Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]

Contents lists available at ScienceDirect

Journal of Cardiothoracic and Vascular Anesthesia

journal homepage: www.jcvaonline.com

Review Article

Perioperative β-Adrenergic Blockade in Noncardiac

and Cardiac Surgery: A Clinical Update
Adriana D. Oprea, MD*, Frederick W. Lombard, MBChB, FANZCA†,
Miklos D. Kertai, MD, PhD†,
1

*
Department of Anesthesiology, Yale School of Medicine, New Haven, CT
†
Division of Cardiothoracic Anesthesiology, Department of Anesthesiology, Vanderbilt University Medical
Center, Nashville, TN

Key Words: atrial fibrillation; beta-adrenergic blockers; cardiac surgery; mortality; noncardiac surgery; pharmacokinetics; pharmacodynamics

BETA-ADRENERGIC BLOCKERS (β-blockers) represent bronchospasm. Nevertheless, overwhelming evidence demon-

a heterogeneous class of cardiovascular drugs with different
characteristics regarding their pharmacologic properties and
clinical effects. As a class, β-blockers have been around for
more than 50 years, and their use in the chronic treatment of
ischemic heart disease and heart failure is well established.1
Currently, β-blockers are indicated as long-term therapy in
patients with a history of prior myocardial infarction (asso-
ciated with a lower reinfarction and mortality rate) and in
patients with systolic heart failure (survival benefit).2,3 Of
note, β-blockers are not indicated as first-line therapy in
patients with uncomplicated hypertension unless there is
concomitant ischemic heart disease or heart failure.4 However,
their chronic use in patients with a history of myocardial
infarction has been challenged recently. Contemporary studies
have demonstrated limited mortality benefit when used for
secondary prevention in patients who have suffered their first
myocardial infarction unless there is evidence for heart
failure.5,6
Traditionally, severe asthma and chronic obstructive pul-
monary disease have been contraindications for β-blocker use,
since β-blockers may increase airway reactivity and
strated that β-blockers are well tolerated in patients with
asthma or chronic obstructive pulmonary disease, and their
use was associated with a significant decrease in morbidity and
mortality due to cardiovascular diseases.7,8 In the elderly
population with a history of myocardial infarction, β-blocker
use also was associated with a significant mortality benefit;
however, this mortality benefit was confined to elderly patients
with pre-existing cognitive impairment.9
Perioperative β-blocker use, however, has been a matter of
ongoing controversy. Initial small-scale clinical trials by
Mangano et al., as well as Poldermans et al., observed
beneficial effects in noncardiac surgery patients who were at
a
moderate to high risk for cardiovascular complications. By
reducing episodes of intraoperative and postoperative tachy-
cardia, perioperative β-blocker use resulted in a decreased risk
for major adverse cardiac events (MACE).10,11 The findings of
these initial clinical trials prompted expert committees of the
European Society of Cardiology and the American College of
Cardiology/American Heart Association (ACC/AHA) to
recommend prophylactic β-blocker use for all moderate- to
high-risk patients ( 4 2 Revised Cardiac Risk Index [RCRI]

1 a
Address reprint requests to Miklos D. Kertai, MD, PhD, Director of Dr. Poldermans’ work (including the DECREASE trials II-VI) has come
Perioperative Precision Medicine Program, Professor of Anesthesiology, under scrutiny for potential scientific misconduct and ethical concerns.
Division of Cardiothoracic Anesthesiology, Department of Anesthesiology, However, DECREASE I trial has never come under scrutiny, and since its
Vanderbilt University Medical Center, 1215 21st Ave South, Suite 5160, results are part of studies on the historical use of perioperative β-blockers, the
Nashville, TN 37232. authors decided to include and review it in this manuscript in an unbiased
E-mail address: miklos.kertai@vanderbilt.edu (M.D. Kertai). manner.

http://dx.doi.org/10.1053/j.jvca.2018.04.045
1053-0770/& 2018 Elsevier Inc. All rights reserved.

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2 A.D. Oprea et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]

Table 1 bypass graft (CABG) surgery for the prevention of post-

Revised Cardiac Risk Index. operative atrial fibrillation (AF).14–17
Revised Cardiac Risk Index criteria60
To date, the controversy surrounding perioperative β-
History of ischemic heart disease blocker use remains with current guidelines giving limited
History of congestive heart failure guidance for their use only in specific patient populations,
History of cerebrovascular disease (stroke or transient ischemic attack) unique clinical scenarios, or special surgical settings. The
History of diabetes mellitus requiring preoperative insulin use purpose of this review is to evaluate the most recent evidence
Chronic kidney disease (creatinine 42 mg/dL)
Undergoing high-cardiac risk surgery (suprainguinal vascular, intraperitoneal,
on perioperative β-blocker use and to provide additional
or intrathoracic) recommendations for perioperative β-blocker use in patients
Estimated risk for cardiac death, nonfatal myocardial infarction, and nonfatal undergoing both cardiac and noncardiac surgery. Although
cardiac arrest: there is a wide array of β-blockers available on the market, the
0 risk factors: 0.4% primary focus will be on β-blockers commonly used in the
1 risk factor: 0.9%
2 risk factors: 6.6%
perioperative period (ie, metoprolol, atenolol, and bisoprolol).
3 or more risk factors: 411%

Pharmacokinetics of β-blockers

criteria) (Table 1) undergoing high-risk noncardiac surgical
procedures (eg, vascular surgery, thoracic, and major abdom-
inal) in 2002.12,13
However, a subsequent large-scale clinical trial, Periopera-
tive Ischemic Evaluation (POISE), challenged those initial
observations and found that prophylactic β-blocker use
initiated on the morning of a noncardiac surgical procedure
was associated with a higher risk for bradycardia, stroke, and
mortality. These findings led to a change and revision of the
recommendations of the relevant European Society of Cardi-
ology and American College of Cardiology/American Heart
Association guidelines for prophylactic β-blocker use in
noncardiac surgery; that is, preoperative initiation and prophy-
lactic use of β-blockers is not recommended in the setting of
noncardiac surgery.13 Nevertheless, prophylactic β-blocker use
still is recommended in patients undergoing coronary artery
As a drug class, β-blockers have similar pharmacodynamic
effects in terms of heart rate control, but individually they have
distinct and wide-ranging pharmacokinetic profiles. Intrave-
nous β-blockers such as esmolol, landiolol, propranolol, and
metoprolol are instantly fully bioavailable. The bioavailability
of oral β-blockers, however, primarily depends on their lipid
solubility, and to a lesser degree on their extent of gastro-
intestinal absorption (most oral β-blockers are well absorbed).
The lipophilic β-blockers such as propranolol, metoprolol, and
carvedilol tend to have shorter half-lives and often need to be
administered more than once a day (Table 2).1 To overcome
this and in an attempt to ensure a more stable effect, extended-
release preparations have been formulated for some β-block-
ers, such as metoprolol. Unfortunately, lipophilic β-blockers,
in particular metoprolol, are also subject to varying degrees of
first-pass hepatic metabolism, resulting in less predictable

Table 2
Pharmacokinetics of β-Blockers.

β-Blocker Absorption (%) Bioavailability (%) Lipophilicity Half-life Degradation/Excretion

Acebutolol 90 40 Yes 3-4 h Hepatic metabolism 30-40%

Renal 50%-60%
Atenolol 50 40 No 6-7 h Renal 50%-80%
Betaxolol 90 89 Yes 14-22 h Hepatic metabolism 15%
Renal 80%
Bisoprolol 90 80-94 Yes 9-12 h Hepatic metabolism 50%
Renal 50%
Carvedilol 90 24 Yes 7-10 h Hepatic metabolism 90%
Esmolol n/a n/a N/A 9 min Plasma esterases
Labetalol 90 33 Yes 5-8 h Hepatic metabolism 50%
Renal 50%-60%
Landiolol n/a n/a N/A 2-4 min Pseudocholinesterase
Liver carboxyesterase
Metoprolol 90 65-70 Yes 3-4 h Hepatic metabolism 95%
Renal 5%
Nadolol 50 30 No 20-24 h Renal 100%
Nebivolol 90 12-96 Yes 12-19 h Hepatic metabolism
Pindolol 90 90 Yes 3-4 h Hepatic metabolism 60-65%
Renal 35%-40%
Propranolol 90 30-40 Yes 3-6 h Hepatic metabolism
Renal o1%

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 A.D. Oprea et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]] 3

plasma concentrations and significant interpatient response
variability. The now-recognized genetic basis for this observed
interpatient variability in extent of liver metabolism is dis-
cussed in more detail in the section on pharmacogenomics
below.18 Of note, though, some lipophilic β-blockers such as
nebivolol demonstrate little or no difference in effect on blood
pressure between rapid and poor metabolizers, likely due to
the fact the metabolites of these β-blockers are active and may
exert similar β-adrenergic receptor blocking properties.19
In contrast to the lipophilic β-blockers, water-soluble β-
blockers such as atenolol and nadolol demonstrate less
gastrointestinal absorption, depend mostly on renal excretion,
and rely less on hepatic metabolism.20 Therefore, typically
have longer half-lives and maintain more stable plasma
concentrations.21 Finally, ultra-short-acting intravenous β-
blocker metabolism also may depend on red blood cell cytosol
esterases (esmolol) or pseudocholinesterase and hepatic
esterases (landiolol) (Table 2).
Pharmacodynamics of β-blockers
The observed differences in cardiovascular effects among
different β-blockers are due predominantly to varying
β-receptor selectivity, but they also are due to unique
drug-specific properties, such as intrinsic sympathomimetic
activity and direct vasodilator activity.
β1-receptor Selectivity
There are 3 different subtypes of β-adrenergic receptors
(ARs) with varying effects on cardiovascular physiology
(Fig 1). β1 ARs are expressed mostly in the myocardium,
and their stimulation results in positive chronotropic and
inotropic effects. β2 and β3 ARs are present mostly in the
vasculature, but also in the myocardium. Stimulation of β2
ARs leads to vasodilation, increased heart rate, and contrac-
tility, whereas stimulation of β3 ARs results in vasodilation
and a negative inotropic effect.22
β1 selective agents, such as acebutolol, betaxolol, bisoprolol,
esmolol, atenolol, nebivolol, and metoprolol, have the theore-
tical advantage over nonselective agents since their use should
reduce the risk for inhibition of β2-mediated cerebral vasodila-
tion, bronchodilation, and metabolic effects. However, at
higher doses, β1 selective agents may lose their receptor
selectivity, which combined with anemia in the perioperative
setting could increase the risk for cardiovascular complications
and stroke23 (Table 3). Finally, nebivolol is the only β-blocker

Fig 1. Presynaptic nerve terminal, cardiac adrenergic receptors, and adrenergic-receptor signaling in the heart. Localization of the common polymorphisms of the
adrenergic receptors with their functional consequences. A coupling of the β2 adrenergic receptor to stimulatory G protein (Gs) and inhibitory G protein (Gi) is
shown in the cardiomyocytes but not in the presynaptic nerve terminal. AC, adenyl cyclase; AR, adrenergic receptor; cAMP, cyclic adenosine monophosphate; Epi,
epinephrine; GRK5, G protein-coupled-receptor kinase; Nepi, norepinephrine (Adapted with permission from Kertai et al. J Cardiothorac Vasc Anesth
2012;26:1101-14).

