — Verapamil and
diltiazem prolong AV nodal refractoriness and are
effective in slowing the ventricular rate in atrial fibrillation or flutter. Their IV use can be complicated by
hypotension or bradycardia in patients with underlying
heart disease, especially with concurrent use of
other cardiodepressant drugs such as beta-blockers.
Verapamil and diltiazem may be preferred over betablockers for long-term use in patients with chronic
obstructive pulmonary disease or asthma. They should
not be used in patients with decompensated heart failure or Wolff-Parkinson-White syndrome.
Unlike verapamil and diltiazem, dihydropyridine
calcium channel blockers (all the other calcium
channel blockers available in the US) generally have
no rate-controlling activity.
AMIODARONE — More often used as a rhythm control
agent, IV amiodarone has been used for ventricular
rate control in some critically ill patients, and oral

amiodarone has been used when other treatments
have failed to control heart rate.
DIGOXIN — Generally used as an adjunctive agent,
digoxin can help control ventricular response in
atrial fibrillation or flutter, but other drugs are more
effective. Digoxin, like verapamil and diltiazem,
55


The Medical Letter

July 7, 2014

Vol. 56 (1446)

®

Table 4. Some Rate Control Agents: Dosage and Adverse Effects
Drug
Beta-Adrenergic Blockers
Esmolol (Brevibloc,
and generics)

Some Oral
Formulations

Usual Adult Dosage1

Some Adverse Effects
Heart block, hypotension, bradycardia,

bronchospasm, pain at infusion site

50, 100 mg tabs;
25, 50, 100, 200 mg
ER tabs
10, 20, 40, 60, 80 mg
tabs; 60, 80, 120,
160 mg ER caps
25, 50, 100 mg tabs

IV : 500 mcg/kg bolus over 1 min,
then 50-300 mcg/kg/min; titrate
to desired effect
PO: 25-400 mg once/d or bid2
IV : 2.5-5 mg over 2 min
(up to 3 doses)
PO: 10-40 mg tid or qid2
IV : 1 mg over 1 min (up to 3
doses every 2 min)
PO: 25-100 mg once/d

5, 10 mg tabs

PO: 2.5-10 mg once/d

3.125, 6.25, 12.5, 25 mg
tabs; 10, 20, 40, 80 mg
ER caps
20, 40, 80 mg tabs

PO: 3.125-25 mg bid

—

Metoprolol (Lopressor,
Toprol XL, and generics)
Propranolol (Inderal LA,
and others)
Atenolol (Tenormin,
and generics)
Bisoprolol (Zebeta,
and generics)
Carvedilol (Coreg, and
generics; Coreg CR)
Nadolol (Corgard, and
generics)

Heart block, hypotension, bradycardia,
bronchospasm, depression
Heart block, hypotension, bradycardia,
bronchospasm, depression
Bradycardia, depression, worsening of
peripheral arterial insufficiency
Bradycardia, depression, worsening of
peripheral arterial insufficiency
Similar to other beta-adrenergic blockers,
but more orthostatic hypotension

PO: 10-240 mg once/d

Bradycardia, depression, worsening of
peripheral arterial insufficiency

30, 60, 90, 120 mg tabs;
120, 180, 240, 300,
360, 420 mg ER caps

PO: 120-360 mg once/d or
divided tid or qid2
IV : 0.25 mg/kg bolus over 2 min,
then 5-15 mg/hr

Heart block, hypotension, heart failure,
bradycardia, edema

40, 80, 120 mg tabs;
120, 180, 240 mg
ER tabs or caps

PO: 120-480 mg once/d or
divided tid or qid2
IV : 0.075-0.15 mg/kg bolus over
2 min (max 20 mg), then
0.005 mg/kg/min

Heart block, hypotension, heart failure,
bradycardia, dizziness, headache,
fatigue, edema, nausea, constipation

Amiodarone

Amiodarone (Cordarone,
and others)

100, 200 mg tabs3

PO: 100-200 mg once/d
IV : 300 mg over 1 hr, then
10-50 mg/h over 24 hrs

Arrhythmias, nausea, vomiting, abnormal
vision, abdominal pain, skin discoloration,
taste disturbances

Digoxin
Digoxin (Lanoxin,
and others)

