Feature Curbside Consult
Through the Decades: β-Blocker Use and Outcomes
in Acute Coronary Syndromes
Alina Kukin, Zachary R. Noel, PharmD, BCPS, Kristin Watson, PharmD, BCPS
Abstract: Beta-adrenergic receptor antagonists, or β-blockers, have been a
cornerstone of treatment in patients with acute coronary syndromes (ACS)
for more than 4 decades. First studied in the 1960s, β-blockers in ACS
have been shown to decrease the risk of death, recurrent ischemic events,
and arrhythmias by reducing catecholamine-mediated effects and reducing
myocardial oxygen demand. Through the decades, the β-blocker of choice,
timing of initiation, duration of therapy, and dosing have evolved consider-
ably. Despite having clear benefits in certain patient populations (eg, patients
with systolic dysfunction who are hemodynamically stable), the benefit of
β-blockers in other populations (ie, in patients at low risk for complications
receiving modern revascularization therapies and optimal medical manage-
ment) remains unclear. This article provides a review of the landmark clinical
trials of β-blockers in ACS and highlights the chronology and evolution of
guideline recommendations through the decades.
Key Words: acute coronary syndrome, beta-adrenergic receptor antagonists,
myocardial infarction
(Cardiology in Review 2018;26: 157–166)
T he management of patients presenting with acute coronary syn-
dromes (ACS) has evolved dramatically over the last several
decades with the advent of coronary intervention procedures and
the development of improved medical therapies, including anti-
coagulants, 3-hydroxy-3-methyl-glutaryl-co-enzyme A reductase
inhibitors and more potent antiplatelet therapies.1–7 One treatment
option that has remained constant since the publication of the first
American College of Cardiology/American Heart Association Acute
Myocardial Infarction guideline in 1990 is the use of β-adrenergic
receptor antagonists, or β-blockers, for select patients.1 β-Blockers,
which have been studied for the management of myocardial infarc-
tion (MI) since the 1960s, reduce myocardial oxygen demand by
attenuating catecholamine stimulation of cardiac myocytes, thereby
improving coronary perfusion, minimizing infarct size, and reduc-
ing arrhythmias.8 Through the decades, the β-blocker of choice, the
timing of administration, duration of therapy, dosing, and patient
populations in which to initiate β-blocker therapy have evolved con-
siderably. This article will review landmark clinical trials regarding
the use of β-blocker therapy for the treatment of ACS and highlight
how therapy has changed over time (Fig. 1). This article focuses
on the use of β-blockers within the first year after an ACS. A sum-
mary of the treatment strategies utilized in the trials discussed in this
article is presented in Table 1.
From the Department of Pharmacy Practice and Science, University of Maryland
School of Pharmacy, Baltimore, MD.
Disclosure: The authors declare no conflicts of interest.
Correspondence: Zachary R. Noel, PharmD, BCPS, Department of Pharmacy
Practice and Science, University of Maryland School of Pharmacy, 20 North
Pine Street, S427 Baltimore, MD. E-mail: znoel@rx.umaryland.edu.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 1061-5377/18/2603-0157
DOI: 10.1097/CRD.0000000000000197
Cardiology in Review  •  Volume 26, Number 3, May/June 2018 www.cardiologyinreview.com  |  157
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
β-BLOCKER USE IN THE PRETHROMBOLYTIC ERA
1960s: Trials of Propranolol in MI
The first prospective, randomized trial to investigate the
effect of β-blockade on clinical outcomes in acute myocardial
infarction (AMI) was conducted in 1965.9 A total of 91 patients
who experienced symptoms suggestive of AMI within 24 hours
of presentation to the hospital were enrolled to receive proprano-
lol or no propranolol. Diagnosis was confirmed by the presence
of electrocardiogram (ECG) changes (ie, Q-waves or ST-segment
changes) and changes in biomarkers (eg, elevations in lactate
dehydrogenase or aspartate transaminase). Patients were random-
ized to treatment with oral propranolol 20 mg every 8 hours or no
treatment for 28 days. No exclusion criteria were noted in the pub-
lished trial. The mean age of patients was 59 years, and 75% were
male. Anticoagulation was administered to all patients unless con-
traindicated, and supportive treatments such as digitalis, diuret-
ics, antihypertensives, and hydrocortisone were used as medically
necessary. The rates of supportive treatment were not recorded, nor
was the median dose of propranolol. A 54% relative risk reduc-
tion (RRR) in mortality was observed in those who received pro-
pranolol (35% vs 16%; no P value provided). Fewer cardiac arrests
and episodes of cardiac pain were recorded in those receiving
propranolol; however, the sample size was too small to accurately
determine statistical significance. Adverse effects were insuffi-
ciently tracked and disclosed, but the absolute number of patients
exhibiting symptoms of heart failure (HF) were similar between
the propranolol and no treatment arms (2 patients vs 4 patients). A
subsequent publication would raise concerns for incomplete data
and poor study design, thus bringing into question the validity and
reliability of the results.10
In light of the concerns with the data reported by Snow,9 mul-
tiple prospective, randomized controlled trials ensued in an attempt
to reproduce the observed effects. Balcon et al11 conducted a pro-
spective, single-center, randomized, placebo-controlled, double-
blind trial that evaluated the role of oral propranolol after an AMI.
A total of 114 patients who experienced symptoms within 24 hours
of presentation had ECG changes consistent with AMI and elevated
biomarkers were randomized to propranolol 20 mg every 6 hours or
placebo. Treatment was administered as soon as possible follow-
ing admission and continued for 28 days. Patients were excluded
if they were unconscious or presented with complete heart block.
The mean age of the patients was 60 years, and approximately two-
thirds were male. The mean time from onset of pain to first treatment
dose was 9.19 ± 0.85 hours and 9.95 ± 0.77 hours in the treatment and
placebo arms, respectively. Bed rest was mandated for 3 weeks in
all patients. Other cardiac medications were discouraged during the
trial period, but anticoagulation, diuretics, digitalis, and vasopressors
could be given as necessary. The rates of these supportive treatments
were not provided. No difference was observed in 28-day mortality
between those treated with propranolol or placebo (23.2% vs 24.1%;
no P value provided). The rates of HF and arrhythmias were similar
between groups, but a significant increase in the rate of symptom-
atic hypotension with bradycardia was observed in those treated with
propranolol (30% vs 14%; P < 0.05).
Kukin et al Cardiology in Review  •  Volume 26, Number 3, May/June 2018

FIGURE 1.  Evolution of guideline recommendations for β-blocker use in acute coronary syndromes. AMI, acute myocardial
infarction; CI, contraindication; HF, heart failure; IV, intravenous; LV, left ventricular; MI, myocardial infarction; po, oral; UA,
unstable angina.

