Download Suggestion from clinicians

Labetolol vs. Other Beta-blockers
Replacement/Addition to the List
Peer Feedback:
"Most common used beta blockers are Acebotolol, Atenolol, Metoprolol, Carvedilol and Sotolol”
“(Metaprolol is a) Very commonly used beta blocker"
Comment: "Labetalol - also should be reassessed - replaced by alterantive beta-blocker"
Literature Review Question:
What is the most effacious and safe beta blocker?
Literature Search:
eCPS – Hypertension, Heart Failure
PubMed - beta blockers AND (acebutolol OR atenolol OR metoprolol OR carvedilol OR sotalol
OR labetolol) AND comparison AND efficacy; “pregnancy AND beta blockers AND (labetalol OR
labetolol) AND safety”
Large scale comparison of bisoprolol, metoprolol, carvedilol and nebivolol (2014)
The four pivotal beta-blocker trials in heart failure (HF) had different inclusion criteria, making
comparison difficult without patient stratifying. The aim of this study was to compare, in similar
patients, the effects of bisoprolol, metoprolol controlled release/extended release (CR/XL),
carvedilol and nebivolol on (i) total mortality, (ii) all-cause mortality or hospitalization due to
cardiovascular causes (time to first event), (iii) all-cause mortality or hospitalization because of
HF and (iv) tolerability, defined as discontinuation of randomized treatment.
The efficacy and tolerability of bisoprolol, carvedilol and metoprolol CR/XL are similar in patients
with systolic HF, irrespective of NYHA class or ejection fraction. Nebivolol is less effective and not
better tolerated.
Wikstrand, John, et al. "The large‐scale placebo‐controlled beta‐blocker studies in systolic heart failure revisited: results
from CIBIS‐II, COPERNICUS and SENIORS‐SHF compared with stratified subsets from MERIT‐HF." Journal of internal
medicine 275.2 (2014): 134-143.
Benefits of β blockers (2013)
Retrospective analyses have compared different β blockers and their effect on clinical endpoints
in chronic heart failure, and no superiority was found for one individual class over another in
reducing mortality or readmissions.40 41 When the surrogate endpoint of improvement in ejection
fraction has been investigated, superiority of any one class of β blockers could not be definitely
established.42 With this robust evidence in favor of β blockers in chronic heart failure, we decided
to assess the efficacy of one β blocker over another by comparing them using a Bayesian
network meta-analysis, in view of paucity of head to head trial data, except for the COMET
study.10
Also, to our knowledge, the question of tolerability and premature discontinuation of β blockers in
chronic heart failure has not been investigated, except in isolated trials,so we decided to pool the
data from different trials to assess the important question of tolerability and the discontinuation
rates of different β blockers in heart failure with reduced ejection fraction.43 Our analysis
reassuringly shows that overall, the tolerability, as indicated by discontinuation rates in different
randomized trials, of β blockers as a class of drugs is generally good and comparable to a range
of pharmacologically active and inactive comparators.
Our analysis shows that among the different β blockers in current use, bisoprolol, carvedilol, and
metoprolol all had significant mortality benefit compared with placebo/standard heart failure
treatment. However, our data additionally indicate that carvedilol was not only superior to
placebo/standard heart failure treatment for all-cause mortality but also had the lowest cardiac
mortality numerically among all β blockers tested, although this was not statistically significant,
indicating a benefit for its use in patients with cardiovascular comorbidities as an empiric initial
treatment of choice. This finding was congruent in our analysis with the results and subgroup
analyses from COMET,10 44 possibly as a result of a beneficial effect of carvedilol on endothelial
function, its stimulatory effects on β arresting signaling, and its anti-oxidant properties.45-47
Carvedilol has also been found to be superior to metoprolol in maintaining a favorable glycemic
profile in patients with diabetes, improved insulin sensitivity, and decreased progression to
microalbuminuria, all of which have been shown to have cardio protective effects.48 Considering
the lack of differences in improvement of mortality with use of individual β blockers in chronic
heart failure, as shown in our data, we consider it pragmatic to infer that, although the data may
be limited, we have three agents (bisoprolol, sustained release metoprolol succinate, and
carvedilol) that have been tested more extensively and have been shown to be superior to
placebo in our analysis (95% credible interval did not include 1)
Chatterjee, Saurav, et al. "Benefits of β blockers in patients with heart failure and reduced ejection fraction: network metaanalysis." BMJ 346 (2013): f55.
