Canadian Journal of Cardiology 30 (2014) S38eS41

Review

b-Blockers and Atrial Fibrillation: Hypertension and Other

Medical Conditions Inuencing Their Use
Paul Dorian, MD, and Paul Angaran, MD
Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Division of Cardiology, St Michaels Hospital, Toronto, Ontario, Canada

ABSTRACT
b-Blockers are among the most frequently used drugs in patients with

atrial brillation. They are often used for ventricular rate control,
acutely in emergency situations and chronically, in patients with
persistent or permanent atrial brillation. They are also used, with less
evidence of benet, to prevent the rst occurrence or recurrence of
atrial brillation, particularly in patients with hypertension. They are
effective in reducing ventricular rate, potentially leading to an
improvement in symptoms and well-being. They are particularly indicated in patients with heart failure and atrial brillation; the choice of
b-blockers in this condition should be guided by tolerability and effects
on symptoms and well-being.

Systemic hypertension is the most common underlying disorder associated with atrial brillation (AF). Hypertension is
present in between 50% and 75% of patients with AF. In
patients with hypertension, and particularly left ventricular
hypertrophy (LVH), new persistent AF occurs in 1%-2% of
patients per year, even when blood pressure is controlled. In
patients with heart rates > 84 beats per minute during followup, this incidence is as high as 2.1% per year.1
The incidence of AF increases with age, and the
concomitant presence of obesity. Other conditions common
in patients with hypertension are additional independent
causes of AF, including obstructive sleep apnea, congestive
heart failure, and valvular disease.
Long-term moderate exercise is associated with a lower
incidence of AF compared with sedentary individuals, but
competitive long-term endurance exercise is associated with a
4- to 6-fold increase in AF incidence.2 In occasional patients,
AF can be precipitated during acute exercise, although most
episodes in most patients occur at rest.

Received for publication August 31, 2013. Accepted September 26, 2013.
Corresponding author: Dr Paul Dorian, St Michaels Hospital, 30 Bond
Street, 6-050Q, Toronto, Ontario M5B 1W8, Canada. Tel.: 1-416-864-5104.
E-mail: dorianp@smh.ca
See page S41 for disclosure information.



RESUM
E
dicaments les plus fre
quemment
Les b-bloquants sont parmi les me

s chez les patients ayant une brillation auriculaire. Ils sont

utilise
s pour matriser la fre
quence ventriculaire, en dose
souvent utilise
unique en situation durgence, et en continu chez les patients ayant
pit de
une brillation auriculaire persistante ou permanente. En de
ne
que, ils sont aussi utilise
s pour pre
venir
moins de preuves deffet be
currence de la brillation auriculaire, particulirela survenue ou la re
ment chez les patients ayant de lhypertension. Ils sont efcaces pour
duire la fre
quence ventriculaire, et peuvent entraner une
re
lioration des symptmes et du bien-tre. Ils sont particulirement
ame
s chez les patients ayant une insufsance cardiaque et une
indique
brillation auriculaire; le choix des b-bloquants pour traiter cette
 par la tole
rabilite
 et les effets sur les
affection devrait tre guide
symptmes et le bien-tre.

Treatment and management of AF can be conveniently

categorized as treatment for primary prevention of AF; secondary prevention (ie, prevention of recurrences in paroxysmal
or persistent AF); treatment of ongoing (recent onset) episodes
to terminate AF, or the control of symptomatic rapid ventricular rates (in an emergency situation, or as chronic therapy).

b-Blockers in the Primary Prevention of AF

AF incidence might presumably be decreased by any

treatment which lowers blood pressure over the long-term,
and particularly treatments that prevent or diminish LVH.
The most common conuence of pathophysiological factors
that lead to AF include left ventricular systolic or diastolic
dysfunction, increases in left ventricular afterload, and mitral
regurgitation, all of which increase left atrial pressure and lead
to left atrial enlargement and brosis. Such left atrial structural
remodelling is the most common nding in patients with AF.
Any treatment that would prevent LVH, or left atrial
enlargement would be expected to reduce the incidence of AF.
There is unfortunately little evidence from placebo-controlled
clinical trials for drug therapy as upstream therapy in
reducing AF incidence. Treatment with blockers of the reninangiotensin system in established AF has also not been shown
to be superior to placebo in reduction of AF recurrences.
Antihypertensive therapy with angiotensin converting enzyme