Similar to the trial by Balcon et al11, Clausen et al12 conducted a
prospective, single-center, randomized trial that examined the effects
of oral propranolol in the setting of AMI. A total of 110 patients who
experienced symptoms of AMI within 24 hours of presentation were
randomized to propranolol 10 mg 4 times daily or no treatment for 14
days. Patients were observed for 22 days following randomization.
The only exclusion criterion was asthma. Routine care consisting of
digitalis, diuretics, and anticoagulation was administered upon phy-
sician discretion, but rates of use were not provided. At the conclu-
sion of the trial, no significant difference in mortality was observed
in those who received propranolol versus those who did not (30% vs
33%; no P value provided), irrespective of age, gender, or severity
of the current condition. No differences in the incidence and type
of arrhythmias or in the incidence of HF was noted between the 2
study arms. There was an increase in the absolute number of patients
experiencing shock, defined as a systolic blood pressure < 90 mm Hg,
in those who received propranolol; however, this was not statistically
significant (47% vs 26%; 0.10 > P > 0.05).
The Propranolol in Acute Myocardial Infarction trial was a
prospective, multicenter, randomized, placebo-controlled, double-
blind trial that investigated the role of propranolol for the prevention
of arrhythmias and reduction in mortality following AMI.13 A total
of 226 patients with diagnostic ECG changes for MI who presented
within 24–48 hours of symptoms were randomized to oral propranolol
20 mg every 6 hours or placebo for 28 days. Exclusion criteria included
bronchospasm, asthma, bradycardia, and hypotension. The average
age was 58 years, 80% were men, and the overall acuity of patients
was low as determined by the Peel’s Coronary Prognostic Index. The
average time from onset of symptoms to treatment initiation was 16.2
hours in the propranolol group and 13.4 hours in the placebo group.
The use of anticoagulants was given based on physician’s practice.
When indicated, digitalis, diuretics, pain relievers, and antiarrhyth-
mic drugs such as quinidine and procainamide were administered, the
rates of which were not disclosed. Overall mortality was nonstatisti-
cally significantly higher in those treated with propranolol compared
with placebo (15% vs 12.6%; no P value provided). Patients receiv-
ing propranolol experienced more cardiac failure (31% vs 14.7%; no
P value provided) and more hypotension (19% vs 10.5%; no P value
provided). Routine ECG monitoring was not performed, and thus no
conclusions could be made regarding the incidence of arrhythmias.
An additional, larger trial was conducted in 1968 to determine
the effect of propranolol on mortality and morbidity in the setting
of AMI.14 This prospective, multicenter, randomized, placebo-con-
trolled, double-blind trial enrolled patients presumed to have AMI
within the previous 3 days. Patients were randomized to treatment
with 20 mg oral propranolol 4 times daily or placebo for 3 weeks.
Key exclusion criteria included shock, HF, heart block, and sinus
bradycardia. A total of 454 patients were deemed to have certain or
probable AMI, as defined by the presence of ECG changes, eleva-
tions in biomarkers, and clinical presentation, and were included in
the analysis. Of the patients with confirmed AMI, those who received
propranolol had similar mortality as those who received placebo
(14% vs 11%; no P value provided). The rates of HF, hypotension,
and chest pain were also similar between groups; however, a signifi-
cant reduction in arrhythmias due to ectopic beats was observed in
those receiving propranolol (12% vs 22%; P < 0.01). No significant
difference in mortality was noted between the treatment and placebo
groups based on age, previous ischemic history, status on admission,
administration of anticoagulants, or time of mobilization. Although
it was stated that patients were included if suspected of having AMI
within 3 days, no further data were reported on the time frame of
symptom onset to propranolol administration.
Summary of the 1960s
The data published by Snow9 in 1965 were among the first to
show a mortality reduction in AMI. The primitive treatment strategies
for AMI at that time—which mainly consisted of anticoagulation and
bed rest for up to 3 weeks to reduce myocardial oxygen demand—
had proven to yield little benefit on outcomes. Although the results
were promising, they were met with great skepticism as flaws in
study design were identified. Of the remaining trials conducted in
the 1960s, none were able to reproduce the beneficial effects on mor-
tality. Three of the 4 trials in this era also tested the hypothesis that
propranolol would prevent arrhythmias. One trial noted more sinus
bradycardia in the propranolol group, another trial observed a reduc-
tion in arrhythmias due to ectopic beats, and the third trial detected

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Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