Cochrane Review (2012)
Though beta-blockers are a heterogeneous group of pharmacological agents, differing in betaadrenergic receptor selectivity, intrinsic sympathomimetic activity, and vasodilatory capabilities
(Pedersen 2007; Kamp 2010; Polónia 2010), we found no outcome trials with head-to-head
comparisons between beta-blockers for the treatment of hypertension. Of the 40,245 participants
using beta-blockers in this review, atenolol was used by 30,150 participants (75%). Due to the
paucity of data using beta-blockers other than atenolol, it is not possible to say whether the (lack
of) effectiveness and (in)tolerability of beta-blockers seen in this review is a property of atenolol or
is a class effect of beta-blockers across the board. From this review we cannot support the claim
by Lindhom and colleagues that cardioselective beta-blockers may be inferior to nonselective
ones in the treatment of hypertension (Carlberg 2004). A limitation of both previous reviews and
ours is the absence of trials assessing the effects of the new vasodilating beta-blockers (e.g.
carvedilol, bucindolol, and nebivolol) on mortality and hard cardiovascular outcomes. Possible
mechanisms to explain the poor ability of beta-blockers to reduce stroke include a propensity to
cause diabetes (Opie 2004), a failure to decrease central aortic pressure as much as brachial
pressure (Williams 2006; Polónia 2010), and others. Diabetes likely requires years to develop
cardiovascular complications (Verdecchia 2004), so we favour the mechanism involving lesser
reduction of central aortic pressure by beta-blockers. Vasodilating beta-blockers (Broeders
2000;Kalinowski 2003) have been shown to reduce central pressures better than conventional
beta-blockers (Kamp 2010; Polónia 2010); most probably because vasodilatation favourably
alters the pattern of the pressure wave reflecting back from the periphery, thereby lowering the
central pressure. Nonetheless, carvedilol and nebivolol also cause bradycardia, which is thought
to be the principal mechanism whereby atenolol ± thiazide may be less able to lower the central
pressure than amlodipine ± perindopril (Williams 2006). At any rate, high-quality outcome studies
are required to show that hard cardiovascular endpoints such as stroke and coronary heart
disease are significantly reduced by beta-blockers not studied in this review.
Wiysonge, Charles Shey, et al. "Beta-blockers for hypertension." Cochrane Database Syst Rev 11 (2012).
Hypertension in Pregnancy (2012)
Methyldopa (FDA pregnancy category B) is the preferred first-line agent to lower maternal blood
pressures in chronic or gestational hypertension.153,155,156 Labetalol (FDA pregnancy category
C) is considered an equally appropriate firstline agent and may be better tolerated than
methyldopa by the mother.153,155,156,158 Six head-to-head studies159-164 compare labetalol
and methyldopa and in all but one,164 maternal tolerance was reported with either agent. In this
study, women with pregnancy-induced hypertension reported less drowsiness, headache, and
hypotension with labetalol compared to methyldopa.164 The small study populations and the trial
designs limit the ability to draw firm conclusions from this data. The adverse effect profile in
general is more favorable for labetalol compared to methyldopa. The most commonly expected
adverse effects associated with labetalol include hypotension, dizziness, and fatigue, while those
most commonly expected with methyldopa include peripheral edema, depression, anxiety,
drowsiness, headache, and dry mouth.
The preferred first-line agent for management of acute, severely elevated blood pressure during
pregnancy is hydralazine, an FDA pregnancy category C drug154-156 (Table 5). Labetalol is an
equally appropriate first-line treatment option whose use is growing with its evolving safety profile
Bulloch, Marilyn N., and Dana G. Carroll. "When One Drug Affects 2 Patients A Review of Medication for the Management
of Nonlabor-Related Pain, Sedation, Infection, and Hypertension in the Hospitalized Pregnant Patient." Journal of
pharmacy practice 25.3 (2012): 352-367.
eCPS (2015)
Class
Beta1-adrenergic
Antagonists, β1selective with
ISA
Beta1-adrenergic
Antagonists, β1selective
Drug
acebutolol
Sectral,
generics
atenolol
Tenormin,
generics
Dose
Adverse Effects
Drug Interactions
Commentsd
Initial:
100 mg/day
Usual:
400 mg/day
Maximum:
800 mg/day
Once daily or
divided BID po
Fatigue, bradycardia,
decreased exercise capacity,
headache, impotence, vivid
dreams.