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4 A.D. Oprea et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]

Table 3
Pharmacodynamic Properties of β-Blockers.

β-Blocker Relative β1Selectivity β1/β2 Affinity Ratio β3 ISA

Acebutolol þ 2.4
Atenolol þþ 4.7
Betaxolol þþ 6.8
Bisoprolol þþ 13.5
Carvedilol - -
Esmolol þþ 33
Labetalol - -
Landiolol þþþ 255
Metoprolol þþ 2.3
Nadolol - -
Nebivolol þþ 46
Pindolol - -
Propranolol - -
Abbreviations: ISA, intrinsic sympathomimetic activity.
with known β3-receptor agonist activity, which is beneficial in
patients with heart failure.24
β-blockers With Vasodilating Properties
Certain β-blockers, such as pindolol and carteolol, also have
partial intrinsic sympathomimetic activity, and their use is
associated with a decrease in peripheral vascular resistance and
less heart rate reduction when compared with β-blockers
without intrinsic sympathomimetic activity.1 Further, other β-
blockers such as labetalol and carvedilol also block the alpha
receptors in addition to β ARs, resulting in vasodilation and
maintenance of the cardiac output.25 Additionally, nebivolol
has a direct vasodilating effect due to direct secretion of nitric
oxide, thought to confer myocardial protection26 (Table 3).
Pharmacogenetics of β-blockers
It is clear that genetic differences could explain some of the
interpatient variability in clinical responses to different β-
blockers.27 These genetic differences could influence both the
pharmacokinetic and the pharmacodynamic properties of β-
blockers. One of the most extensively studied and best
characterized pharmacogenetic variations is the cytochrome
(CYP) P450 (CYP2D6) isoenzyme, which is involved in the
hepatic biotransformation of several of the lipophilic β-
blockers (eg, metoprolol, propranolol, carvedilol, labetalol,
and timolol). CYP2D6 is highly polymorphic, and at least 105
functional variants have been identified (www.pharmvar.org/
htdocs/archive/cyp2d6.htm; accessed April 14, 2018).28 Based
on the presence of polymorphisms and the number of
functional alleles, patients can be stratified as ultrarapid
metabolizers, extensive metabolizers (the normal phenotype),
intermediate metabolizers, and poor metabolizers29(Fig 2).
Further, the prevalence of different CYP2D6 enzyme poly-
morphisms show a great variation by ethnicity.30,31
Metoprolol, the most frequently prescribed β-blocker for
either primary or secondary prevention of cardiovascular
complications, also happens to be the β-blocker most
- þ
- -
- -
- -
-
- -
þ
- -
- - Fig 2. Cytochrome P-450 2D6 (CYP2D6) dependency of β-blockers. NOTE:
- Extensive metabolizers are subjects with 2 copies of normal activity alleles of
þ - CYP2D6—no need for β-blocker dose change. Intermediate metabolizers are
þþ patient subjects with only 1 copy of normal activity alleles of CYP2D6—β-
- blocker dose reduction should be considered. Poor metabolizers are patients
without any copy of normal activity alleles of CYP2D6—further β-blocker
dose reduction should be considered. Ultrafast metabolizers are patients with
more than 2 copies of normal activity alleles of CYP2D6—higher β-blocker
dose should be considered.
dependent on CYP2D6 isoenzyme for its biotransformation.
In fact, 70% to 80% of metoprolol metabolism is dependent on
this isoenzyme.32
Previous studies indicated that subjects who were CYP2D6
poor metabolizers, that is, subjects without any functional
alleles of the CYP2D6 gene, had 3- to 10-fold higher
metoprolol plasma concentrations compared to subjects who
were extensive metabolizers (2 functional alleles of the
CYP2D6 gene resulting in a normal CYP2D6 isoenzyme
activity). Predictably, in poor metabolizers, the elimination
half-life of metoprolol increased to 7.5 hours as opposed to
2.5 hours in extensive (normal) metabolizers.32,33 This
decrease in metoprolol clearance and subsequent drug accu-
mulation in poor metabolizers has been shown previously to
translate into significantly more pronounced and prolonged
decreases in heart rate during exercise.34 Several further
studies corroborated that poor metabolizers on metoprolol
had a significantly higher risk for bradycardia.35,36 In contrast,
in a study of patients with acute myocardial infarction,
ultrarapid metabolizers started on metoprolol had lower trough
metoprolol plasma concentrations, higher mean heart rates,
and a higher incidence of ventricular rhythm disturbance
compared with patients with other CYP2D6 genotypes.37
The findings of these studies suggest that CYP2D6 poly-
morphisms significantly influence β-blocker pharmacokinetics,
in particular with regard to metoprolol.
However, in the ambulatory setting, the potential impact of
genotyping for these pharmacokinetic genetic variants prior to
long-term cardiovascular risk management is diminished, since
in practice there is sufficient time to titrate β-blockers.38
In contrast, studies on how CYP2D6 polymorphisms could
influence the efficacy of lipophilic β-blockers in preventing or
treating perioperative cardiovascular complications are com-
pletely lacking. As such, Badgett et al. recently proposed
several hypotheses about why some clinical trials were unable
to demonstrate a beneficial effect of perioperative β-blockers in
preventing cardiovascular complications.39 In their meta-

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 A.D. Oprea et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
analysis of clinical trials in which patients received CYP2D6-
dependent β-blockers in the perioperative period, where the
drug titration period was limited, an increased risk for
mortality was observed. Furthermore, an interaction analysis
between the duration of titration period and CYP2D6 meta-
bolism indicated that the highest mortality was observed in
clinical trials that administered β-blockers dependent on
CYP2D6 metabolism over a short titration period.
Thus, these findings support the concept that the efficacy of
β-blockers metabolized via the CYP2D6 isoenzyme is affected
by relevant polymorphisms with potential implications for the
perioperative use of β-blockers. Indeed, when there is an
indication for preoperative initiation of β-blockers, adminis-
tration of β-blockers that do not require a long titration period
and do not rely on hepatic biotransformation, such as atenolol,
should be considered.39
Several genetic variations involving the β1 AR have been
described, and some of these are prevalent and potentially
could influence the efficacy and safety of β-blockers40–42
(Table 4). However, as indicated in Table 4, the majority of
studies evaluating the role of these polymorphisms are lacking
a sufficient level of scientific evidence to meet the expectations
for personalized perioperative β-blocker use in patients with an
elevated risk for cardiovascular complications and mortality.
These studies were mostly underpowered and were conducted
in ambulatory patients, and the replication of positive results
still is lacking. Also, the majority of these studies only
examined associations between individual genetic polymorph-
isms and cardiovascular risk or long-term cardiovascular event
survival, and not with treatment response to β-blockers.
Therefore, it remains unknown how the effects of these genetic
polymorphisms may influence clinical therapeutic responses to
β-blockers with different pharmacologic properties.
Perioperative Use of β-blockers
Patients With Chronic β-blocker Use
Perioperative continuation of β-blockers in patients on
chronic β-blockers for various cardiovascular indications (eg,
coronary artery disease, AF, hypertension) is a matter of less
controversy than compared to the initiation of therapy pre-
operatively. Chronic β-blocker therapy leads to upregulation of
β AR, therefore abrupt cessation of therapy leads to an
increased number of unoccupied β AR being stimulated by
endogenous catecholamines. Withdrawal of β-blockers is
known to increase the risk for reflex tachycardia and hyperten-
sion, with a potential for oxygen supply/demand mismatch due
to a shortened diastolic coronary perfusion time.43 This, in
turn, could lead to cardiac ischemia, subsequently increasing
the risk for perioperative cardiovascular events, including
mortality. Discontinuation of chronic β-blocker use in the
perioperative period or nonadherence to the perioperative
medication instructions is particularly concerning in patients
taking agents with a shorter (metoprolol, propranolol) rather
than a longer half-life (atenolol).44 To date, there are no studies
with data on risk of cardiovascular events in patients who were
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5
discontinued from extended-release metoprolol. Moreover, in
patients with uncomplicated hypertension, perioperative treat-
ment with β-blockers may be associated with an increased risk
for perioperative MACEs and all-cause mortality.45
In a study of 140 patients undergoing vascular surgery,
withdrawal of β-blockers was associated with increased odds
for cardiovascular mortality and postoperative myocardial
infarction (odds ratio [OR] 17.7, 95% confidence interval
[CI], 2.6-113; p ¼ 0.003).46 Another trial on 711 patients
undergoing vascular surgery indicated a higher 1-year mortal-
ity in patients who had β-blockers discontinued before surgery
as compared to nonusers (OR 2.7, 95% CI, 1.2-5.9; p o
0.001).47 In another cohort of 38,779 surgical patients
(including cardiac and vascular surgical procedures), disconti-
nuation of β-blockers was associated with an increase for 30-
day (OR 3.93; 95% CI, 2.57-6.01; p o 0.0001) and 1-year
mortality (OR 1.96; 95% CI, 1.49-2.58; p o 0.0001).48
Similarly, data from 8,431 patients undergoing colorectal
and bariatric procedures showed an increased risk for com-
bined adverse events at 30 days, 90 days, and 1 year in
patients with a higher cardiac risk profile who were discon-
tinued preoperatively from β-blockers.49 Recently, a large
retrospective study in 19,145 patients demonstrated that with-
drawal of β-blockers was associated with increased risk for
mortality within 48 hours after noncardiac surgery. However,
β-blocker withdrawal also was associated with a decreased risk
for need of vasopressor use during the early postoperative
period and resulted in a shorter stay in the post-anesthesia care
unit. Although these studies were retrospective in nature, they
provided important supporting evidence for not withdrawing
β-blockers in the perioperative period in patients who were on
chronic β-blocker therapy.50 In addition, the findings of these
studies also highlighted the potential risk for hemodynamic
perturbations (hypotension requiring use of vasopressors) and
an increase in utilization of health care resources (ie, extended
post-anesthesia care) when β-blockers are continued periopera-
tively.51 These specific concerns about the consequences of the
withdrawal of β-blockers were reflected in the latest 2014
ACC/AHA Guideline on Perioperative Cardiovascular Evalua-
tion and Management of Patients Undergoing Noncardiac
Surgery, which has a class I recommendation for continuing
perioperative β-blocker therapy in patients with chronic β-
blocker use.15 However, the current guidelines do not provide
recommendations as to how to modify regimens or potentially
discontinue perioperative β-blocker therapy when clinical
circumstances dictate (eg, anticipated significant surgical
blood loss, or preoperative hypotension/bradycardia).
Preoperative Initiation of Preoperative β-blocker Use
Patients Undergoing Noncardiac Surgery
Patients undergoing noncardiac surgery, especially patients
with 1 or more RCRI risk factors, can be at increased risk for
perioperative myocardial ischemia and infarction. Although
results from previous small-scale trials on preoperative initia-
tion of atenolol and bisoprolol had led the committee of the
 6
Table 4
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Common single nucleotide polymorphisms of the adrenergic receptors and their intracellular signaling system with their functional consequences.