0828-282X 2014 Canadian Cardiovascular Society Published by Elsevier

. Inc . Open access under CC BY-NC-ND license.
http://dx.doi.org/10.1016/j.cjca.2013.09.029

Dorian and Angaran

b-Blockers and AF

inhibitors or angiotensin receptor blockers, compared with

placebo, does result in a small (12%), however not signicant,
reduction in AF incidence.3
In patients with hypertension and electrocardiographic
evidence of LVH, the incidence of new AF was less in patients
treated with losartan, compared with patients treated with
atenolol, despite a similar extent of blood pressure reduction.4
This effect might have been associated with a reduction in
LVH during antihypertensive treatment with losartan.5
In patients with hypertension and no previous history of
AF, particularly if LVH is present, b-blockers are not the
preferred therapy for the prevention of incident AF. Although
the presence of sinus tachycardia is an important risk marker
for future incident AF and overall cardiovascular mortality,
there is no clear evidence that reduction in sinus tachycardia
using increasing doses of b-blockers is protective from newonset AF or cardiovascular mortality.

b-Blockers in the Secondary Prevention of AF

Although b-blockers are not generally considered to be as

effective as antiarrhythmic drugs, there is some evidence

supporting their direct antiarrhythmic benet. In a relatively
small, but randomized study of long-acting metoprolol vs
placebo in 394 patients, recurrent AF was reduced from 60%
to 49% using metoprolol CR/XL, at an average dose of 100
mg per day, compared with placebo, in patients with persistent AF undergoing cardioversion.6
In another study, bisoprolol was associated with a similar
rate of AF recurrence compared with sotalol, although it
merits emphasis that sotalol, at doses  160 mg/d in patients
with normal renal function, exerts its effects primarily by bblockade, as opposed to a direct class III antiarrhythmic
mechanism of action.7
b-Blockers have documented efcacy in the prevention of
AF after open heart surgery, and guidelines indicate a
recommendation for b-blocker use in most patients after
bypass surgery or valvular surgery, particularly if at high
perioperative risk of AF.8

b-Blockers for AF in Heart Failure and After

Myocardial Infarction
b-Blockers are the rate control drugs of choice in any
condition in which b-blockers are indicated for a given condition, such as heart failure, or after myocardial infarction
(MI). Multiple b-blockers are of proven benet in reducing
morbidity and mortality in patients with heart failure,
including
carvedilol,
metoprolol,
bisoprolol,
and
nevibolol.9-12 Considering that AF is very common in heart
failure, occurring in 30%-40% of such patients, the effect of
b-blockers on incidence of AF and outcomes in patients with
AF is of considerable interest.
Overall, b-blocker therapy is associated with a reduced
incidence of new onset AF. In the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure
(MERIT-HF) study, long-acting metoprolol led to a 48%
reduction in the risk of developing new AF compared with
placebo, from 14% to 6% at 18 months of follow-up.13
However, the individual trials, and the combined results of
all of the trials of b-blockers, failed to showed a reduction in