 TABLE 1.  Key Trials of β-Blockers
Study
Snow9
Balcon et al11
Clausen et al12
Propranolol in Acute Myocardial
Infarction: A Multicentre Trial
196613
Norris et al14
The Norwegian Multicenter Study
© 2018 Wolters Kluwer Health, Inc. All rights reserved.
of Timolol after Myocardial
Infarction17,18
The Göteborg Metoprolol Trial19
β-blocker Heart Attack Trial20
The Metoprolol in Acute
Myocardial Infarction trial21
Long-Term Treatment With
Metoprolol After Myocardial
Infarction Trial22
The first international study of
infarct survival23
The Thrombolysis in Myocardial
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
Infarction Phase II trial27
Atenolol use in the Global
Utilization of Streptokinase and
Tissue Plasminogen Activator--I
Trial28
www.cardiologyinreview.com | 159
Agent/Initial Dose
Propranolol PO 20 mg
every 8 hr
Propranolol PO 20 mg
every 6 hr
Propranolol PO 10 mg 4 times
daily
Propranolol 20 mg PO
every 6 hr
Propranolol 20 mg PO
4 times daily
Timolol 5 mg PO twice daily
Metoprolol 5 mg (up to 15 mg)
IV followed by metoprolol
tartrate 50 mg PO every 6 hr
for 48 hr
Propranolol 20 mg PO 3 times
daily
Metoprolol 5 mg (up to 15 mg)
IV followed by metoprolol
tartrate 50 mg PO every
6 hr for 48 hr
Metoprolol tartrate PO 100 mg
twice daily
Atenolol 5–10 mg
intravenously, depending on
heart rate
“Immediate” group: metoprolol
5 mg (up to 15 mg) IV
followed by metoprolol
tartrate 50 mg PO every 12 hr
for the first 24 hr
“Delayed” group: metoprolol
25 mg PO every 12 hr
Atenolol 5 mg (up to 10 mg)
IV followed by atenolol
50–100 mg atenolol PO daily
Duration of
Timing of Initial Dose Maximal Dose Treatment Key Findings
Within 24 hr of symptom onset Propranolol 20 mg 28 d Propranolol use associated with a reduced
PO every 8 hr risk of death; concerns with validity of
results.
Within 24 hr of symptom onset; Propranolol 20 mg 28 d No difference in the rate of death,
mean time from onset of pain PO every 6 hr arrhythmia, or HF.
to first treatment dose was
9.19 ± 0.85 hr in treatment group
and 9.95 ± 0.77 hr in placebo group
Within 24 hr of symptom onset Propranolol 10 mg 14 d No difference in the rate of death,
PO 4 times daily arrhythmia, or HF.
Within 24–48 hr of symptom onset; Propranolol 20 mg 28 d No difference in the rate of death.
average of 16.2 hr from symptom PO every 6 hr Cardiac failure higher in the propranolol
onset in the propranolol group group.
and 13.4 hr in the placebo group
Within 3 d of symptom onset Propranolol 20 mg 3 wk No difference in the rate of death or HF.
PO 4 times daily Risk of arrhythmia lower with propranolol.
7–28 d after MI; average of Timolol 10 mg PO 17 mo (median) Timolol use associated with lower risk of
11.5 d from presentation twice daily all-cause death and reinfarction; reduction
persisted at 6 yr.
Average of 11.3 hr from Metoprolol tartrate 90 d Metoprolol use associated with a lower risk
symptom onset PO 100 mg twice of death.
daily
Cardiology in Review  •  Volume 26, Number 3, May/June 2018
5–21 d after myocardial infarction; Propranolol PO 60 25 mo (average) Propranolol use associated with lower risk
average of 14 d from presentation to 80 mg 3 times of all-cause death.
to treatment daily
Within 24 hr of symptom onset; Metoprolol tartrate 16 d Overall, no difference in the risk of death.
average of 6.7 hr from PO 100 mg twice Metoprolol use associated with lower risk of
symptom onset daily death in “high-risk” patients.
Metoprolol use associated with lower risk of
supraventricular arrhythmias.
1–2 wk after MI Metoprolol tartrate 36 mo Overall, no difference in the rate of death.
PO 100 mg twice Metoprolol use associated with lower risk of
daily cardiac death in those with a large infarct.
Average of 5 hr from Atenolol 100 mg 7d Atenolol use associated with lower risk of
symptom onset PO daily vascular death at 7 d; no difference at 1 yr.
Atenolol associated with lower risk of
nonfatal cardiac arrest and reinfarction.
“Immediate” group: average of Metoprolol tartrate Not reported No difference in LVEF.
3.3 hr from symptom onset PO 100 mg twice At 6 wk, metoprolol use associated with
“Delayed” group: 6 d after MI daily lower risk of nonfatal/fatal reinfarction;
difference did not persist at 1 yr.
Overall, no difference in mortality. Mortality
benefit observed with metoprolol in the “low-
risk” group who received immediate therapy
Within 2 d of MI; 92% of patients Atenolol 50–100 mg 30 d Atenolol use associated with lower rate of
who received both IV + oral and PO daily death, HF and ventricular arrhythmias.
68% of patients who received
oral only received first dose
within 1 d
(Continued )
β-Blocker Use and Outcomes in ACS
Kukin et al Cardiology in Review  •  Volume 26, Number 3, May/June 2018

no difference in incidence or type of arrhythmias.11,12,14 Supportive

risk of cardiovascular shock, especially in

Carvedilol use associated with lower risk of
all-cause death, cardiovascular death and
treatment strategies during this time drastically differed from cur-

those at high risk for developing shock.

Metoprolol use associated with increased

Primary outcome did not include clinical

No difference in the composite of death,
reinfarction, or cardiac arrest; or all-
rent practice and consisted of anticoagulation, digitalis, and in some
No difference in the composite of all-

instances select class I antiarrhythmics. It is possible that the use of

cause death or hospitalization.

these antiarrhythmic drugs actually increased the rates of arrhyth-

Metoprolol use associated with

Key Findings

mias based on currently available literature.15 Unfortunately, the rates

No difference in infarct size.

HF, heart failure; IV, intravenous; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; PO = oral; STEMI, ST-segment elevation myocardial infarction.
of utilization of these medications were often unreported. Not to be

improvement in LVEF.
underappreciated are the limitations in diagnosing AMI during this
era. Cardiac-specific biomarkers, such as creatinine kinase myo-
globin and troponins I or T, were not available until the 1970s and
nonfatal MI.

cause death.

1980s, respectively; thus, less sensitive biomarkers such as lactate

outcomes.
dehydrogenase and aspartate aminotransferase were used to aid in
diagnosing AMI. The lack of specificity for AMI of these biomarkers
may have contributed to incorrect diagnoses of AMI.16 Study design
is also a significant limitation of data generated from this era. Pla-
cebo-controlled blinded studies were not routinely performed, thus
earlier; average
whichever was

introducing potential bias and confounders that, for many, brought

Duration of

1.3 yr (average)
Treatment

into question their validity. In summation, the evidence provided by

or hospital
discharge,

1d

1d

these trials was not sufficient to recommend β-blockade as a standard

Up to 28 d

of 15 d

therapy following AMI during this time.