Adrenergic Gene Physiologic response SNP Allele frequency Functional effect Clinical studies
receptor or location
signaling

β1 AR 10q24-26  Expressed in the  Amino acid  Whites, 15%-22%  Ser49 resistance to receptor downregulation
myocardium substitution of  Blacks, 13%-22%
 Positive inotropic and serine (Ser) by
chronotropic effect glycine (Gly) at
residue 49

 Arginine (Arg)
β2 AR 5q31-q32  Expressed in the  Arginine to
myocardium and blood
vessels
 Mediates smooth mus-
cle cell relaxation,  Glutamine to
increased contractility,
heart rate, antiapopto-
tic effects
 Threonine to
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(Ser49Gly)
 Whites, 27%  Altered G-protein coupling  Swiss BB in Spinal Anesthesia Study: 1) Arg389
by glycine  Blacks, 42%  Arg389 genotype: 2-fold greater basal and 3-fold genotype, lower incidence of cardiovascular morbidity
(Gly) at residue greater agonist-mediated adenyl cyclase activities compared to Gly389 genotype98; 2) selective use of
389  Higher resting heart rate, diastolic blood pressure in bisoprolol had no differential effect in patients with the
(Arg389Gly) Arg389 homozygous subjects Arg389 or the Gly389 genotype compared with
 placebo98
Gluy389 genotype: a loss-of-function variant, atte-
nuated β1 AR signaling cascade  Parvez et al99 in ambulatory patients with atrial
fibrillation: 1) Gly389 genotype better response to rate
control therapy (BBs and calcium channel blockers)
compared to Arg389 genotype
 Liu et al,100 Gly389 variant increased risk for heart
failure in East Asians, but decreased risk for whites;
patients with Arg389 variant showed a better response
to BB use
 Gly16 and  Gly16 and Glu27, enhanced effect on agonist-  Gly16
glycine at Glu27, 40%- promoted receptor downregulation  Case-control studies in patients ischemic heart dis-
residue 16 50% in whites  Ile164, defective receptor coupling to the stimulatory ease101,102: no association with cardiovascular mor-
(Arg16Gly) and blacks G protein, impaired agonist-promoted sequestration, bidity and mortality
 Ile164, 1% in and lower agonist binding affinity, impaired vasodi-  No interaction with BB use on the risk of myocar-
glutamic acid at white and lation, increased peripheral vascular resistance dial infarction and ischemic stroke102
residue 27 o2% in blacks  Swiss BB in Spinal Anesthesia Study98 intraopera-
(Gln27Glu) tive hypotension independent of bisoprolol use
 Patients with acute coronary syndrome,103 the
isoleucine at Gly16 variant compared to the Arg16 variant was
residue 164 associated with a lower long-term mortality in
(Thr164Ile) BB users
 Gln27
 Lower risk for heart failure, cardiac transplantation
and death from heart failure in patients with dilated
cardiomyopathy104
 Hypertensive patients, the Gln27 variant in the
presence of the Gly16 variant, a higher systolic
blood pressure, but no increased risk for myocardial
infarction105
 Patients with acute coronary syndrome,103 the
Gln27 variant was associated with a higher long-
term mortality in BB users; haplotypes of Arg16 and
Gln27, highest risk for mortality

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β2 AR 8p11-p12  Heart and blood vessels
 Smooth muscle and
endothelial cell
mediated vasodilation
 In the cardiomyocytes,
a negative inotropic,
positive lusitropic, and
antihypertrophic
effects
GRK5 10q26.11-  Myocardium
26.11  β AR desensitization
through phosphorylation
of the receptor
GNAS 20q13-  Encodes the stimulatory
q32 G protein-alpha-subunit
 Myocardium
 Ile164
 Thomsen et al,106 in women this variant was
associated with the severity of blood pressure
elevation, the frequency of hypertension, increased
cardiovascular risk
 Liggett et al,107 in patients with heart failure: a
higher risk for death or cardiac transplantation
 Littlejohn et al,108 in patients with heart failure: no
association with death, but BB use negatively
impacted survival in the Ile164 group
 Piscione et al,109 in patients with percutaneous
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coronary artery intervention: earlier onset of cor-
onary artery disease, multivessel disease, higher
incidence of myocardial infarction, repeat percuta-
neous coronary intervention, and cardiac mortality
 Tryptophan to  Whites, 8%  Candelore et al,110 no difference in agonist-binding  Zafarmand et al, [Ref64] in patients with coronary
arginine at  Blacks, 12% characteristics between the Arg64 and Trp64 variants artery disease: no evidence of Arg64 in acute
residue 64  Mexican  Pietri-Rouxel et al,111 Arg64 variant is associated myocardial infarction
(Trp64Arg) Americans, 13% with attenuated agonist-promoted coupling, reduced  Nebivolol use in heart failure patients,112 a selective β1
 Pima intracellular cyclic adenosine monophosphate AR antagonist with β3 AR agonist properties was
Indians, 31% accumulation associated with improved survival
 Glutamine to  Whites, 1%-2.4%  Leu41 more effective in blunting the effects of β AR  Liggett et al,113 Leu41 variant protected against early
leucine at  Blacks, 23%-35% agonists through enhanced desensitization113 death and cardiac transplantation in blacks with heart
residue 41 Chinese, 29%-35%  Leu41 protective effect similar to BB use113 failure
(Gln41Leu)  Cresci et al,114 Leu41 variant is associated with
 rs4752292 improved survival in blacks with heart failure
 rs11198893  Kang S et al,115 Leu41 variant was not found in a
Chinese population. Arg389 no association with sys-
tolic heart failure related morbidity
 4 intronic SNPs  Whites, 9%-26%  Kertai et al,86 minor alleles of these intronic SNPs were
associated with postoperative atrial fibrillation despite
perioperative BB use in patients who underwent
coronary artery bypass grafting surgery
 Haplotype pairs,  Whites, 11.3%  Increased heart rate and cardiac contractility117  Frey et al,118 improved survival after coronary artery
G(-1211) and  Blacks15.2%  Enhanced expression and activity of the G protein- bypass grafting surgery
T2291C116  Chinese, 48% alpha-subunit  Frey et al,116 haplotype in the GNAS gene associated
 rs7121  Whites, 51%
with stimulatory G protein-alpha-subunit expression
 rs12481583  Whites 37%
with altered intraoperative hemodynamics in patients
with coronary artery bypass grafting surgery; in
patients with chronic BB use cardiac performance
was dependent on stimulatory G protein-alpha-subunit
expression
 Wieneke H et al,119 increased risk for ventricular
tachycardia in patients with implantable cardioverter-
defibrillator
7
 8
Please cite this article as: Oprea AD, et al. (2018), http://dx.doi.org/10.1053/j.jvca.2018.04.045

Table 5
Guideline-Based and Best-Practice Approach Recommendations for Perioperative Use of β-Blockers.

Surgery Perioperative β- ACC/AHA Guideline-Based Best-Practice Approach

Type Blocker Status Recommendations Recommendations (Evidence-Based) (Not Evidence-Based)

Noncardiac On chronic β Continue perioperatively.15 Dose adjustment or temporary discontinuation suggested if systolic blood Transition from short-acting metoprolol to atenolol (less risk of
and blockade pressure o100, heart rate o50, or high-risk bleeding procedures51,70,95 withdrawal).
cardiac
Noncardiac Not on Consider starting β-blocker for  High-risk patients with known ischemia on stress testing before high-  Oral β-blocker regimen needs to be slowly titrated and started

A.D. Oprea et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
β-blocker only specific conditions.15 risk surgery (ie, vascular) 41 week prior to surgery.
preoperatively  Intermediate or high-risk patients ( 42-3 RCRI criteria) before high-  Metoprolol may need to be avoided or dose reduced in
risk surgery
 Patients with clear indications for long-term β blockade (systolic heart patients with liver disease or known genetic varia-
failure/myocardial infarction)
tionsaffecting metabolism and response.
 Atenolol may be avoided or dose reduced in patients with renal
disease.
 Carvedilol, extended-release metoprolol, or bisoprolol may be
preferred in patients with heart failure.96
 Atenolol or extended-release metoprolol may be preferred after
myocardial infarction.97
Cardiac Not on β- Start oral β-blocker before  Carvedilol may be the preferred oral agent to prevent AF.89
blocker CABG/valve surgery to  In urgent/emergent procedures, intravenous β-blockers may be
preoperatively prevent AF84. considered (may worsen hemodynamics).
 Landiolol, an ultra-short- acting, intravenous β-blocker, may have
a safer profile and is efficacious in preventing postoperative AF.

Abbreviations: ACC/AHA, American College of Cardiology/American Heart Association.