0.125, 0.25 mg tabs

PO: 0.125-0.25 mg once/d
IV loading: 0.25 mg (max 1.5 mg
in 24 hrs)

Bradycardia, AV block, arrhythmias,
anorexia, nausea, vomiting, diarrhea,
abdominal pain, headache, confusion,
abnormal vision

Calcium Channel Blockers
Diltiazem (Cardizem LA,

and others)

Verapamil (Calan,
Calan SR, and others)

ER = Extended-release
1. Dosage adjustment may be required for hepatic or renal impairment.
2. Dosage given as a range; dose and interval will vary depending on formulation used.
3. Cordarone is only available in 200-mg tablets.

should not be used in patients with Wolff-ParkinsonWhite syndrome.
RHYTHM CONTROL
The treatment of choice for urgent conversion of atrial
fibrillation is DC cardioversion. Antiarrhythmic drugs,
particularly amiodarone, can be used to restore and
maintain normal sinus rhythm.
DRUG THERAPY — The antiarrhythmic drugs most
commonly used now to prevent episodes of paroxysmal atrial fibrillation and to maintain sinus rhythm after
cardioversion are listed in Table 5.
Amiodarone is the most effective antiarrhythmic
drug for maintenance of sinus rhythm, but it can
cause multiple adverse effects, some severe, and
56

has many interactions with other drugs (see Table 6).
Dronedarone, a non-iodinated analog of amiodarone,
has been less effective than amiodarone and has
been associated with severe adverse effects, including increased mortality in patients with persistent
atrial fibrillation.15
Propafenone and flecainide are generally reserved

for patients with structurally normal hearts; they
should only be used with a beta-blocker, verapamil,
or diltiazem. Sotalol, a non-selective beta-blocker, is
better tolerated than quinidine or some other older
drugs now seldom used for this indication, but it increases the QT interval and can cause torsades de
pointes; it should be avoided in patients with baseline
QT prolongation and in those receiving other drugs


The Medical Letter

Vol. 56 (1446)

®

July 7, 2014

Table 5. Some Rhythm Control Agents: Dosage and Adverse Effects1
Drug
Amiodarone3
(Cordarone, and others)

Some Oral
Formulations

Usual Adult Dosage2

Some Adverse Effects

100, 200 mg tabs4

PO: 400-600 mg daily in divided
doses for 2-4 weeks, then 100-200
mg q24h
IV: 150 mg over 10 min, then
1 mg/min for 6 hrs, then 0.5 mg/min
for 18 hrs; after 24 hrs 0.25 mg/min
IV maintenance: 0.5-1 mg/min
Cardiac arrest: 300 mg IV push

PO: Pulmonary fibrosis, bradycardia,
heart block, QT prolongation and possible
torsades de pointes (unusual; <1%), hyperor hypothyroidism, GI upset, alcoholic-like
hepatitis, peripheral neuropathy, ataxia,
tremor, dizziness, photosensitivity, bluegray skin, corneal microdeposits, optic
neuritis
IV: Hypotension, bradycardia, phlebitis at
site of administration, torsades de pointes

Disopyramide5
(Norpace, and generics;
Norpace CR)

100, 150 mg caps;
100, 150 mg ER caps

PO: 100-400 mg q6-12h6

Anticholinergic effects (urinary retention,
aggravation of glaucoma, constipation),

hypotension, heart failure, ventricular
tachyarrhythmias, QT prolongation and
possible torsades de pointes, heart
block, nausea, vomiting, diarrhea, hypoglycemia, nervousness

Dofetilide7
(Tikosyn)

0.125, 0.25, 0.5 mg caps

PO: 0.125-0.5 mg q12h

QT prolongation and torsades de pointes

Dronedarone8
(Multaq)

400 mg tabs

PO: 400 mg q12h

Hepatotoxicity, worsening heart failure with
increased mortality possible, bradycardia,
diarrhea, nausea, vomiting, abdominal
pain, photosensitivity, QT prologation and
possible torsades de pointes

50, 100, 150 mg tabs

PO: 50-200 mg q12h

Bradycardia, heart block, new ventricular
fibrillation, sustained ventricular tachycardia, rapid atrial flutter, heart failure,
dizziness, blurred vision, nervousness,
headache, GI upset, neutropenia, QT prolongation and possible torsades de pointes