The 1980s: Trials of Short and Long-Term β-blocker
Therapy and Impact on Mortality
200 mg PO daily
Maximal Dose

The Norwegian Multicenter Study of Timolol after Myocardial

PO twice daily
Carvedilol 25 mg

Infarction trial was a prospective, multicenter, randomized, placebo-

succinate

15 mg IV

10 mg IV

controlled, double-blind trial that examined the effect of timolol on

Metoprolol

Metoprolol

Metoprolol

mortality and reinfarction following MI.17 A total of 1884 clinically

stable post-MI patients were randomized to receive oral timolol 10 mg
or placebo twice daily. Patients who met inclusion criteria had 2 of
the following: (1) chest pain, cardiogenic shock, or acute pulmonary
edema; (2) characteristic ECG changes; or (3) 2 elevated aspartate
median of 10 min after STEMI
Within 4.5 hr of symptom onset;

aminotransferase levels. Key exclusion criteria included contraindi-

Within 12 hr of symptom onset
Timing of Initial Dose

cations for a β-blocker (eg, bradycardia, uncontrolled cardiac failure,

onset; average of 10.3 hr
Within 24 hr of symptom

severe lung disease), serious illness that would impact follow-up or

from symptom onset

affect the end-point (eg, alcoholism, malignancy), and an alterna-

tive indication for a β-blocker. The average age of enrollees was 61
3–21 d after MI

years, with 80% being male, 20% having a previous infarction, and
33% having HF. Although treatment with digitalis and diuretics was
diagnosis

permitted, the use of antiarrhythmic agents was prohibited. Random-

ization occurred at a median of 11.5 days following presentation, and
treatment duration was a median of 17 months. Patients were clas-
sified into 3 risk groups based on the presence of high risk factors,
including left ventricular (LV) failure, enlarged heart, atrial fibrilla-
Metoprolol 5 mg (up to 15 mg)

tartrate 50 mg PO every 6 hr

IV followed by metoprolol

tion or flutter, transient fall in systolic blood pressure to < 100 mm

Agent/Initial Dose

Hg, and serum aspartate aminotransferase levels exceeding 4 times

Carvedilol 6.25 mg PO

the upper limit of normal. Risk group I was identified as the highest
(up to 15 mg) IV

(up to 10 mg) IV

risk group, whereas risk group III was the lowest risk group. Overall,
for the first day

Metoprolol 5 mg

Metoprolol 5 mg

those treated with timolol had a 39.3% RRR in all-cause mortality

twice daily

(21.9 % vs 13.3%; P = 0.0003), a 28.4% RRR in reinfarction rates

(20.1% vs 14.4%; P = 0.0006), and 50% RRR in cardiac death (12%
vs 6%; P < 0.001). The impact on mortality appeared to persist for
at least 24 months, whereas the impact on reinfarction appeared to
diminish after 6 months. When analyzed by level of risk, the effects
Cardioprotection During an Acute
The Clopidogrel and Metoprolol in

on mortality were driven by a reduction in death in risk group II

with STEMI (EARLY-BAMI)35
Ventricular Dysfunction Trial30

before Primary PCI in Patients

Early β-Blocker Administration
Myocardial Infarction Trial31

(13.6% vs 7.1%; P < 0.01), which consisted of those who experi-

Myocardial Infarction trial32
TABLE 1.  (Continued )

enced their first MI and had a high risk condition (ie, LV failure,
The Carvedilol Post-Infarct
Survival Control in Left-

enlarged heart on chest x-ray, transient hypotension, or atrial fibril-

Effect of Metoprolol in

lation). No differences in mortality were noted among age groups.

Adverse effects that were more common in those treated with timolol
included bradycardia (5% vs 0%; P < 0.001), hypotension (3.1% vs
1.6%; P < 0.05), fatigue (4.8% vs 1.2%; P < 0.001), and cold extrem-
ities (7.7% vs 0.6%; P < 0.001). The most common reasons for study
Study

drug discontinuation were requirement for a β-blocker, need for an

antiarrhythmic, bradycardia, and hypotension.