 A.D. Oprea et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
2002 ACC/AHA guidelines for preoperative risk assessment
and management to recommend the initiation of preoperative
β-blocker therapy in patients not already on chronic β-
blockers, subsequent trials and observational studies chal-
lenged that practice given efficacy and safety concerns
associated with the initiation of β-blocker therapy in the
perioperative period.10–12,14
The Metoprolol after Vascular Surgery trial was the first
study that challenged those previous findings on the potential
beneficial effect of β-blockers, recruiting 494 patients under-
going major vascular surgery. These patients were randomized
to receive metoprolol versus placebo, starting 2 hours pre-
operatively until hospital discharge, for a maximum of 5 days
postoperatively. The results of the trial indicated that pre-
operative metoprolol was not effective in reducing 30-day or
6-month adverse cardiac events (nonfatal myocardial infarc-
tion, unstable angina, new congestive heart failure, new atrial
or ventricular dysrhythmia requiring treatment, or cardiac
death). At the same time, patients receiving metoprolol had a
higher incidence of bradycardia and hypotension.52
The Diabetic Postoperative Mortality and Morbidity trial,
which included 921 patients with diabetes mellitus undergoing
major nonvascular surgery, found that metoprolol started
before the day of surgery and continued for 8 days post-
operatively was not associated with a significant reduction in
the risk for mortality, but its use again was associated with
higher incidences of hypotension and bradycardia.53
Metoprolol administrated twice daily initiated at the time of
admission and continued until 7 days postoperatively did not
provide any mortality benefit in the Perioperative β Blockade
trial that was conducted in 103 patients who underwent
infrarenal vascular surgery.54
In contrast, a retrospective study of 3,062 patients who
underwent vascular surgery demonstrated that a combination
of β-blocker (agent not specified) and statin use was associated
with a 33% reduction in mortality at 2 years after surgery
(relative risk [RR] 0.33, p ¼ 0.0106).55
These conflicting results about the efficacy and safety of
preoperative β-blocker use for the prevention of cardiovascular
complications and mortality led the investigators of the
Perioperative Ischemic Evaluation group to design and con-
duct a large-scale clinical trial (POISE) in patients who were
undergoing noncardiac surgery. In the trial, 8,351 patients
were assigned randomly to perioperative β-blocker use (200
mg of extended-dose metoprolol started 2-4 hours before
surgery, continued for 30 days postoperatively) or placebo.14
The results of the trial showed that metoprolol use was
associated with a reduced risk for myocardial infarction, but
it also was associated with a higher risk for hypotension,
bradycardia, stroke, and mortality. Of note, metoprolol in this
trial was started in a higher dose, on the day of surgery, which
accounted for higher rates of bradycardia and hypotension, and
a higher risk for stroke and mortality in patients randomized to
metoprolol.
Following the publication of the findings of the POISE trial,
several investigators attempted to address some of the sig-
nificant limitations of the individual trials and observational
Please cite this article as: Oprea AD, et al. (2018), http://dx.doi.org/10.1053/j.jvca.2018.04.045
9
studies on the efficacy and safety of perioperative β-blocker
use by conducting meta-analyses. The most recent meta-
analysis by Bouri and colleagues analyzed all randomized
trials (excluding the DECREASE trials) and found that
initiation of β-blockers before surgery was associated with
an increased risk for hypotension (RR, 1.51; 95% CI, 1.37-
1.67; p o 0.00001), stroke (RR, 1.73; 95% CI, 1.00-2.99;
p ¼ 0.05), and 30-day all-cause mortality (RR 1.27; 95% CI,
1.01-1.6; p ¼ 0.04). In contrast, β-blocker use was associated
with a reduced risk for nonfatal myocardial infarction (RR,
0.73; 95% CI, 0.61-0.88; p ¼ 0.001).56
There are several factors that may explain some of the
differences in the efficacy and safety of β-blockers reported by
these prior clinical trials and observational studies:
1. Initiation of β-blockers immediately prior to the day of
surgery is associated with a higher risk for adverse events
and mortality: In support of this concern, a recent meta-
analysis that included 16 randomized control trials with a
total number of 12,043 patients examined the risk asso-
ciated with perioperative β-blocker use that was initiated
less than a day before noncardiac surgery.57 The results of
the study showed that perioperative β-blocker use initiated
less than a day before noncardiac surgery was associated
with a decreased risk for nonfatal myocardial infarction
(RR, 0.69; 95% CI, 0.58-0.82; p o 0.001), but it was
associated with a higher risk for hypotension (RR, 1.47;
95% CI, 1.34-1.60; p o 0.001), bradycardia (RR, 2.61;
95% CI, 2.18-3.12; p o 0.001), and nonfatal stroke (RR,
1.79; 95% CI, 1.09-2.95; p ¼ 0.02). When a sensitivity
subanalysis was performed by excluding the DECREASE
trials, the results of the analysis indicated that perioperative
β-blocker use initiated less than a day before noncardiac
surgery also was associated with an increased risk for all-
cause mortality (RR, 1.30; 95% CI, 1.03-1.64; p ¼ 0.03).
However, there is a paucity of data on how far in
advance of noncardiac surgery perioperative β-blocker
therapy should be initiated to enable safe titration in an
effort to minimize these risks. Flu and colleagues, in a study
of 940 vascular surgery patients, studied the association
between 3 different regimens of perioperative β-blocker
initiation (started 0 to 1 weeks prior, 4 1 to 4 weeks prior,
and 44 weeks prior to surgery) and 30-day cardiac events
and long-term mortality.58 When β-blocker use was
initiated 4 1 to 4 weeks or 4 4 weeks compared to
treatment initiated o1 week prior to vascular surgery, its
use was associated with a lower incidence of 30-day cardiac
events (OR 0.46, 95% CI, 0.27-0.76; and OR 0.48; 95% CI,
0.29-0.79) and long-term mortality (OR 0.52, 95% CI,
0.21-0.67 and OR 0.50, 95% CI, 0.25-0.71). Based on the
findings of this and prior studies, recommendations on the
timing of initiation of perioperative β-blocker therapy
before noncardiac surgery was revised in the 2014 ACC/
AHA guidelines for preoperative cardiac risk assessment
and management, indicating that initiation of β-blocker use
on the day of surgery is not recommended (class III).15
More recently, these recommendations were corroborated
10 A.D. Oprea et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
further by the findings of Chen and colleagues, who
observed in a nationwide population-based cohort of
patients with diabetes mellitus who underwent noncardiac
surgery that patients who were taking β-blockers for more
than 30 days prior to noncardiac surgery were at lower risk
for mortality compared to patients who were started on β-
blockers less than 30 days prior to noncardiac surgery.59
2. Not all patient populations undergoing noncardiac surgery
may benefit from perioperative β-blocker use: Patients with
long-term indications for β-blocker use for either primary or
secondary cardiovascular prevention, or high-risk patients
as defined by the RCRI criteria ( 4 3 risk factors), may
represent a particular subset of patients.50,60 The issue of
perioperative β-blocker use in these patients has been
addressed in several studies. In the DECREASE I trial,
the most pronounced benefit from perioperative β-blocker
use was observed in a subset of patients who were at
intermediate risk for perioperative myocardial infarction
and mortality.61 In a large retrospective study of 782,969
patients undergoing major noncardiac surgery, the relation-
ship between perioperative β-blocker use and risk of death
varied directly with cardiac risk.62 Among the 580,665
patients with an RCRI score of 0 to 1, treatment was
associated with no benefit or possible harm. In contrast,
among patients with an RCRI score of 2,3,4, or more, the
adjusted ORs for in-hospital death were 0.88 (95% CI, 0.80
to 0.98), 0.71 (95% CI, 0.63 to 0.80), and 0.58 (95% CI,
0.50 to 0.67), respectively.62
In another large-scale observational study of 28,263
patients undergoing noncardiac surgery, patients with a
history of stable ischemic heart disease benefited from
perioperative β-blocker use in terms of an overall reduction
in both MACE and 30-day mortality.63 Of note, the most
pronounced benefit from perioperative β-blocker use was
observed in a subset of patients with heart failure.63
In a more recent meta-analysis that included studies with a
total of 55,138 VA patients (undergoing noncardiac surgical
procedures including vascular surgery), it was observed that
patients with more than 2 RCRI risk factors who received β-
blockers prior to noncardiac surgery were at a lower risk for
nonfatal Q-wave infarction or cardiac arrest (RR, 0.67; 95% CI,
0.57-0.79; p o 0.001) and 30-day mortality (RR, 0.73; 95%
CI, 0.65-0.83; p o 0.001) compared to patients who did not
receive β-blockers prior to noncardiac surgery.64
Similarly, in a retrospective observational study of 314,114
patients undergoing noncardiac surgery, it was found that
perioperative β-blocker use was associated with a reduced 30-
day risk for mortality in patients with 3 to 4 RCRI criteria (OR
0.63, 95% CI, 0.43-0.93).65 In the same study, perioperative β-
blocker use in patients with 1 to 2 RCRI criteria was not
associated with a significant reduction in postoperative mortal-
ity, whereas in patients without cardiac risk factors, periopera-
tive β-blocker use was associated with a significantly higher
risk for mortality (OR 1.19, 95% CI, 1.06-1.35).65
Consequently, in patients with a long-term indication for β-
blocker use (eg, ischemia identified on preoperative stress
testing or patients with 43 RCRI criteria), the 2014 ACC/
Please cite this article as: Oprea AD, et al. (2018), http://dx.doi.org/10.1053/j.jvca.2018.04.045
AHA guidelines for preoperative risk assessment and manage-
ment for noncardiac surgery recommend careful perioperative
titration of β-blockers (class IIB).15
Despite the current evidence pointing toward beneficial
effects of β-blockers only in the high-risk patients, it is plausible
that the beneficial effects of lowering MACE may extend to the
lower-risk patients. The incidence of myocardial injury after