S39

mortality or cardiovascular hospitalizations in the subgroup

with pre-existing AF.14 The inability to show benet on heart
failure-related outcomes is speculated to be potentially related
to the small number of events and a lack of power in these
studies, or the inability of b-blockers to modify outcome in a
generally higher risk population with heart failure. These
observations do not of course suggest that b-blockers should
be withheld in patients with heart failure and AF, but
emphasize that there is no clear benet in using b-blocker
doses greater than those used in the clinical trials in patients
with heart failure and AF.
b-Blockers are indicated in patients with MI or angina, and
are the rate control drugs of choice in such patients who also
have AF.2,15 In the Metoprolol in Acute Myocardial Infarction (MIAMI) trial of intravenous metoprolol after MI, AF,
and other supraventricular tachycardia (rates > 120/min) was
reduced from 19.4% to 12.7% (P < 0.001).16
In the modern era, the benet of b-blocker therapy after
MI is smaller than in the pre-acute reperfusion era, but
b-blockers are likely to have similar relative benets in the
reduction of AF, similarly to their effects after bypass
surgery.17
Special Situations
b-Blockers might be particularly effective in AF in patients
with hyperthyroidism, in whom they can be considered as
therapy of choice for rate control, and direct treatment of
hyperthyroidism until the latter can be directly treated. In
patients with AF and very rapid ventricular rates, leading to
acute reductions in left ventricular systolic function (so called
tachycardiomyopathy), particularly in patients who have
alcohol excess, a condition associated with sympathetic overactivity, b-blockers are empirically very effective and should be
used as therapies of rst choice, in addition to cardioversion
and sinus rhythm maintenance. In some of these patients,
b-blockers (and avoidance of alcohol excess) might be sufcient to prevent future recurrences.
In a minority of patients, episodes of AF are reproducibly
precipitated by vigorous physical exercise, and b-blockers
might be particularly effective in such patients.
Many patients might receive antiarrhythmic drugs with
class Ic properties (eg, ecainide, propafenone) for the prevention of AF recurrences, either as chronic therapy, or
acutely as pill-in-the-pocket for chemical cardioversion.
Canadian guidelines recommend the coadministration of
atrioventricular nodal blocking agents, such as b-blockers, in
all patients receiving antiarrhythmic therapy with class Ic
agents, to mitigate the potential for paradoxical increases in
ventricular rate because of the class Ic antiarrhythmic drug
mechanism of action.15 This occurs as a result of organization
of AF into slower atrial utter rates by the class Ic agent,
resulting in a 1:1 conduction of atrial utter unless an atrioventricular nodal blocking agent is also administered.
For patients with relatively infrequent and self-limiting
recurrences of AF, b-blockers as acute symptomatic treatment (as pill-in-the-pocket rate control) can be very useful
in reducing symptom severity and improving quality of life,
and potentially avoiding emergency room visits. This strategy
can be particularly effective in patients with relatively short
duration paroxysms of AF, which are destined to

S40

Canadian Journal of Cardiology

Volume 30 2014

Table 1. Special considerations for BB usage

Special consideration
AF with WPW and pre-excited AF
Tachy-Brady syndrome with
conversion pauses
After MI
Depression and fatigue
BB adverse effects with intensive rate
control
Chronic kidney disease
BB with more potent BP effect
desired

Action to be considered
Avoid BBs, particularly intravenous
BBs
Use lowest doses possible, consider
BBs with less effect on sinus node
function*
Avoid BBs with intrinsic
sympathomimetic activity*
Avoid BBs that cross the blood-brain
barriery
Consider reducing BB dose and
adding digoxin or a calcium
channel blocker
Avoid BBs with renal eliminationz
BBs with mixed antagonism of both
b and a1 receptors or direct
vasodilating propertiesx

AF, atrial brillation; BB, b-blocker; BP, blood pressure; MI, myocardial
infarction; WPW, Wolff-Parkinson-White syndrome.
* BBs with intrinsic sympathomimetic activity include acebutolol and
pindolol.
y
BBs that are lipid soluble and cross the blood-brain barrier include
acebutolol, bisoprolol, carvedilol, labetolol, metoprolol, pindolol and
propranolol.
z
BBs that are renally cleared include acebutolol, atenolol, bisoprolol,
nadolol, and sotalol.
x
BBs with mixed antagonism of both b and a1 receptors which provide
additional arteriolar vasodilation include labetolol and carvedilol. Nevibolol is
a BB which also acts as a direct vasodilator by increasing nitric oxide in blood
vessels.

spontaneously terminate in less than 24 hours. Specic situations in which a specic strategy involving b-blockers can be
considered are listed in Table 1.

b-Blockers for Rate Control in AF

The most common indication for b-blocker use in patients

with AF is for rate control. In the European Heart Rhythm

Association survey of AF treatments, b-blockers are rst-line
therapy in 43% of patients with hypertension and LVH,
51% with coronary disease, and 51% of patients with heart
failure, and 19% of patients without structural heart disease,
when used for AF therapy, presumably primarily for the
prevention of AF recurrences.18 In patients with persistent or
permanent AF, b-blockers are used in 60%-70% of all patients for rate control.19-21
b-Blockers are generally considered the most potent of the
rate control agents with respect to the reduction in ventricular
rate both at rest and with exercise, in patients with persistent/
permanent AF. They are generally the treatment of rst choice
for most practitioners for this indication, based on the belief
that the primary cause of symptoms in AF is related to the
ventricular rate, with respect to symptoms directly attributable
to rapid rates, and also to symptoms attributable to a drop in
cardiac output associated with the short diastolic intervals
in AF.
However, 2 lines of evidence suggest considerable caution
in the assumption that ventricular rate should be aggressively controlled in patients with AF. In a large randomized
study, the Rate Control Efcacy in Permanent Atrial Fibrillation II (RACE II) study, strict rate control aiming to
achieve a resting heart rate of < 80 beats per minute, was not