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Cardiology in Review  •  Volume 26, Number 3, May/June 2018 β-Blocker Use and Outcomes in ACS
A follow-up of the Norwegian Multicenter Study of Timo-
lol after Myocardial Infarction trial found a persistent benefit of
β-blockade in patients who continued to take timolol for 6 years
after the index infarction.18 Of the surviving patients who completed
the double-blind period and participated in the open-label follow-up
study, 87.2% of timolol patients continued on treatment, and 88.1%
of the placebo patients continued without a β-blocker. At 6 years, a
significant reduction in mortality (26.4% vs 32.3%; P = 0.0028) was
sustained in the timolol group.
The Göteborg Metoprolol Trial was a prospective, multicenter,
randomized, placebo-controlled, double-blind trial that assessed the
impact of early β-blockade with metoprolol on mortality.19 Unlike the
Norwegian Multicenter Study of Timolol after MI trial, β-blockade
was administered soon after presentation for an AMI. A total of 1395
patients were randomized to receive metoprolol 15 mg intravenously,
administered as 5 mg every 2 minutes for 3 doses, followed by 50 mg
oral metoprolol tartrate every 6 hours for 48 hours, and then 100 mg
metoprolol tartrate twice daily, or matching placebo for 90 days.
Major exclusion criteria included contraindication to β-blocker ther-
apy (eg, cardiogenic shock) and the presence of an alternative indica-
tion for receiving a β-blocker. Approximately two-thirds of included
patients were younger than 64 years, and 76% were male. At baseline
and prior to treatment, about 25% of patients in each treatment group
were already on a β-blocker. An average of 11.3 hours elapsed from
onset of pain to treatment initiation. The rate of withdrawal from
the study was equal between the 2 groups (19.1%); however, more
patients receiving metoprolol withdrew due to hypotension (4.2% vs
1.9%; P = 0.018) and bradycardia (2.6% vs 0.7%; P = 0.011). At the
conclusion of the 90-day follow-up period, a significant 36% RRR
in mortality was observed in the metoprolol arm (8.9% vs 5.7%; P
< 0.03). Subgroup analyses suggested a benefit regardless of patient
age, previous MI, or prior β-blockade use.
The β-blocker Heart Attack Trial (BHAT) was a prospective,
multicenter, randomized, placebo-controlled, double-blind trial eval-
uating the impact of propranolol on mortality following MI.20 Nearly
4000 patients were randomized between 1978 and 1980 to proprano-
lol 20 mg 3 times daily or placebo within 5–21 days of MI. Doses
were titrated to 40 mg 3 times daily as tolerated, and at 4 weeks, the
dose was increased to 60 or 80 mg 3 times daily depending on serum
propranolol concentrations. Key exclusion criteria included severe
HF, bradycardia, and asthma. The mean age was 55 years, and about
85% of the patients were male. Aspirin was administered to 21%
of patients in both groups, and antiarrhythmic drugs were used in
21% of patients in the treatment group and in 25% in the placebo
group. The average time from presentation to randomization was 14
days. Eighty-two percentage of patients received propranolol 60 mg
3 times daily. The RRR in the primary endpoint, all-cause mortality,
was 26% in the propranolol group (9.8% vs 7.2%; P < 0.005) with a
number needed to treat of 38 over a mean of 25 months. Patients were
stratified into risk groups, similar to those used in the Norwegian
Multicenter Study of Timolol after MI study.17 An analysis based on
these groups revealed that the beneficial effects of propranolol were
consistent, regardless of risk factors; however, post hoc subgroup
analyses suggested a greater benefit in those who had electrical or
mechanical complications (eg, pulmonary edema or hypotension)
during their hospitalization.
The Metoprolol in Acute Myocardial Infarction (MIAMI) trial
was a prospective, multicenter, randomized, placebo-controlled, dou-
ble-blind trial conducted in 17 countries, which evaluated the signifi-
cance of early intravenous metoprolol on short-term mortality.21 A
total of 5778 patients under 75 years of age with suspected AMI were
included. Patients were administered 15 mg of intravenous metopro-
lol, given as 5 mg every 2 minutes for 3 doses, within 24 hours of
onset of symptoms. Following the intravenous metoprolol, 50 mg
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Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
metoprolol tartrate was administered every 6 hours for 48 hours fol-
lowed by 100 mg twice daily thereafter until day 16. Exclusion crite-
ria included current β-blocker or calcium channel blocker use, heart
rate < 60 beats per minute, systolic blood pressure < 105 mm Hg, and
LV failure. The average age was 60 years, and 78% of the patients
were male. Before treatment, glycosides and diuretics were used in
3% and 11% of patients, respectively. The average time from onset of
symptoms to randomization was 6.7 hours. A nonstatistically signifi-
cant 13% (95% CI, ˗8 to 33) decrease in mortality was observed in
those who received metoprolol (4.3% vs 4.9%; P = 0.29). Subgroup
analyses showed a statistically significant 29% RRR in mortality
in high-risk patients, defined by having 3 or more of the following
characteristics: age > 60 years, ECG changes consistent with MI,
history of MI, hypertension, angina pectoris, congestive HF, diabe-
tes, and treatment with diuretics or cardiac glycosides. A reduction
in supraventricular arrhythmias and chest pain, as demonstrated by
a significantly lower calcium channel blocker and narcotic require-
ment, was observed in the metoprolol arm. The rates of hypotension
and bradyarrhythmias were 9.8% and 4.8% for the placebo group and
18.4% and 12.9% for the treatment group, respectively (P < 0.001).
The long-term treatment with Metoprolol after Myocardial
Infarction Trial was a prospective, multicenter, randomized, placebo-
controlled, double-blind study that aimed to determine the effect of
metoprolol on long-term morbidity and mortality in patients for 36
months following MI.22 The study consisted of 301 patients, all of
whom were hospitalized within 48 hours of the onset of symptoms.
Patients were randomized to a study treatment of oral metoprolol tar-
trate 100 mg twice daily or placebo, which was initiated 1–2 weeks
after the acute infarction. Key exclusion criteria included HF, bundle
branch block, a need for β-blocker therapy, and atrial fibrillation. The
average age was 60 years, and 80% of the patients were male. Digitalis
and diuretics were prescribed in 24% and 45% of patients, respec-
tively. Approximately 6% of patients in each group were on antiar-
rhythmic medications. The withdrawal rates were 18% for each arm;
however, more patients in the metoprolol arm required withdrawal
for HF. The dose was reduced to 50 mg twice daily in 25% of patients
receiving metoprolol and in 10% of patients receiving placebo, pri-
marily due to symptomatic bradycardia. The intent-to-treat analysis
showed a nonstatistically significant decrease in all-cause mortality
(21.1% vs 16.2%; P-value = non-significant) and cardiac mortality
(19.7% vs 13%; P-value = NS) in those receiving metoprolol. In those
with a large infarct, as determined by lactate dehydrogenase levels,
a significant reduction in cardiac mortality was observed (32.1%
vs 12.5%; P < 0.05) as well as a reduction in sudden cardiac death
(13 events vs 1 event; P < 0.001). A significant reduction in non-