surgery is 8% in a nonselected, surgical population of 445
years of age, well above the number of troponin measurements
performed. However, due to the practical restrictions of
measuring troponin T levels to detect only in symptomatic or
high-risk patients, myocardial injury after surgery events likely
are underdiagnosed. It is possible that a benefit of perioperative
β blockade could be detected with the widespread use of
troponin measurements postoperatively. However, at present,
these events would be difficult to detect under most of the
current observational studies.
3. The efficacy and safety of perioperative β-blockers may be
related to the type of β-blocker used: Interestingly, the trials
that were able to demonstrate a beneficial effect for
perioperative β-blockers in the prevention of cardiac
complications and mortality used atenolol or bisoprolol,
whereas studies that used metoprolol demonstrated a great
variability in efficacy and safety.10,11,66 As such, Redelme-
ier and colleagues in a large-scale observational study of
37,151 patients who either received perioperative atenolol
or metoprolol found that the incidence of myocardial
infarction or death was significantly lower in patients who
received atenolol compared to patients who received
metoprolol.44 Similarly, Wallace and colleagues observed
in a cohort of 38,779 patients who underwent noncardiac
and cardiac surgery that patients who received atenolol
compared to patients who received metoprolol had a
significantly lower incidence of 30-day mortality (1% v
3%) and 1-year mortality (7% v 13%).67 London and
colleagues also noted a significant association of type of
β-blocker with stroke in a cohort of 55,128 patients
undergoing major noncardiac surgery (atenolol v metopro-
lol, OR 0.63, 95% CI, 0.45-0.89; p ¼ 0.008).64
Recently, Badgett and colleagues published an elegant
summary of the pharmacologic properties of β-blockers that
could explain the often contradictory findings of observa-
tional studies and clinical trials on the efficacy and safety of
perioperative β-blocker use.39 According to their summary,
genetic variations in CYP2D6, the timing of initiation of
perioperative β-blocker use, and the degree of selectivity of
different β-blockers for β1/β2 ARs could explain some of
the variability in efficacy and safety of perioperative β-
blockers for the prevention of perioperative cardiac com-
plications and mortality. Indeed, these observations suggest
that metoprolol, which has the least β1 AR selectivity and
also is metabolized extensively by the highly polymorphic
CYP2D6 (and therefore requires more prolonged and
individualized dose titration both for safety and adequacy
of effect), may not be an ideal β-blocker for use in the
perioperative setting.39 On the other hand, while a lower
reduction in resting heart rate may be obtained with
 A.D. Oprea et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
atenolol (-19 beats per minute, 95% CI, -20.6 to -17.6)
versus metoprolol (-13.2 beats per minute, 95% CI, -14.7 to
-11.7), an appropriate titration period may decrease the
variability in response and the choice of β-blocker may not
matter.39,68
4. The perioperative use of some β-blockers may confer a
higher risk for postoperative stroke, which could offset
their beneficial effects in the prevention of cardiac compli-
cations and mortality. A meta-analysis by Bangalore and
colleagues found an increased risk of nonfatal stroke,
hypotension, and bradycardia with the use of β-blockers
in patients undergoing noncardiac surgery, with the POISE
trial carrying the greatest weight in the analysis.14,69
Although there is an association between β-blocker use,
hypotension, and stroke, this cannot be assumed to be a
direct cause-and-effect relationship. It is possible that acute
anemia precipitated by surgical bleeding also could con-
tribute to the risk of stroke, as patients on β-blockers cannot
compensate for a significant drop in hematocrit (30%-
35%).70
In a single-center study of 44,092 consecutive patients
who underwent noncardiac, non-neurologic surgery, the use
of bisoprolol was associated with a lower risk for post-
operative stroke compared to metoprolol or atenolol use
(OR 0.2, 95% CI, 0.04-0.99). The investigators suggested
that the higher risk for postoperative stroke with metoprolol
or atenolol use was due to these β-blockers being less
selective for β1 ARs and their effect on β2 ARs impairing
cerebral vasodilation.23 Mashour and colleagues also found
in 57,218 consecutive patients who underwent noncardiac
surgery that routine use of preoperative metoprolol (OR
4.2, 95% CI, 2.2-8.1, p o 0.001) compared to atenolol was
associated with a higher risk for postoperative stroke after
noncardiac surgery. Further, intraoperative use of metopro-
lol (OR 3.3, 95% CI, 1.4-7.8, p ¼ 0.003) compared to
esmolol or labetalol was associated with an increased risk
for perioperative stroke.71
Patients Undergoing Cardiac Surgery
Perioperative β-blocker use in patients undergoing cardiac
surgery is similarly controversial since β-blockers may affect
certain outcomes (eg, AF) more than others (eg, mortality).
Initial evidence from an observational study showed a small
but consistent survival benefit in patients who received β-
blockers prior to CABG surgery. Patients who received
preoperative β-blockers had a lower incidence of mortality
(2.8% v 3.4%, OR 0.80, 95% CI, 0.78-0.82; p o 0.001).
Unadjusted morbidity rates in patients who received β-
blockers compared to patients who did not receive β-
blockers were also significantly lower for stroke, 1.6% versus
1.7% (OR 0.93, 95% CI, 0.89-0.96); prolonged ventilation,
5.6% versus 6.6% (OR 0.85, 95% CI, 0.83-0.87); reoperation,
4.9% versus 5.3% (OR 0.94, 95% CI, 0.92-0.96); and renal
failure, 3.4% versus 3.8% (OR 0.87, 95% CI, 0.85-0.89); but
not for deep sternal wound infection, 0.62% versus 0.64% (OR
0.98, 95% CI, 0.92-1.04).72 The beneficial effect of
Please cite this article as: Oprea AD, et al. (2018), http://dx.doi.org/10.1053/j.jvca.2018.04.045
11
preoperative β-blocker use remained consistent in the majority
of patient subgroups, including patients of advanced age;
women; and patients with chronic lung disease, diabetes, or
moderately depressed ventricular function. In contrast, an
elevated mortality risk, albeit statistically nonsignificant, was
observed in patients with β-blocker use who had a left
ventricular ejection fraction of less than 30% (OR 1.13, 95%
CI, 0.96-1.33, p ¼ 0.23).72 Nevertheless, the findings of this
study resulted in a recommendation for preoperative β-blocker
use, which eventually also became a national quality metric for
patients undergoing CABG surgery.16,73
In contrast, subsequent large-scale observational studies
were not able to validate the benefit of perioperative β- blocker
use in patients undergoing CABG surgery. A retrospective
study of 12,855 patients undergoing CABG surgery found that
preoperative β-blocker use was not associated with a decreased
risk for morbidity and mortality. Nevertheless, a small benefit
was detected as far as the rates of deep sternal wound infection
(0.3% v 0.5%, p ¼ 0.032), pneumonia (1.9% v 2.4%, p ¼
0.039), and intraoperative blood usage (37.2% v 34.1%, p o
0.001) compared with patients who did not receive preopera-
tive β-blockers.73
Similarly, a retrospective analysis of 43,747 patients from
the Society of Thoracic Surgeons Adult Cardiac Surgery
Database observed that after risk adjustment, preoperative β-
blocker use was not associated with a reduced risk for
mortality, morbidity, length of stay (LOS), or hospital read-
mission, but patients who received preoperative β-blockers had
greater intraoperative blood usage.74 Of note, the lack of
benefit of perioperative β-blockers in this study led the
investigators to challenge their use as a quality metric in
patients with CABG surgery.74
Further, another recent large-scale retrospective analysis of the
Society of Thoracic Surgeons Adult Cardiac Surgery Database of
506,110 patients, who were free from recent myocardial infarction
and underwent CABG surgery, found that preoperative β-blocker
use was not associated with a lower risk for operative mortality
(OR 0.96, 95% CI, 0.87-1.06, p ¼ 0.38), permanent stroke (OR
0.99, 95% CI, 0.89-1.10, p ¼ 0.81), prolonged ventilation (OR
1.02, 95% CI, 0.98-1.07, p ¼ 0.26), any reoperation (OR 0.97,
95% CI, 0.92-1.03, p ¼ 0.35), renal failure (OR 1.04, 95% CI,
0.97-1.11, p ¼ 0.3), or deep sternal wound infection (OR 0.86,
95% CI, 0.71-1.04, p ¼ 0.12 ) compared to patients without
preoperative β-blocker use.75
A recent observational study corroborated the findings of
these previous studies and also found in 4,076 patients who
underwent elective CABG surgery, CABG surgery with valve
surgery, or valve surgery that preoperative β-blocker use was
not associated with a lower risk for postoperative delirium,
stages I and III of acute kidney injury, stroke, AF, mortality, or
prolonged LOS.76
In summary, as proposed in the section on perioperative β-
blocker use in noncardiac surgery, the different pharmacologic
properties of β-blockers, such as their dependence on CYP2D6
metabolism, genetic variations in β1 ARs, and receptor
selectivity, could explain some of the heterogeneities in the
outcomes reported in these studies.
12 A.D. Oprea et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
In support of these observations, a retrospective study of
5,248 patients who underwent urgent or elective CABG
surgery demonstrated that among these patients, preoperative
use of β-blockers not dependent on CYP2D6 biotransforma-
tion (OR 0.33, 95% CI, 0.13-0.83, p ¼ 0.02), but not
preoperative use of β-blockers dependent on CYP2D6 bio-
transformation (OR 0.44, 95% CI, 0.16-1.07, p ¼ 0.06), was
associated with a decreased risk of operative mortality.77
One of the most frequent complications after cardiac surgery
is postoperative AF, which occurs in 25% to 40% of
patients.78 This potentially life-threatening complication is
associated with increased risks for adverse neurologic events,
congestive heart failure, myocardial infarction, perioperative
mortality, prolonged LOS, and increased hospital costs.79
Sympathetic activation or an exaggerated response to adrener-
gic stimulation is an important trigger for postoperative AF.80
β-Blockers are a mainstay in the prevention and treatment of
postoperative AF.81
Indeed, an earlier meta-analysis of 58 studies that included a
total of 8,565 patients who underwent cardiac surgery also