Flecainide9

Propafenone9
(Rythmol, Rythmol SR,
and generics)

Sotalol10
(Betapace,
Betapace AF,
and others)

150, 225, 300 mg tabs;
PO: 150-425 mg q8-12h6
225, 325, 425 mg ER caps

Bradycardia, heart block, new ventricular
fibrillation, sustained ventricular tachycardia, heart failure, dizziness, lightheadedness, metallic taste, GI upset,
bronchospasm, hepatic toxicity

80, 120, 160, 240 mg tabs11 PO: 40-160 mg q12h

Heart block, hypotension, bronchospasm,
bradycardia; higher doses are associated
with increased adverse effects including

QT prolongation and torsades de pointes

ER = Extended-release
1. For maintenance of sinus rhythm. All of these drugs require monitoring at initiation for proarrhythmias.
2. Dosage adjustment may be required for hepatic or renal impairment.
3. Should not be used in patients with cardiogenic shock or second or third degree AV block.
4. Cordarone is only available in 200-mg tablets.
5. Should not be used in patients with cardiogenic shock, pre-existing second or third degree AV block, or congenital QT prolongation.
6. Dosage given as a range; dose and interval will vary depending on formulation used.
7. Available through a restricted distribution program. Contraindicated in patients with long QT syndrome or severe renal impairment.
8. Should not be used in patients with NYHA class III or IV heart failure (HF) or permanent atrial fibrillation or in patients with decompensated HF in the past 4 weeks.
9. Should be used with a beta-blocker, verapamil, or diltiazem for cardioversion. Should not be used in patients with coronary artery disease and significant
structural heart disease.
10. Should not be used in patients with bronchospasm, uncontrolled heart failure, long QT syndrome, sinus bradycardia, or second or third degree AV block.
11. Betapace AF is not available in 240-mg tablets.

that also prolong the QT interval.16 Disopyramide is
sometimes used to maintain normal sinus rhythm in
patients with vagally-induced atrial fibrillation. Dofetilide has been effective in patients with compromised
left ventricular function, but it requires in-hospital
dose titration and can cause torsades de pointes.

CATHETER ABLATION — Radiofrequency catheter
ablation of the cardiac tissue causing an arrhythmia
can restore sinus rhythm and may be superior to
antiarrhythmic drugs in maintaining sinus rhythm and
improving symptoms, exercise capacity, and quality of
life.13 Complications are rare, but can be fatal.
57

The Medical Letter

Vol. 56 (1446)

®

July 7, 2014

Table 6. Some Cardiovascular Drug Interactions with Amiodarone
Interacting Drug

Effect

Amlodipine (Norvasc, and others)
Apixaban (Eliquis)
Atorvastatin (Lipitor, and generics)
Beta-adrenergic blockers
Dabigatran (Pradaxa)
Digoxin (Lanoxin, and others)
Diltiazem (Cardizem, and others)
Felodipine (Plendil, and generics)
Ibutilide (Corvert, and others)
Isradipine
Lovastatin (Mevacor, and others)
Nicardipine (Cardene, and others)
Nifedipine (Procardia, and others)
Nimodipine
Nisoldipine (Sular, and generics)
Rivaroxaban (Xarelto)

Simvastatin (Zocor, and generics)
Sotalol (Betapace, and others)
Verapamil (Calan, and others)
Warfarin (Coumadin, and others)

Possible increased serum concentrations of amlodipine
Possible increased serum concentrations of apixaban
Possible increased risk of myopathy and rhabdomyolysis
Possible increased beta-blocker effect
Possible increased serum concentrations of dabigatran
Possible digoxin toxicity
Possible increased serum concentrations of amiodarone and/or diltiazem
Possible increased serum concentrations of felodipine
Possible QT interval prolongation
Possible increased serum concentrations of isradipine; possible QT interval prolongation
Possible increased risk of myopathy and rhabdomyolysis
Possible increased serum concentrations of nicardipine; possible QT interval prolongation
Possible increased serum concentrations of nifedipine
Possible increased serum concentrations of nimodipine
Possible increased serum concentrations of nisoldipine
Possible increased serum concentrations of rivaroxaban
Possible increased risk of myopathy and rhabdomyolysis
Possible QT interval prolongation and possible increased risk of bradycardia and sinus arrest
Possible increased serum concentrations of amiodarone and/or verapamil
Increased serum concentrations of warfarin