fatal reinfarction was also observed in the metoprolol arm (21.1%
vs 11.7%; P < 0.05), which was consistent among all risk groups.
Patients in the metoprolol arm experienced more symptomatic
bradycardia (12.3% vs 2.7%; P < 0.01) and HF (5.2% vs 1.4%;
P < 0.05), but less uncontrolled angina than those in the placebo
group (3.9% vs 10.9%; P < 0.05). The benefits of long-term metopro-
lol treatment appeared to persist throughout the study period.
The First International Study of Infarct Survival (ISIS-1)
was a prospective, multicenter, randomized, placebo-controlled,
open-label trial designed to assess the impact of early, intravenous
β-blocker therapy on cardiovascular mortality in patients with sus-
pected MI.23 Over 16,000 patients were randomized to atenolol 5 mg
intravenously, plus an additional 5 mg 10 minutes after the initial
injection if the heart rate remained > 60 beats per minute, followed
by 100 mg of oral atenolol daily for an additional 6 days or match-
ing placebo. Exclusion criteria included patients with a clear con-
traindication to β-blocker therapy, including persistent bradycardia
or hypotension, second- or third-degree heart block, severe HF,
or bronchospasm. The average age was 60 years, and 77% of the
Kukin et al Cardiology in Review  •  Volume 26, Number 3, May/June 2018
patients were male. Other drugs administered during the treatment
period included diuretics and antiarrhythmics in similar proportions
among both groups, as well as calcium antagonists, which were
utilized more by the control group (17% vs 9%; no P-value pro-
vided). Treatment was initiated an average of 5 hours after the onset
of symptoms. The mean intravenous dose achieved was 8.1 mg, and
37% of patients required a dose reduction of intravenous or oral
atenolol at some point during treatment. A statistically significant
15% RRR (95% CI, 0.01–0.27) in vascular mortality was observed
in the atenolol group during the 7-day treatment period (3.89% vs
4.57%; P < 0.04), with the benefit being limited to days 0–1. During
the 1-year follow-up, no significant difference in vascular mortal-
ity was observed outside of the initial 7-day treatment period. The
atenolol group was observed to have an increased use of inotropic
agents (5.0% vs 3.4%; P < 0.0001). The authors did not find sig-
nificant differences among outcomes between higher risk patients
(eg, older age, electrocardiographic signs of MI, diabetes, previous
MI, first-degree block, atrial fibrillation, and systolic blood pressure
< 120 mm Hg combined with heart rate > 90 bpm).
Summary
Although many β-blocker trials were conducted during the
1980s, results were inconsistent and left clinicians with no clear con-
sensus of how or when to incorporate β-blockade into the manage-
ment of AMI. Among trials that studied long-term treatment with
β-blockers, ranging from 25 to 36 months, the BHAT and Norwegian
Multicenter Study of Timolol after MI trials demonstrated a reduc-
tion in mortality.17,24 The trial conducted by Olsson et al22, however,
found no difference in mortality between the metoprolol-treated and
placebo groups. In all these trials, β-blockade was started multiple
days after infarction (ie, 5–28 days). One consistency across these
trials is the distinction of low-risk patients (eg, good exercise toler-
ance, normal LV function, no arrhythmias) garnering little, if any,
benefit from β-blockade, in contrast to moderate high risk patients
(eg, symptoms of HF or arrhythmias), which had long-term benefits.
The Göteborg Metoprolol trial was the first trial to show mor-
tality reduction with early β-blockade, initiated within 24 hours of
infarction. A few years later, the ISIS-I trial corroborated these find-
ings, demonstrating a 15% reduction in vascular death at 7 days with
immediate atenolol administration. The MIAMI trial contradictorily
found no mortality benefit with early metoprolol. ISIS-I noted no
differences among risk groups, but a retrospective analysis of the
MIAMI trial revealed a statistically significant reduction of mortal-
ity in high-risk patients. A large, comprehensive meta-analysis pub-
lished in 1985 analyzed 65 trials and concluded that published data
at the time did not support early β-blockers therapy, but did support
long-term benefit, citing a relative reduction in mortality of 20%.25
An editorial by Griggs et al26 suggested that the published data at
the time did not support the need for β-blockers in low-risk patients.
Low-risk patients, estimated to have a 1–2% risk of death per year,
were defined as those with good exercise tolerance, normal LV func-
tion, and no ventricular arrhythmia. The authors criticized the BHAT
and Norwegian studies for not incorporating ambulatory and elec-
trocardiographic monitoring or exercise testing into their criteria
for determining risk levels of patients in their studies, speculating
that these trials could have underestimated the risk level of the “low-
risk” patients, leading to trends indicating survival benefit among all
groups.
It is important to consider that treatment strategies for AMI
during this time were still quite limited. Aspirin was not routinely
used until after 1988, and reperfusion strategies (ie, thrombolysis)
were not available until after these trials were completed.27 In addi-
tion, statins and P2Y12 inhibitors would not become available until
the late 1990s and early 2000s.
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Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
β-BLOCKER USE IN THE REPERFUSION ERA
The 1990s: Timing of β-Blocker Initiation After
Thrombolysis
The Thrombolysis in Myocardial Infarction Phase II (TIMI
II-B) trial was the first large trial to assess the role of β-blockers in the
setting of reperfusion therapy among patients with MI.28 In the over-
all prospective, multicenter TIMI II trial, 2948 patients presenting
with an AMI were randomized to an invasive (routine angiography
and percutaneous transluminal coronary angiogram between 18 and
48 hours after presentation) or a conservative strategy (angiography
to evaluate for percutaneous transluminal coronary angiogram in set-
ting of recurrent ischemia or a positive submaximal exercise study)
after treatment with recombinant tissue-type plasminogen activator.
All patients also received aspirin and unfractionated heparin. Of the
enrolled patients, 1434 received β-blocker therapy with either “imme-
diate” treatment consisting of 3 doses of 5 mg intravenous metopro-
lol or “delayed” treatment with 25 mg oral metoprolol tartrate every
12 hours on day 6. Placebo controls were not utilized. Notable exclu-
sion criteria included a history of a cerebrovascular event, previous
coronary artery bypass surgery, prosthetic heart valve replacement,
dilated cardiomyopathy, asthma, and chronic obstructive lung dis-
ease. The average age was 55 years, and 85% were male. Twice
daily oral metoprolol tartrate was initiated in 94.7% of the “imme-
diate” treatment group who did not meet hemodynamic goals with
intravenous metoprolol. Treatment was initiated an average of 3.3
hours from symptom onset in the immediate group. In the delayed
group, treatment was initiated at the scheduled time in 73.2% of
patients. No difference was observed in the primary end point, global
LV ejection fraction (EF) at discharge, between the immediate and
delayed groups (51.0% vs 50.1%; P = 0.22). At 6 days, there was a
significant reduction in nonfatal or fatal reinfarction (2.7% vs 5.1%;