found that β-blocker use was associated with the greatest
reduction in the risk of postoperative AF.82 Based on these and
earlier findings, the 2011 American College of Cardiology
Foundation/AHA Guideline for Coronary Artery Bypass Graft
Surgery recommends perioperative β-blockers to prevent post-
operative AF after CABG surgery, a class I designated
recommendation.16
A more recent meta-analysis of 33 trials that included a total
of 4,698 patients who underwent cardiac surgery reconfirmed
the findings of the previous meta-analysis and supported the
2011 American College of Cardiology Foundation/AHA
Guideline for Coronary Artery Bypass Graft Surgery recom-
mendations. This study demonstrated that β-blocker use was
associated with a significant reduction in the risk for post-
operative AF compared to placebo (OR 0.33, 95% CI, 0.26-
0.43, I2 ¼ 55%).83
A systematic review and meta-analysis of 5 randomized
controlled trials with a total number of 688 patients also
demonstrated that preoperative β-blocker administration prior
to elective cardiac surgery was associated with a significant
reduction in the risk for postoperative AF (OR 0.43, 95% CI,
0.30-0.61, I2 ¼ 0%) without significantly increasing the risk
of ischemic stroke, nonfatal myocardial infarction, overall
mortality, or LOS.84
Nevertheless, approximately 20% of patients undergoing
cardiac surgical procedures such as CABG surgery develop
postoperative AF despite β-blocker use.81,82 Several patient-
specific and procedure-related risk factors associated with
postoperative AF despite β-blocker use have been identified
in cardiac surgery patients.79,85,86 As the authors described in
more detail above, genes coding for β ARs and hepatic
metabolism of several β-blockers are highly polymorphic,
and thus potentially could affect pharmacodynamic and
pharmacokinetic responses of β-blockers.80,87,88 These poly-
morphisms affect the risk for cardiovascular complications
during β-blocker therapy.36,88 Indeed, a candidate-gene study
in CABG surgery patients found that genetic variation in G
Please cite this article as: Oprea AD, et al. (2018), http://dx.doi.org/10.1053/j.jvca.2018.04.045
protein-coupled receptor kinase 5 was associated with post-
operative AF despite perioperative β-blocker therapy.86 A
more recent genome-wide association study identified genetic
variation in the lymphocyte 96 antigen receptor, an essential
coreceptor of toll-like receptor 4 signaling, which plays a role
in initiating the innate immune response to cardiac surgery, to
be associated with a decreased risk for postoperative AF.78
These latter findings indicated not only that innate immune
responses play a central role in the development of post-
operative AF, but also why β-blockers in a subset of patients
undergoing cardiac surgery may not prevent postoperative AF.
This study illustrates the importance of mechanisms unrelated
to β AR signaling as potential targets for therapeutic interven-
tion in AF after cardiac surgery. Although there are no
pharmacogenomic studies with a specific focus on the phar-
macokinetics of β-blockers in the prevention of postoperative
AF, when orally administered carvedilol (less dependent on
CYP2D6 biotransformation) was compared to metoprolol
(highly dependent on CYP2D6 biotransformation), patients
who received carvedilol had a significantly lower risk of
postoperative AF than patients who received metoprolol (OR
0.50, 95% CI, 0.32-0.80, I2 ¼ 15%).89
Intravenous β-blockers also have been compared to orally
administered β-blockers in the prevention of AF after cardiac
surgery. In a small study of 50 CABG surgery patients,
intravenous esmolol compared to orally administered meto-
prolol was less well tolerated hemodynamically, and its
administration provided no additional benefit in preventing
postoperative AF.90 Another moderate-size study of 240
patients undergoing CABG surgery, aortic valve replacement,
or combined aortic valve replacement and CABG surgery
randomized patients to either a 48-hour infusion of metoprolol
or orally administered metoprolol (both regimens titrated to
heart rate) started on the morning of the first postoperative day.
The results of the study showed that intravenously adminis-
tered metoprolol was more effective than orally administered
metoprolol in the prevention of postoperative AF.91 More
recently, the introduction of landiolol (an ultra-short-acting
selective intravenous β-blocker) in Japan and Europe led to
several investigators studying the efficacy of landiolol in the
prevention of AF after cardiac surgery. Similar to esmolol,
landiolol is administered intravenously and has a short half-life
of 4 minutes, but compared to esmolol, it is highly selective
for β1 ARs (esmolol 33  selective v landiolol 233 
selective), which makes landiolol a potentially ideal intrave-
nous β-blocker for rapid intraoperative and postoperative
titration and prevention of postoperative AF.92 However, since
landiolol is ultra-short-acting, ideally a combination with a
longer-acting β-blocker should be considered. In this respect,
Sezai and colleagues recently showed that intravenous land-
iolol in combination with oral bisoprolol was more effective in
preventing postoperative AF than intravenous landiolol
alone.93 A subsequent meta-analysis of 6 trials that included
a total of 560 patients concluded that intravenous landiolol was
associated with a significant reduction in the incidence of
postoperative AF after cardiac surgery (OR 0.26, 95% CI,
0.17-0.40, p o 0.0001).94
 A.D. Oprea et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
Conclusion
In summary, supporting evidence for the perioperative use
of β-blockers to decrease perioperative morbidity and mortality
remains inconclusive. Over the past 2 decades, a plethora of
studies on perioperative β-blocker use, both in patients already
on β-blockers and in patients who are candidates for β-blocker
therapy, have thus far failed to provide definitive answers
regarding the type of β-blocker, timing of drug initiation, and
effective yet safe dose adjustments. The evidence that emerged
from these studies suggests that when it comes to perioperative
β-blocker use, one type and dose of β-blocker will not fit all
patients. As reviewed above, several studies suggest that an
individualized approach to perioperative β-blocker use should
be adopted (Table 5). However, studies that investigated the
impact of individualized perioperative β-blocker protocols in
the prevention of cardiac complications and mortality after
surgery are still lacking. Until such protocols are validated and
become available, a rational approach to perioperative β-
blocker use should take into account several factors, based
on information from conventional observational studies, ran-
domized clinical trials, and expert opinion, including clinical-
and procedure-related factors, impact on desired outcomes,
and genetic variations with potential influence on pharmaco-
kinetics and pharmacodynamics of specific β-blockers.
References
1 Frishman WH. β-Adrenergic blockade in cardiovascular disease. J Cardi-
ovasc Pharmacol Ther 2013;18:310–9.
2 Teo KK, Yusuf S, Furberg CD. Effects of prophylactic antiarrhythmic drug
therapy in acute myocardial infarction. An overview of results from
randomized controlled trials. JAMA 1993;270:1589–95.
3 Brophy JM, Joseph L, Rouleau JL. Beta-blockers in congestive heart
failure. A Bayesian meta-analysis. Ann Intern Med 2001;134:550–60.
4 Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/
ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Pre-
vention, Detection, Evaluation, and Management of High Blood Pressure
in Adults: A Report of the American College of Cardiology/American
Heart Association Task Force on Clinical Practice Guidelines. Hyperten-
sion 2017. [epub ahead of print].
5 Bangalore S, Steg G, Deedwania P, et al. β-Blocker use and clinical
outcomes in stable outpatients with and without coronary artery disease.
JAMA 2012;308:1340–9.
6 Abbasi J. Do all patients need β-blockers after a heart attack?. JAMA
2018;319:853–5.
7 Minor DS, Meyer AM, Long RC, et al. β-Blockers and chronic obstructive
pulmonary disease: Inappropriate avoidance?. J Clin Hypertens 2013;15:
925–30.
8 Malerba M, Montuschi P, Radaeli A, et al. Role of beta-blockers in
patients with COPD: Current perspective. Drug Discov Today 2015;20:
129–35.
9 Steinman MA, Zullo AR, Lee Y, et al. Association of β-blockers with
functional outcomes, death, and rehospitalization in older nursing home
residents after acute myocardial infarction. JAMA Intern Med 2017;177:
254–62.
10 Mangano DT, Layug EL, Wallace A, et al. Effect of atenolol on mortality
and cardiovascular morbidity after noncardiac surgery. Multicenter Study
of Perioperative Ischemia Research Group. N Engl J Med 1996;335:
1713–20.
11 Poldermans D, Boersma E, Bax JJ, et al. The effect of bisoprolol on
perioperative mortality and myocardial infarction in high-risk patients
Please cite this article as: Oprea AD, et al. (2018), http://dx.doi.org/10.1053/j.jvca.2018.04.045
13
undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk
Evaluation Applying Stress Echocardiography Study Group. N Engl J
Med 1999;341:1789–94.
12 Eagle KA, Berger PB, Calkins H, et al. ACC/AHA guideline update for
perioperative cardiovascular evaluation for noncardiac surgery—executive
summary: A report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines (Committee to Update the
1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncar-
diac Surgery). Circulation 2002;105:1257–67.
13 Durham J, Mackey WC. Perioperative β-blockade in noncardiac surgery: A
cautionary tale of over-reliance on small randomized prospective trials.
Clin Ther 2016;38:2302–16.
14 Devereaux PJ, Yang H, Yusuf S, et al. Effects of extended-release
metoprolol succinate in patients undergoing non-cardiac surgery (POISE
trial): A randomised controlled trial. Lancet 2008;371:1839–47.
15 Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA
guideline on perioperative cardiovascular evaluation and management of
patients undergoing noncardiac surgery: A report of the American College
of Cardiology/American Heart Association Task Force on practice guide-
lines. J Am Coll Cardiol 2014;64:e77–137.
16 Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA Guideline for
Coronary Artery Bypass Graft Surgery: Executive summary: A report of
the American College of Cardiology Foundation/American Heart Associa-
tion Task Force on Practice Guidelines. Circulation 2011;124:2610–42.