Less common: hyperglycemia,
depression, heart failure, heart
block.
Bradycardia with
digoxin or
nondihydropyridine
CCBs.
Cardiodepressant
effects with
nondihydropyridine
CCBs and amiodarone.
Agents with
ISA have less
effect on
resting heart
rate than those
without ISA.
Initial:
25 mg/day
Usual:
50 mg/day
Maximum:100
mg/day
Fatigue, bradycardia,
decreased exercise capacity,
headache, impotence, vivid
dreams.
Less common: hyperglycemia,
depression, heart failure, heart
block.
Once daily or
divided BID po
Beta1-adrenergic
Antagonists
carvedilol
generics
Initial: 3.125 mg
BID po
Fewer noncardiac effects due to
cardioselectivity.
Fewer noncardiac effects due to
cardioselectivity.
Orthostatic hypotension,
worsening HF/fluid retention,
bronchospasm (less with beta1Target: 25 mg BID selective), dyspnea,
bradycardia, malaise, fatigue,
asthenia, erectile dysfunction,
may mask hypoglycemia.
More likely to cause orthostatic
Bradycardia with
digoxin or
nondihydropyridine
CCBs.
Cardiodepressant
effects with
nondihydropyridine
CCBs and amiodarone.
Digoxin, amiodarone,
diltiazem, verapamil:
increased bradycardia.
Nondihydropyridine
calcium channel
blockers: additive
cardiodepressant
effect.
Costa
$
$
Nonselective
beta-blocker
with alphablocking
activity. Has
some
vasodilating
Class
Drug
Beta1-adrenergic
Antagonists with
alpha1-blocking
activity
Dose
labetalol
Trandate,
generics
Adverse Effects
Initial:
50 mg BID po
Usual:
200 mg BID po
Maximum:
1200 mg/day
Drug Interactions
Class III
Antiarrhythmics
metoprolol,
Lopresor,
generics
sotalol
CYP2D6 inhibitors.
Fatigue, bradycardia,
decreased exercise capacity,
headache, impotence, vivid
dreams.
Less common: hyperglycemia,
depression, heart failure, heart
block.
Bradycardia with
digoxin or
nondihydropyridine
CCBs.
Cardiodepressant
effects with
nondihydropyridine
CCBs and amiodarone.
$$
Bradycardia with
digoxin or
nondihydropyridine
CCBs.
Cardiodepressant
effects with
nondihydropyridine
CCBs and amiodarone.
$
Initial:
50 mg/day
Usual:
100–200 mg/day
Maximum:
400 mg/day
Give regular
formulations BID
po; SR
formulations once
daily po
Fatigue, bradycardia,
decreased exercise capacity,
headache, impotence, vivid
dreams.
Less common: hyperglycemia,
depression, heart failure, heart
block.
Usual:
Digoxin, verapamil, other betablockers may cause AV block,
bradycardia.
160–480 mg/day
po
generics
Elderly: Reduce
initial dose to 40
mg Q12H po
a.
Costa
hypotension than bisoprolol.
Edema, dizziness and nasal
congestion and postural
hypotension due to
alpha1antagonism.
Beta1-adrenergic
Antagonists, β1selective
Commentsd
effects.
Fewer noncardiac effects due to
cardioselectivity.
CYP2D6 inhibitors
increase levels of
metoprolol.
With digoxin, Ca++ channel
blockers, amiodarone, reduce
dose 25–50%.
Torsades de pointes,
especially at higher
doses or with renal
dysfunction.
Fatigue, bradycardia,
AV block, decreased
exercise capacity,
headache, erectile
dysfunction, vivid
dreams.
Less common:
hyperglycemia,
depression, heart
failure.
May be
$
especially
effective in
exerciserelated
arrhythmias.
Likely more
effective than
other drugs in
suppressing
inducibility of
VT.