P = 0.02) and recurrent chest pain (18.8% vs 24.1%; P < 0.02) among
those who were in the immediate treatment group. At 6 weeks, the
lower risk of nonfatal or fatal reinfarction persisted (4.5% vs 7.3%;
P = 0.03) in the immediate treatment group, but these differences did
not persist at 1 year. There was no difference in mortality between the
groups. The subgroup of patients with low-risk features (ie, younger
age, no history of MI, not presenting with an anterior MI) appeared
to derive a mortality benefit from the immediate treatment compared
with deferred treatment (0.4% vs 3.6%; P = 0.009). Patients were
identified as low risk if they did not possess any of the following
characteristics: history of MI, ST-segment elevation of anterior elec-
trocardiographic leads, rales extending upward to include more than
one-third of the lung fields, hypotension and sinus tachycardia, atrial
fibrillation or flutter, age 70 years or higher, pulmonary edema, or
cardiogenic shock.
The Global Utilization of Streptokinase and Tissue Plasmino-
gen Activator for Occluded Coronary Arteries (GUSTO-I) trial was
a prospective, multicenter, randomized, open-label trial that com-
pared 4 thrombolytic strategies in MI patients.29 The protocol recom-
mended 2 doses of 5 mg intravenous atenolol followed by 50–100 mg
oral atenolol daily, during hospitalization, in patients without hypo-
tension, bradycardia, or HF. All patients were to receive aspirin
therapy. A prospectively planned, observational post hoc analysis of
the GUSTO-I dataset was conducted to assess the 30-day mortal-
ity among patients who did or did not receive atenolol.30 The aver-
age age was 60 years, and 75% of the patients were male. Of the
41,021 patients enrolled in GUSTO-1, 24.8% did not receive ateno-
lol; 44.5% only received the intravenous form, and 30.7% received
only the oral form. Ninety-two percentage of those who received
both forms of atenolol received the first oral dose within the first
day of enrollment, and 68% of those who received only oral atenolol
received it within the first day of enrollment. A lower rate of 30-day
Cardiology in Review  •  Volume 26, Number 3, May/June 2018 β-Blocker Use and Outcomes in ACS
mortality was observed among those who received any atenolol
treatment (3.8%) versus no atenolol (16.5%), and the median time
to death was longer among those who received atenolol (79.1 hours
vs 18.8 hours). Patients who received atenolol had lower risk features
than those who did not, including younger age, higher systolic blood
pressure, and lower Killip class, but a significant mortality difference
persisted after adjustment for differences in baseline characteristics
(odds ratio [OR], 0.33 [95% CI, 0.31–0.36], P < 0001). The adjusted,
30-day risk of death was increased in those who received the com-
bination of oral and intravenous therapy versus oral atenolol alone
(OR, 1.2 [1.1–1.5]; P = 0.0001). Patients who received any form of
atenolol vs no atenolol also had a lower incidence of shock (3.9%
vs 12.4%), HF (14.1% vs 22.7%), ventricular tachycardia (5.1% vs
9.6%), and ventricular fibrillation (5.7% vs 9.9%). When compared
with oral atenolol administered within 24 hours, intravenous atenolol
was associated with a significantly higher incidence of congestive
HF (14.3% vs 10.7%; P < 0.01), cardiogenic shock (3.3% vs 2.2%;
P < 0.01), recurrent ischemia (22.1% vs 18.9%; P < 0.01), and need
for pacing (6% vs 4%; P < 0.01). Because this was an observational
study, it is limited by the fact that patients were not randomized with
respect to atenolol treatment, but rather reperfusion treatment.
Summary
The 1990s included the first trials evaluating the usefulness
of β-blockers in the setting of AMI and treatment with reperfusion
therapy. The TIMI II-B and GUSTO-I trials both evaluated timing
of β-blocker administration in the setting of thrombolytic therapy in
addition to aspirin. There was no difference in mortality observed
among those treated with metoprolol immediately after presenta-
tion or on day 6 in TIMI II-B. In the GUSTO-I, the use of atenolol
decreased the risk of cardiovascular events, but immediate intrave-
nous β-blockade was associated with an increased risk of harm com-
pared with oral atenolol therapy. The timing and dosing of initiation
of β-blocker were therefore further explored.
THE 2000s: ADDITIONAL TRIALS OF β-BLOCKERS
WITH THROMBOLYSIS
The Carvedilol Post-Infarct Survival Control in Left-ventricu-
lar Dysfunction (CAPRICORN) trial was a prospective, multicenter,
randomized, placebo-controlled, double-blind trial evaluating the use
of carvedilol in patients with LV dysfunction with or without signs
of HF following MI.31 A total of 1959 patients were enrolled and
followed for a mean of 1.3 years. Three to 21 days after infarction,
patients were started on carvedilol 6.25 mg twice daily or placebo,
and the dose was titrated over 4–6 weeks to a goal of 25 mg twice
daily. Background therapy with an angiotensin-converting enzyme
inhibitor (ACEi) was required. Notable exclusion criteria were unsta-
ble angina, indication for β-blocker therapy, and insulin-dependent
diabetes. The average age was 63 years, 75% were male, and the
average EF was 32.8%. At baseline, 86% were receiving aspirin
therapy, 97% were receiving an ACEi, 33% were receiving intrave-
nous diuretic therapy, and 46% underwent reperfusion predominately
using thrombolytic therapies. Treatment discontinuation was simi-
lar between those receiving carvedilol and placebo (20% vs 18%,
respectively). The maximum dose was achieved by 74% of those in
the carvedilol group. There was no difference in primary endpoint of
composite all-cause mortality or hospital admission due to cardiovas-
cular causes between those receiving carvedilol or placebo (35% vs
37%; hazard ratio [HR] 0.92 [95% CI, 0.80–1.07]; P = 0.296). There
was, however, a reduction in the risk of all-cause mortality among
those who received carvedilol (12% vs 15%; HR, 0.77 [95% CI,
0.6–0.98]; P = 0.031). This difference appeared to be most apparent
after 6 months of therapy. The use of carvedilol was also associated
with reductions in the risk of cardiovascular death and nonfatal MI.
© 2018 Wolters Kluwer Health, Inc. All rights reserved. www.cardiologyinreview.com | 163
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
The Clopidogrel and Metoprolol in Myocardial Infarction
Trial (COMMIT)/Second Chinese Cardiac Study was a prospective,
multicenter, randomized, placebo-controlled trial that evaluated the
addition of early metoprolol to standard therapy in those presenting
within 24 hours of an acute MI.32 This study utilized a 2 × 2 factorial
design and also evaluated the use of clopidogrel in addition to aspirin
in those with a suspected AMI. A total of 45,852 patients were ran-
domized to receive placebo or a combination of intravenous and oral
metoprolol. Those randomized to the metoprolol group received 5 mg
intravenously, for up to 3 doses, depending on their hemodynamics,
followed by metoprolol tartrate 50 mg every 6 hours for the first day
and then metoprolol succinate 200 mg daily thereafter. Therapy was
continued until 28 days, death, or hospital discharge, whichever
occurred first. Key exclusion criteria included primary percutaneous
coronary intervention (PCI), hypotension, bradycardia, heart block,
and cardiogenic shock. Moderate HF of Killip class II or III was not
an exclusion, unlike many previous trials. The average age was 61