17 Kristensen SD, Knuuti J, Saraste A, et al. 2014 ESC/ESA Guidelines on
non-cardiac surgery: Cardiovascular assessment and management: The
Joint Task Force on non-cardiac surgery: Cardiovascular assessment and
management of the European Society of Cardiology (ESC) and the European
Society of Anaesthesiology (ESA). Eur J Anaesthesiol 2014;31:517–73.
18 Kirchheiner J, Heesch C, Bauer S, et al. Impact of the ultrarapid
metabolizer genotype of cytochrome P450 2D6 on metoprolol pharmaco-
kinetics and pharmacodynamics. Clin Pharmacol Ther 2004;76:302–12.
19 Lefebvre J, Poirier L, Poirier P, et al. The influence of CYP2D6 phenotype
on the clinical response of nebivolol in patients with essential hyperten-
sion. Br J Clin Pharmacol 2007;63:575–82.
20 Mann SJ. Redefining beta-blocker use in hypertension: Selecting the right
beta-blocker and the right patient. J Am Soc Hypertens 2017;11:54–65.
21 Frishman WH, Saunders E. β-adrenergic blockers. J Clin Hypertens
2011;13:649–53.
22 Gauthier C, Rozec B, Manoury B, et al. Beta-3 adrenoceptors as new
therapeutic targets for cardiovascular pathologies. Curr Heart Fail Rep
2011;8:184–92.
23 Ashes C, Judelman S, Wijeysundera DN, et al. Selective β1-antagonism
with bisoprolol is associated with fewer postoperative strokes than atenolol
or metoprolol: A single-center cohort study of 44,092 consecutive patients.
Anesthesiology 2013;119:777–87.
24 Cannavo A, Koch WJ. Targeting β3-adrenergic receptors in the heart:
Selective agonism and β-blockade. J Cardiovasc Pharmacol 2017;69:71–8.
25 Frishman WH. Cardiovascular pharmacotherapeutics, 3rd ed. Minneapolis,
MN: Cardiotext Inc; 57–86.
26 Mangrella M, Rossi F, Fici F. Pharmacology of nebivolol. Pharmacol Res
1998;38:419–31.
27 Johnson JA, Cavallari LH, Beitelshees AL, et al. Pharmacogenomics:
Application to the management of cardiovascular disease. Clin Pharmacol
Ther 2011;90:519–31.
28 Available at: 〈http://www.pharmvar.org/htdocs/archive/cyp2d6.htm〉.
Accessed April 11, 2018.
29 Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical
significance: Part I. Clin Pharmacokinet 2009;48:689–723.
30 Ingelman-Sundberg M, Sim SC, Gomez A, et al. Influence of cytochrome
P450 polymorphisms on drug therapies: Pharmacogenetic, pharmacoepi-
genetic and clinical aspects. Pharmacol Ther 2007;116:496–526.
31 Aklillu E, Persson I, Bertilsson L, et al. Frequent distribution of ultrarapid
metabolizers of debrisoquine in an Ethiopian population carrying dupli-
cated and multiduplicated functional CYP2D6 alleles. J Pharmacol Exp
Ther 1996;278:441–6.
32 Shin J, Johnson JA. Pharmacogenetics of beta-blockers. Pharmacotherapy
2007;27:874–87.
14 A.D. Oprea et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
33 Kertai MD, Fontes M, Podgoreanu MV. Pharmacogenomics of β-blockers
and statins: Possible implications for perioperative cardiac complications. J
Cardiothorac Vasc Anesth 2012;26:1101–14.
34 Lennard MS, Silas JH, Freestone S, et al. Oxidation phenotype — a major
determinant of metoprolol metabolism and response. N Engl J Med
1982;307:1558–60.
35 Bijl MJ, Visser LE, van Schaik RH, et al. Genetic variation in the CYP2D6
gene is associated with a lower heart rate and blood pressure in beta-
blocker users. Clin Pharmacol Ther 2009;85:45–50.
36 Rau T, Wuttke H, Michels LM, et al. Impact of the CYP2D6 genotype on
the clinical effects of metoprolol: A prospective longitudinal study. Clin
Pharmacol Ther 2009;85:269–72.
37 Goryachkina K, Burbello A, Boldueva S, et al. CYP2D6 is a major
determinant of metoprolol disposition and effects in hospitalized Russian
patients treated for acute myocardial infarction. Eur J Clin Pharmacol
2008;64:1163–73.
38 Fux R, Mörike K, Pröhmer AM, et al. Impact of CYP2D6 genotype on
adverse effects during treatment with metoprolol: A prospective clinical
study. Clin Pharmacol Ther 2005;78:378–87.
39 Badgett RG, Lawrence VA, Cohn SL. Variations in pharmacology of beta-
blockers may contribute to heterogeneous results in trials of perioperative
beta-blockade. Anesthesiology 2010;113:585–92.
40 Mason DA, Moore JD, Green SA, et al. A gain-of-function polymorphism
in a G-protein coupling domain of the human beta1-adrenergic receptor. J
Biol Chem 1999;274:12670–4.
41 Rathz DA, Brown KM, Kramer LA, et al. Amino acid 49 polymorphisms
of the human beta1-adrenergic receptor affect agonist-promoted trafficking.
J Cardiovasc Pharmacol 2002;39:155–60.
42 Sandilands A, Yeo G, Brown MJ, et al. Functional responses of human
beta1 adrenoceptors with defined haplotypes for the common 389R G and
49S G polymorphisms. Pharmacogenetics 2004;14:343–9.
43 Frishman WH. Beta-adrenergic blocker withdrawal. Am J Cardiol
1987;59:26–32F.
44 Redelmeier D, Scales D, Kopp A. Beta blockers for elective surgery in elderly
patients: Population based, retrospective cohort study. BMJ 2005;331:932.
45 Jørgensen ME, Hlatky MA, Køber L, et al. β-Blocker-associated risks in
patients with uncomplicated hypertension undergoing noncardiac surgery.
JAMA Intern Med 2015;175:1923–31.
46 Shammash JB, Trost JC, Gold JM, et al. Perioperative beta-blocker
withdrawal and mortality in vascular surgical patients. Am Heart J
2001;141:148–53.
47 Hoeks SE, Scholte Op Reimer WJ, van Urk H, et al. Increase of 1-year
mortality after perioperative beta-blocker withdrawal in endovascular and
vascular surgery patients. Eur J Vasc Endovasc Surg 2007;33:13–9.
48 Wallace AW, Au S, Cason BA. Association of the pattern of use of
perioperative β-blockade and postoperative mortality. Anesthesiology
2010;113:794–805.
49 Kwon S, Thompson R, Florence M, et al. β-blocker continuation after
noncardiac surgery: A report from the surgical care and outcomes
assessment program. Arch Surg 2012;147:467–73.
50 Karam D, Arora R. Perioperative β-blockers in patients undergoing
noncardiac surgery-Scientific misconduct and clinical guidelines. Am J
Ther 2017;24:e435–41.
51 Kertai MD, Cooter M, Pollard RJ, et al. Is compliance with Surgical Care
Improvement Project Cardiac (SCIP-Card-2) measures for perioperative β-
blockers associated with reduced incidence of mortality and
cardiovascular-related critical quality indicators after noncardiac surgery?.
Anesth Analg 2017. [epub ahead of print].
52 Yang H, Raymer K, Butler R, et al. The effects of perioperative beta-
blockade: Results of the Metoprolol after Vascular Surgery (MaVS) study,
a randomized controlled trial. Am Heart J 2006;152:983–90.
53 Juul AB, Wetterslev J, Gluud C, et al. Effect of perioperative beta
blockade in patients with diabetes undergoing major non-cardiac surgery:
Randomised placebo controlled, blinded multicentre trial. BMJ 2006;332:
1482.
54 Brady AR, Gibbs JS, Greenhalgh RM, et al. Perioperative beta-blockade
(POBBLE) for patients undergoing infrarenal vascular surgery: Results of
a randomized double-blind controlled trial. J Vasc Surg 2005;41:602–9.
Please cite this article as: Oprea AD, et al. (2018), http://dx.doi.org/10.1053/j.jvca.2018.04.045
55 Barrett TW, Mori M, De Boer D. Association of ambulatory use of statins
and beta-blockers with long-term mortality after vascular surgery. J Hosp
Med 2007;2:241–52.
56 Bouri S, Shun-Shin MJ, Cole GD, et al. Meta-analysis of secure
randomised controlled trials of β-blockade to prevent perioperative death
in non-cardiac surgery. Heart 2014;100:456–64.
57 Wijeysundera DN, Duncan D, Nkonde-Price C, et al. Perioperative beta
blockade in noncardiac surgery: A systematic review for the 2014 ACC/
AHA guideline on perioperative cardiovascular evaluation and manage-
ment of patients undergoing noncardiac surgery: A report of the American
College of Cardiology/American Heart Association Task Force on practice
guidelines. J Am Coll Cardiol 2014;64:2406–25.
58 Flu WJ, van Kuijk JP, Chonchol M, et al. Timing of pre-operative beta-
blocker treatment in vascular surgery patients: Influence on post-operative
outcome. J Am Coll Cardiol 2010;56:1922–9.
59 Chen RJ, Chu H, Tsai LW. Impact of beta-blocker initiation timing on
mortality risk in patients with diabetes mellitus undergoing noncardiac
surgery: A nationwide population-based cohort study. J Am Heart Assoc
2017;6. [epub ahead of print].
60 Lee TH, Marcantonio ER, Mangione CM, et al. Derivation and prospective
validation of a simple index for prediction of cardiac risk of major
noncardiac surgery. Circulation 1999;100:1043–9.
61 Boersma E, Poldermans D, Bax JJ, et al. Predictors of cardiac events after
major vascular surgery: Role of clinical characteristics, dobutamine
echocardiography, and beta-blocker therapy. JAMA 2001;285:1865–73.
62 Lindenauer PK, Pekow P, Wang K, et al. Perioperative beta-blocker therapy and
mortality after major noncardiac surgery. N Engl J Med 2005;353:349–61.
63 Andersson C, Mérie C, Jørgensen M, et al. Association of β-blocker
therapy with risks of adverse cardiovascular events and deaths in patients
with ischemic heart disease undergoing noncardiac surgery: A Danish
nationwide cohort study. JAMA Intern Med 2014;174:336–44.
64 London MJ, Hur K, Schwartz GG, et al. Association of perioperative β-
blockade with mortality and cardiovascular morbidity following major
noncardiac surgery. JAMA 2013;309:1704–13.
65 Friedell ML, Van Way CW, Freyberg RW, et al. β-Blockade and operative
mortality in noncardiac surgery: Harmful or helpful?. JAMA Surg 2015;150:
658–63.
66 Beattie WS, Wijeysundera DN, Karkouti K, et al. Does tight heart rate
control improve beta-blocker efficacy? An updated analysis of the
noncardiac surgical randomized trials. Anesth Analg 2008;106:1039–48.
67 Wallace AW, Au S, Cason BA. Perioperative β-blockade: Atenolol is
associated with reduced mortality when compared to metoprolol. Anesthe-
siology 2011;114:824–36.
68 Cucherat M, Borer JS. Reduction of resting heart rate with antianginal
drugs: Review and meta-analysis. Am J Ther 2012;19:269–80.
69 Bangalore S, Wetterslev J, Pranesh S, et al. Perioperative beta blockers in
patients having non-cardiac surgery: A meta-analysis. Lancet 2008;372:
1962–76.
70 Beattie WS, Wijeysundera DN, Karkouti K, et al. Acute surgical anemia
influences the cardioprotective effects of beta-blockade: A single-center,
propensity-matched cohort study. Anesthesiology 2010;112:25–33.
71 Mashour GA, Sharifpour M, Freundlich RE, et al. Perioperative metoprolol and
risk of stroke after noncardiac surgery. Anesthesiology 2013;119:1340–6.
72 Ferguson TB, Coombs LP, Peterson ED, et al. Preoperative beta-blocker
use and mortality and morbidity following CABG surgery in North
America. JAMA 2002;287:2221–7.