CONCLUSION
Anticoagulant therapy reduces the risk of thromboembolic stroke in patients with atrial fibrillation, but
it can cause intracranial and other serious bleeding.
The risk of bleeding must be weighed against the

benefit of thromboembolic risk reduction. Patients
with nonvalvular atrial fibrillation and a CHA2DS2VASc score ≥2 for risk of stroke should take either
warfarin or one of the newer oral anticoagulants
(apixaban, dabigatran, or rivaroxaban). Patients with
atrial fibrillation associated with a mechanical valve,
a bioprosthetic valve, prior mitral valve repair, or mitral stenosis should take warfarin.
Ventricular rate control is now widely used as
first-line therapy for management of chronic atrial
fibrillation. Lenient rate control (resting heart rate
<110 beats/minute) may be a reasonable alternative
to strict control (resting heart rate <80 beats/minute).
A beta-blocker, verapamil, or diltiazem is generally
used for long-term rate control. A beta-blocker is preferred for patients with coronary disease or systolic
dysfunction. Verapamil or diltiazem may be preferred
over beta-blockers in patients with COPD or asthma.
Amiodarone may be effective when other drugs have
failed to control ventricular rate.
Antiarrhythmic drugs, particularly amiodarone, can
be used to restore and maintain normal sinus rhythm.
The treatment of choice for urgent conversion of
atrial fibrillation is DC cardioversion. Radiofrequency
catheter ablation of cardiac tissue responsible for
triggering or maintaining an arrhythmia can also
restore sinus rhythm. ■
58

1. CT January et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the
American College of Cardiology/American Heart Association
task force on practice guidelines and the Heart Rhythm Society.
Circulation 2014 April 10 (epub).

2. AJ Camm et al. 2012 focused update of the ESC guidelines for
the management of atrial fibrillation: an update of the 2010 ESC
guidelines for the management of atrial fibrillation. Developed
with the special contribution of the European Heart Rhythm
Association. Eur Heart J 2012; 33:2719.
3. SJ Connolly et al. Dabigatran versus warfarin in patients with
atrial fibrillation. N Engl J Med 2009; 361:1139.
4. MR Patel et al. Rivaroxaban versus warfarin in nonvalvular atrial
fibrillation. N Engl J Med 2011; 365:883.
5. CB Granger et al. Apixaban versus warfarin in patients with
atrial fibrillation. N Engl J Med 2011; 365:981.
6. Dabigatran etexilate (Pradaxa) – a new oral anticoagulant. Med
Lett Drugs Ther 2010; 52:89.
7. MR Southworth et al. Dabigatran and postmarketing reports of
bleeding. N Engl J Med 2013; 368:1272.
8. FDA. Pradaxa (dabigatran): drug safety communication – lower
risk for stroke and death, but higher risk for GI bleeding compared to warfarin. Available at />medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm397179.htm. Accessed June 26, 2014.
9. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2013; 55:e44.
10. Rivaroxaban (Xarelto) – a new oral anticoagulant. Med Lett
Drugs Ther 2011; 53:65.
11. Kcentra: a 4-factor prothrombin complex concentrate for reversal of warfarin anticoagulation. Med Lett Drugs Ther 2013; 55:53.
12. Apixaban (Eliquis) - a new oral anticoagulant for atrial
fibrillation. Med Lett Drugs Ther 2013; 55:9.
13. SM Al-Khatib et al. Rate- and rhythm-control therapies in patients with atrial fibrillation: a systematic review. Ann Intern Med
2014; 160:760.
14. IC Van Gelder et al. Lenient versus strict rate control in patients
with atrial fibrillation: a systemic review. N Engl J Med 2010;
362:1363.
15. Safety of dronedarone (Multaq). Med Lett Drugs Ther 2011;

53:103.
16. Combined list of all QTdrugs and the list of drugs to avoid
for patients with congenital long QT syndrome. Available at
/>Accessed June 26, 2014.


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Explain the current approach to the management of a patient with atrial fibrillation including anticoagulation, rate control, and rhythm control strategies.
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Discuss the pharmacologic agents available for rate and rhythm control in patients with atrial fibrillation and compare them based on their efficacy, dosage and administration,
drug interactions, and potential adverse effects.
Determine the most appropriate therapy given the clinical presentation of an individual patient with atrial fibrillation.