superior to lenient rate control aiming to achieve a resting

heart rate of < 110 beats per minute, on either morbidity,
mortality, or quality of life.20
Strict rate control, usually using b-blockers, was however
associated with an increased risk of adverse effects and some
evidence for worsening quality of life.22 In an overview of
multiple relatively small, but randomized studies of b-blockers
vs calcium channel blockers vs digoxin in patients with AF,
b-blockers were most effective at reducing ventricular rates at
rest and with exercise, but were more likely to be associated
with a reduction in or no change in maximum effort tolerance
on treadmill exercise, compared with calcium channel
blockers which were associated with no change or an increase
in exercise tolerance.15,23
As a consequence, the primary outcome for rate control
strategies, in patients with persistent or permanent AF, should
be the achievement of a resting heart rate of < 100 beats per
minute, and an acceptable reduction in symptoms perceived
to be caused by rapid ventricular rates.15 The primary method
of follow-up of such patients should be careful assessment of
quality of life and exercise tolerance, and not primarily the
effect of the rate control drugs on ventricular response.15 In
patients with paroxysmal AF, specic rate control targets have
not been studied, and there is no clear basis for recommending any particular target for desired rate during paroxysms, excepting reduction in symptoms as much as possible,
and avoiding adverse effects potentially associated with rate
control drugs.
b-Blockers can be very useful for such patients, but their
effects on overall patient well-being (particularly with respect
to fatigue, which might be a drug adverse effect and not due to
the arrhythmia) should be carefully assessed. There is no
indication for adding or intensifying b-blocker therapy for
exercise-related rapid ventricular rates in patients with AF, if
they have good control of overall symptoms, and the resting
heart rate is < 100 beats per minute.

b-Blockers for Acute Rate Control in Emergency

Situations
b-Blockers are safe and effective in achieving rapid control
of ventricular rate in symptomatic patients who present to the
emergency room with recent-onset AF. They are effective at
controlling symptoms and indirectly in improving ventricular
function, even though they might have negative inotropic
properties. Even in patients with left ventricular dysfunction,
b-blockers are relatively safe, (but should be used with
caution) because the reduction in ventricular rate and
increased diastolic lling time outweighs potentially negative
inotropic effects.2 They are recommended as initial treatment
in patients with symptomatic AF and rapid ventricular rates in
an emergency setting.24
Specic Choice of b-Blocker Therapies
There have been no comparative trials of different
b-blockers with respect to their efcacy at rate control or
symptom control in AF. Such trials would be very difcult to
conduct, because a drug effect would be importantly related to
drug dose and plasma concentration achieved. Theoretical
considerations would suggest that drugs that are more

Dorian and Angaran

b-Blockers and AF

cardioselective and less lipid-soluble, such as bisoprolol,

metoprolol, or nebivolol might be preferred, and in patients
with heart failure, drugs that have been shown to reduce
mortality in heart failure are preferred. Carvedilol is less
effective for rate control of AF compared with metoprolol.25
The efcacy in rate control of a particular drug will depend
on dose and individual pharmacokinetics, and there is no
specic recommended dose for effective rate control; it is most
reasonable to start with an arbitrarily low dose, to minimize
adverse effects, and increase the dose as tolerated to achieve
the desired dual end points of decreased symptoms and
improved quality of life, and achieving a resting ventricular
rate < 100/min. To enhance compliance, drugs that can be
administered once daily are generally preferred. Used
cautiously and conservatively, b-blockers will remain one of
the cornerstones of therapy in patients with AF.
Funding Sources
Publication of this article was supported by an unrestricted
educational grant from Forest Laboratories, Inc. The sponsor
had no input into the content or composition of any of the
papers, and the authors did not receive any nancial support
from the sponsor for their efforts or time in writing the paper.
Funds from the sponsor were used exclusively for covering
publication costs.
Disclosures
The authors have no conicts of interest to disclose.
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