73 Brinkman WT, Herbert MA, Prince SL, et al. Preoperative beta-blocker
usage: Is it really worthy of being a quality indicator?. Ann Thorac Surg
2011;92:788–95. discussion 795-6.
74 LaPar DJ, Crosby IK, Kron IL, et al. Preoperative beta-blocker use should
not be a quality metric for coronary artery bypass grafting. Ann Thorac
Surg 2013;96:1539–44. discussion 1544-5.
75 Brinkman W, Herbert MA, O’Brien S, et al. Preoperative β-blocker use in
coronary artery bypass grafting surgery: National database analysis. JAMA
Intern Med 2014;174:1320–7.
76 O’Neal JB, Billings FT, Liu X, et al. Effect of preoperative beta-blocker
use on outcomes following cardiac surgery. Am J Cardiol 2017;120:
1293–7.
 A.D. Oprea et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
77 Kertai MD, Esper SA, Akushevich I, et al. Preoperative CYP2D6
metabolism-dependent β-blocker use and mortality after coronary artery
bypass grafting surgery. J Thorac Cardiovasc Surg 2014;147:
1368–75. e1363.
78 Kertai MD, Li YJ, Ji Y, et al. Genome-wide association study of new-onset
atrial fibrillation after coronary artery bypass grafting surgery. Am Heart J
2015;170:580–90. e528.
79 Mathew JP, Fontes ML, Tudor IC, et al. A multicenter risk index for atrial
fibrillation after cardiac surgery. JAMA 2004;291:1720–9.
80 Parvez B, Chopra N, Rowan S, et al. A common β1-adrenergic receptor
polymorphism predicts favorable response to rate-control therapy in atrial
fibrillation. J Am Coll Cardiol 2012;59:49–56.
81 Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused
updates incorporated into the ACC/AHA/ESC 2006 guidelines for the
management of patients with atrial fibrillation: A report of the American
College of Cardiology Foundation/American Heart Association Task Force
on practice guidelines. Circulation 2011;123:e269–367.
82 Crystal E, Garfinkle MS, Connolly SS, et al. Interventions for preventing
post-operative atrial fibrillation in patients undergoing heart surgery.
Cochrane Database Syst Rev 2004;1. CD003611.
83 Arsenault KA, Yusuf AM, Crystal E, et al. Interventions for preventing
post-operative atrial fibrillation in patients undergoing heart surgery.
Cochrane Database Syst Rev 2013;1. CD003611.
84 Thein PM, White K, Banker K, et al. Preoperative use of oral beta-
adrenergic blocking agents and the incidence of new-onset atrial fibrillation
after cardiac surgery. A systematic review and meta-analysis. Heart Lung
Circ 2018;27:310–21.
85 Kertai MD, Qi W, Li YJ, et al. Gene signatures of postoperative atrial
fibrillation in atrial tissue after coronary artery bypass grafting surgery in
patients receiving β-blockers. J Mol Cell Cardiol 2016;92:109–15.
86 Kertai MD, Li YW, Li YJ, et al. G protein-coupled receptor kinase 5 gene
polymorphisms are associated with postoperative atrial fibrillation after
coronary artery bypass grafting in patients receiving β-blockers. Circ
Cardiovasc Genet 2014;7:625–33.
87 Liggett SB, Cresci S, Kelly RJ, et al. A GRK5 polymorphism that inhibits
beta-adrenergic receptor signaling is protective in heart failure. Nat Med
2008;14:510–7.
88 Johnson JA, Liggett SB. Cardiovascular pharmacogenomics of adrenergic
receptor signaling: Clinical implications and future directions. Clin
Pharmacol Ther 2011;89:366–78.
89 DiNicolantonio JJ, Beavers CJ, Menezes AR, et al. Meta-analysis
comparing carvedilol versus metoprolol for the prevention of postoperative
atrial fibrillation following coronary artery bypass grafting. Am J Cardiol
2014;113:565–9.
90 Balcetyte-Harris N, Tamis JE, Homel P, et al. Randomized study of early
intravenous esmolol versus oral beta-blockers in preventing post-CABG
atrial fibrillation in high risk patients identified by signal-averaged ECG:
Results of a pilot study. Ann Noninvasive Electrocardiol 2002;7:86–91.
91 Halonen J, Hakala T, Auvinen T, et al. Intravenous administration of
metoprolol is more effective than oral administration in the prevention of
atrial fibrillation after cardiac surgery. Circulation 2006;114:I1–4.
92 Oprea AD. Do we need another short-acting beta-blocker? A definite
maybe…. J Clin Anesth 2017;39:96–7.
93 Sezai A, Nakai T, Hata M, et al. Feasibility of landiolol and bisoprolol for
prevention of atrial fibrillation after coronary artery bypass grafting: A
pilot study. J Thorac Cardiovasc Surg 2012;144:1241–8.
94 Sakamoto A, Hamasaki T, Kitakaze M. Perioperative landiolol adminis-
tration reduces atrial fibrillation after cardiac surgery: A meta-analysis of
randomized controlled trials. Adv Ther 2014;31:440–50.
95 Feringa HH, Bax JJ, Boersma E, et al. High-dose beta-blockers and tight
heart rate control reduce myocardial ischemia and troponin T release in
vascular surgery patients. Circulation 2006;114:I344–9.
96 Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for
the management of heart failure: A report of the American College of
Cardiology Foundation/American Heart Association Task Force on Prac-
tice Guidelines. J Am Coll Cardiol 2013;62:e147–239.
97 Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 Guidelines
for the Management of Patients With Unstable Angina/Non-ST-elevation
Please cite this article as: Oprea AD, et al. (2018), http://dx.doi.org/10.1053/j.jvca.2018.04.045
15
Myocardial Infarction: A report of the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines (Writing
Committee to Revise the 2002 Guidelines for the Management of
Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction):
Developed in collaboration with the American College of Emergency
Physicians, the Society for Cardiovascular Angiography and Interventions,
and the Society of Thoracic Surgeons: Endorsed by the American
Association of Cardiovascular and Pulmonary Rehabilitation and the
Society for Academic Emergency Medicine. J Am Coll Cardiol 2007;50:
e1–157.
98 Zaugg M, Bestmann L, Wacker J, et al. Adrenergic receptor genotype but not
perioperative bisoprolol therapy may determine cardiovascular outcome in at-
risk patients undergoing surgery with spinal block: the Swiss Beta Blocker in
Spinal Anesthesia (BBSA) study: a double-blinded, placebo-controlled, multi-
center trial with 1-year follow-up. Anesthesiology. 2007;107:33–44.
99 Parvez B, Chopra N, Rowan S, et al. A common β1-adrenergic receptor
polymorphism predicts favorable response to rate-control therapy in atrial
fibrillation. J Am Coll Cardiol 2012;59:49–56.
100 Liu WN, Fu KL, Gao HY, et al. β1 adrenergic receptor polymorphisms
and heart failure: a meta-analysis on susceptibility, response to β-blocker
therapy and prognosis. PLoS One 2012;7:e37659.
101 Tseng ZH, Aouizerat BE, Pawlikowska L, et al. Common beta-adrenergic
receptor polymorphisms are not associated with risk of sudden cardiac death in
patients with coronary artery disease. Heart Rhythm. 2008;5:814–21.
102 Lemaitre RN, Heckbert SR, Sotoodehnia N, et al. beta1- and beta2-
adrenergic receptor gene variation, beta-blocker use and risk of myocar-
dial infarction and stroke. Am J Hypertens 2008;21:290–6.
103 Lanfear DE, Jones PG, Marsh S, et al. Beta2-adrenergic receptor
genotype and survival among patients receiving beta-blocker therapy
after an acute coronary syndrome. JAMA. 2005;294:1526–33.
104 Forleo C, Resta N, Sorrentino S, et al. Association of beta-adrenergic
receptor polymorphisms and progression to heart failure in patients with
idiopathic dilated cardiomyopathy. Am J Med 2004;117:451–8.
105 Wallerstedt SM, Eriksson AL, Ohlsson C, et al. Haplotype association analysis
of the polymorphisms Arg16Gly and Gln27Glu of the adrenergic beta2
receptor in a Swedish hypertensive population. J Hum Hypertens. 19 2005:
705–8.
106 Thomsen M, Dahl M, Tybjaerg-Hansen A, et al. β2 -adrenergic receptor
Thr164IIe polymorphism, blood pressure and ischaemic heart disease in
66 750 individuals. J Intern Med 2012;271:305–14.
107 Liggett SB, Wagoner LE, Craft LL, et al. The Ile164 beta2-adrenergic
receptor polymorphism adversely affects the outcome of congestive heart
failure. J Clin Invest 1998;102:1534–9.
108 Littlejohn MD, Palmer BR, Richards AM, et al. Ile164 variant of beta2-
adrenoceptor does not influence outcome in heart failure but may interact
with beta blocker treatment. Eur J Heart Fail 2008;10:55–9.
109 Piscione F, Iaccarino G, Galasso G, et al. Effects of Ile164 polymorphism
of beta2-adrenergic receptor gene on coronary artery disease. J Am Coll
Cardiol 2008;52:1381–8.
110 Candelore MR, Deng L, Tota LM, et al. Pharmacological characterization
of a recently described human beta 3-adrenergic receptor mutant.
Endocrinology. 1996;137:2638–41.
111 Piétri-Rouxel F, St John Manning B, Gros J, et al. The biochemical effect
of the naturally occurring Trp64–4Arg mutation on human beta3-
adrenoceptor activity. Eur J Biochem 1997;247:1174–9.
112 van Veldhuisen DJ, Cohen-Solal A, Böhm M, et al. Beta-blockade with
nebivolol in elderly heart failure patients with impaired and preserved left
ventricular ejection fraction: Data From SENIORS (Study of Effects of
Nebivolol Intervention on Outcomes and Rehospitalization in Seniors
With Heart Failure). J Am Coll Cardiol 2009;53:2150–8.
113 Liggett SB, Cresci S, Kelly RJ, et al. A GRK5 polymorphism that inhibits
beta-adrenergic receptor signaling is protective in heart failure. Nat Med.
2008;14:510–7.
114 Cresci S, Kelly RJ, Cappola TP, et al. Clinical and genetic modifiers of
long-term survival in heart failure. J Am Coll Cardiol 2009;54:432–44.
115 Kang S, Hong X, Ruan CW, et al. Effects of GRK5 and ADRB1
polymorphisms influence on systolic heart failure. J Transl Med 2015;
13:44.
16 A.D. Oprea et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]

116 Frey UH, Adamzik M, Kottenberg-Assenmacher E, et al.
A novel functional haplotype in the human GNAS gene alters
Galphas expression, responsiveness to beta-adrenoceptor stimulation,
and peri-operative cardiac performance. Eur Heart J 2009;30:
1402–10.
117 Iwase M, Uechi M, Vatner DE, et al. Cardiomyopathy induced by cardiac
Gs alpha overexpression. Am J Physiol 1997;272:H585–589.
118 Frey UH, Kottenberg E, Kamler M, et al. Genetic interactions in the β-
adrenoceptor/G-protein signal transduction pathway and survival after coronary
artery bypass grafting: a pilot study. Br J Anaesth 2011;107:869–78.
119 Wieneke H, Svendsen JH, Lande J, et al. Polymorphisms in the GNAS
Gene as Predictors of Ventricular Tachyarrhythmias and Sudden Cardiac
Death: Results From the DISCOVERY Trial and Oregon Sudden
Unexpected Death Study e 003905. J Am Heart Assoc 2016;5.

Please cite this article as: Oprea AD, et al. (2018), http://dx.doi.org/10.1053/j.jvca.2018.04.045