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Issue 1446 Questions

(Correspond to questions #1-10 in Comprehensive Exam #71, available January 2015)
1. A 72-year-old man with nonvalvular atrial fibrillation and a
CHA2DS2-VASc score of 2 asks you whether or not he needs to be
on anticoagulant therapy. Considering the new US guidelines, which
of the following would you recommend?
a. oral anticoagulation therapy
b. no anticoagulation therapy
c. aspirin
d. none of the above
2. Which of the following oral anticoagulants is recommended for
patients with atrial fibrillation associated with a mechanical valve,
a bioprosthetic valve, prior mitral valve repair, or mitral stenosis?
a. apixaban
b. dabigatran etexilate
c. rivaroxaban
d. warfarin
3. A 65-year-old man with nonvalvular atrial fibrillation recently
saw advertisements for apixaban and rivaroxaban and asks
whether he should take one of the newer anticoagulants instead of
warfarin. You could tell him that, compared to warfarin, apixaban,
rivaroxaban, and dabigatran etexilate:
a. do not require routine INR-type monitoring
b. have fewer interactions with other drugs
c. cause less intracranial bleeding
d. all of the above
4. Which of the following oral anticoagulants is a direct thrombin
inhibitor?
a. warfarin
b. dabigatran etexilate

c. apixaban
d. rivaroxaban
5. The drugs most commonly used for rate control in patients with
atrial fibrillation include:
a. beta-blockers
b. verapamil
c. diltiazem
d. all of the above

6. Which of the following beta-blockers is not available in an oral
formulation?
a. metoprolol
b. propranolol
c. esmolol
d. carvedilol
7. The treatment of choice for urgent conversion of atrial fibrillation
to normal sinus rhythm is:
a. anticoagulation
b. catheter ablation
c. DC cardioversion
d. digoxin
8. Adverse effects of amiodarone include:
a. taste disturbances
b. skin discoloration
c. visual disturbances
d. all of the above
9. Which of the following rhythm control agents should not be used
in patients with atrial fibrillation and significant structural heart
disease?
a. propafenone

b. amiodarone
c. dofetilide
d. dronedarone
10. The most effective drug available for maintenance of sinus
rhythm is:
a. sotalol
b. amiodarone
c. diltiazem
d. dronedarone

ACPE UPN: Per Issue Exam: 0379-0000-14-446-H01-P; Release: July 7, 2014, Expire: July 7, 2015
Comprehensive Exam 71: 0379-0000-15-071-H01-P; Release: January 2015, Expire: January 2016

EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.;
ASSISTANT EDITORS, DRUG INFORMATION: Susan M. Daron, Pharm.D., Corinne Z. Morrison, Pharm.D., Michael P. Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M. Shah, Pharm.D.,
F. Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard
CONTRIBUTING EDITORS: Carl W. Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K. Dalton, M.D., M.P.H., University of Michigan Medical
School; Eric J. Epstein, M.D., Albert Einstein College of Medicine; Jane P. Gagliardi, M.D., M.H.S., F.A.C.P, Duke University School of Medicine; Jules Hirsch, M.D., Rockefeller
University; David N. Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B. Kim, M.D., University of Western Ontario; Hans Meinertz, M.D., University Hospital,
Copenhagen; Sandip K. Mukherjee, M.D., F.A.C.C., Yale School of Medicine; Dan M. Roden, M.D., Vanderbilt University School of Medicine; Esperance A.K. Schaefer, M.D., M.P.H.,
Harvard Medical School; F. Estelle R. Simons, M.D., University of Manitoba; Neal H. Steigbigel, M.D., New York University School of Medicine; Arthur M. F. Yee, M.D., Ph.D., F.A.C.R.,
Weill Medical College of Cornell University
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VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy
Founded in 1959 by
Arthur Kallet and Harold Aaron, M.D.
Copyright and Disclaimer: The Medical Letter, Inc. is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations. The editorial
process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants. The Medical Letter,
Inc. is supported solely by subscription fees and accepts no advertising, grants, or donations. No part of the material may be reproduced or transmitted by any process in whole or in part without

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