Contraindicated
in asthma.
Cost of 30-day supply of usual dose of drug; includes drug cost only.
b.
The Canadian Hypertension Education Program recommends initiating therapy with a combination of two first-line agents if a
patient's SBP is ≥20 or DBP is ≥10 mm Hg above the recommended target.
c. It is generally recommended that the dose of each component is titrated before starting a combination product.z
d.
Beta-blockers should not be used as initial therapy in patients aged >60 y unless specifically indicated. Avoid in patients with
asthma.29 Avoid abrupt withdrawal (may precipitate rebound hypertension and ischemia). Taper the dose before discontinuation.
Avoid in patients with severe PAD. Contraindicated in patients with 2ndor 3rd degree heart block in the absence of a pacemaker.
Legend: $ <$20
$-$$ <$20–40
$$ $20–40
$$$ $40–60
$$$$ $60–80
Cardiovascular Disorders: Hypertension; Norm R.C. Campbell, MD, FRCPC, Paul Gibson, MD,
FRCPC and Ross T. Tsuyuki, PharmD, MSc, FCSHP, FACC; Date of revision: March 2015
Table 1 : Beta-adrenergic Blocking Agents - Health Canada-approved Indications
Beta-adrenergic
Blocking Agent
HTN, Mild to
Moderate
HTN Crisis,
Emergency
Treatment
HF
Angina
Pectoris
Acute
MI
Post-MI
Perioperative
HTN
Supraventricular
Arrhythmias
Ventricular
Arrhythmias
Migraine
Prophylaxis
Hypertrophic
Subaortic
Stenosis
Pheochromocytoma
Acebutolol
Yes
—
—
Yes
—
—
—
—
—
—
—
—
Atenolol
Yes
—
—
Yes
—
—
—
—
—
—
—
—
Bisoprolol
Yes
—
—
—
—
—
—
—
—
—
—
—
Carvedilol
—
—
Yes
—
—
—
—
—
—
—
—
—
Esmolol
—
—
—
—
—
—
Yes
Yes
—
—
—
—
Yes (oral)
Yes (iv)
—
—
—
—
—
—
—
—
—
—
Metoprolol
Yes
—
—
Yes
Yes (iv)
Yes (oral)
—
—
—
—
—
—
Nadolol
Yes
—
—
Yes
—
—
—
—
—
—
—
—
Nebivolol
Yes
—
—
—
—
—
—
—
—
—
—
—
Pindolol
Yes
—
—
Yes
—
—
—
—
—
—
—
—
Propranolol
Yes
—
—
Yes
—
Yes (oral)
—
Yes
Yes
Yes
Yes
Yes
Sotalol
—
—
—
—
—
—
—
—
Yes
—
—
—
Timolol
Yes
—
—
Yes
—
Yes
—
—
—
Yes
—
—
Labetalol
Medication
Uses
Contraindications (CI), drug interactions
(DI) or cautions
labetalol
hypertension,
ischemic heart
disease
CI: asthma, bradycardia, AV block, 2nd/3rd
deg block or PR>0.24sec, hepatic dysfunction,
uncompensated HF severe peripheral arterial
disease
DI: amiodarone, CCB (decrease HR),
cimetidine(increases effect),
digoxin(decreases HR), NSAIDs (increase BP
and decrease renal function) and
phenobarbital (decreases efficacy)
bisoprolol
hypertension ,
heart failure
(HF)
CI: COPD, asthma, bradycardia, AV block,
2nd/3rd deg block or PR>0.24sec, renal and
hepatic dysfunction, uncompensated HF,
peripheral arterial disease,
pheochromocytoma
DI: amiodarone, calcium channel blockers
(CCB), cimetidine (increases effect), digoxin
(decreases HR), NSAIDs (increase BP and
decrease renal function), phenobarbital
(decrease efficacy)
Adverse Effects
(common and
severe)
hypotension,
bronchospasm,
dizziness,
lightheadedness,
fatigue, nausea,
impotence
hypotension,
bronchospasm,
dizziness,
lightheadedness,
fatigue, nausea,
impotence
Initial dose;
typical dose
Monitoring
100mg; 100600mg one
time a day
BP
5mg; 5-20mg
one time a
day
BP