years; 72% of the patients were male, and over 50% of the patients
received thrombolytic agents. The majority of patients received anti-
coagulation therapy; 68.2% received an ACEi, and 11.8% received a
calcium channel blocker. An average of 10.3 hours elapsed between
the onset of symptoms and randomization, and mean treatment dura-
tion was 15 days. Of those allocated to metoprolol, 90% received all
3 intravenous doses, and 86.2% received the scheduled oral treat-
ment. Of those who completed the oral regimen, 1.9% required a per-
manent dose reduction. Reinfarction (2.0% vs 2.5%; OR, 0.82 [95%
CI, 0.72–0.92]; P = 0·001) and ventricular fibrillation (2.5% vs 3.0%;
OR, 0.83 [95% CI, 0.75–0.93]; P = 0·001) occurred less frequently
in the metoprolol group. However, there was no difference in the
composite primary outcome (death, reinfarction, or cardiac arrest;
OR, 0.96 [95% CI, 0.90–1.01; P = 0.10) or the co-primary outcome
of death (OR, 0.99 [95% CI, 0.92–1.05]; P = 0.69) between the 2
groups. Significantly more patients in the metoprolol arm developed
cardiogenic shock (5.0% vs 3.9%; OR, 1.30 [95% CI, 1.19–1.41]; P
< 0·0001), which predominately occurred on days 0–1. In particular,
patients identified as being at high risk of developing shock, such as
those with Killip class III HF (absolute increase of 56.9 [standard
error (SE), 14.4] deaths per 1000), systolic blood pressure < 120 mm
Hg (absolute increase of 23.3 [SE, 4.0] deaths per 1000), or heart
rate > 110 bpm at presentation (absolute increase of 34.6 [SE, 11.5]
deaths per 1000), experienced a notable net hazard.
Summary
The CAPRICORN trial demonstrated a clear benefit of
β-blockade in those with concurrent MI and LV dysfunction. It
is important to note that the β-blocker was not started until 3–21
days after infarction, titrated slowly (eg, every 2 weeks), and that
all patients in this trial were on an ACEi. In COMMIT, early intra-
venous metoprolol did not result in a difference in mortality com-
pared with placebo. Patients at higher risk of developing cardiogenic
shock experienced greater mortality, implying that β-blocker initia-
tion should be reserved for hemodynamically stable patients. These
findings are similar to findings in GUSTO-1, which suggested that
a delay in β-blocker therapy may be optimal. It is also important
to recognize that the majority of patients who received reperfusion
therapy in CAPRICORN and COMMIT included few patients who
underwent PCI, as thrombolysis was the preferred and most readily
accessible treatment at the time.
THE 2010s: β-BLOCKER USE IN PATIENTS
UNDERGOING PCI
The Effect of Metoprolol in Cardioprotection During an
Acute Myocardial Infarction (METOCARD-CNIC) trial was a pro-
spective, multicenter, randomized, controlled, single-blinded trial
Kukin et al Cardiology in Review  •  Volume 26, Number 3, May/June 2018
that evaluated the effect of metoprolol, administered before PCI, on
infarct size in patients with an anterior ST elevation MI (STEMI) and
Killip class II or less symptoms.33 A total of 270 patients undergoing
PCI within 6 hours of symptom onset were enrolled and followed
for an average of 2 years. Patients randomized to prereperfusion
β-blockade received up to 3 doses of 5 mg intravenous metopro-
lol during transfer to the PCI center. All patients except those who
developed contraindications received oral metoprolol within 12–24
hours of infarction. The control group did not receive a placebo.
Cardiac magnetic resonance (CMR) imaging was scheduled for 5–7
days after the index event to evaluate infarct size. Exclusion criteria
included systolic blood pressure < 120 mm Hg, type II–III atrioven-
tricular block, heart rate < 60 beats/min, prior infarction, or active
treatment with β-blockers. The average age was 58 years, and 86%
were male. Over 95% received heparin, aspirin, and a thienopyridine
at the time of PCI. Grade 2–3 TIMI flow was achieved in 93.7% after
PCI. Patients randomized to prereperfusion β-blockade received
metoprolol a median of 10 minutes after STEMI diagnosis, and 67%
of these patients received all 3 boluses. All patients received meto-
prolol tartrate within 12–24 hours after the MI, unless a contraindica-
tion to use developed, mean infarct size, the primary end point, was
smaller in the group treated with intravenous metoprolol a week after
infarction (25.6 g vs 32.0 g; adjusted treatment effect ˗6.52 [95%
CI, ˗11.39 to ˗1.78]; P = 0.012). There was a statistically significant
increase in mean left ventricular ejection fraction (LVEF) 1 week
after STEMI, in those who received intravenous metoprolol (46.1%
vs 43.4%; adjusted treatment effect, 2.67 [95% CI, 0.09–5.21;
P = 0.045). There was no difference in the rate of major cardiovascu-
lar adverse events (composite of death, malignant ventricular arrhyth-
mia, cardiogenic shock, atrioventricular block, and reinfarction) at
24 hours between groups (7.1% metoprolol group vs 12.3% control);
however, this study was not designed to determine a difference in
clinical outcomes. Six months after enrollment, there was a statisti-
cally significant higher mean LVEF in the metoprolol arm (48.7%
vs 45.0%; adjusted treatment effect, 3.49 [95% CI, 0.44–6.55];
P = 0.025) and a significantly lower occurrence of severely depressed
LVEF of ≤ 35% (11% vs 27%; P = 0.006).34 Because this study was
not developed to show effects on clinical endpoints, its application to
clinical practice is limited.
The Outcomes of Beta-blocker Therapy After Myocardial
Infarction (OBTAIN) study was an observational multicenter regis-
try that analyzed the effect of β-blocker dose on survival post-MI.35
The authors’ hypothesis was that higher β-blocker dose would be
associated with improved survival. The primary endpoint was the dif-
ference in time to all-cause death right-censored at 2 years. Doses
were categorized as no β-blocker, > 0% to 12.5%, > 12.5% to 25%,
> 25% to 50%, and > 50% of the target dose. Target doses were defined
as atenolol 100 mg/day, bisoprolol 10 mg/day, carvedilol immediate
release 50 mg/day or carvedilol controlled release 80 mg/day, meto-
prolol 200 mg/day, propranolol 180 mg/day, and timolol 20 mg/day.
Data were collected from a registry of patients admitted with an acute
MI. A total of 6682 patients who were discharged from the hospi-
tal post-MI, with a median follow-up of 2.1 years, were included in
the analysis. The average age of patients studied was 64 years, and
approximately 65% of the patients were male. The majority of patients
presented with a non-STEMI. Upon discharge, 91.5% were receiving
a β-blocker; the most commonly prescribed agent was metoprolol fol-
lowed by carvedilol. The average length of stay was 5 days, and 13.4%
of patients were discharged on > 50% of the target dose β-blocker
dose. The mean administered dose was 38.1% of the target. The tim-
ing of β-blocker initiation relative to MI symptoms was not reported.
The use of aspirin, clopidogrel, or the combination of the 2 was simi-
lar between groups. Discharge prescriptions for an ACEi or angioten-
sin II receptor blocker and 3-hydroxy-3-methyl-glutaryl-co-enzyme
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Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
A reductase inhibitors were higher in those discharged on a
β-blocker. Numerous multivariable analyses, which incorporated
adjustments for differences in baseline characteristics among dose
groups, revealed no significant association between higher doses and
increased survival (HR, 0.889 [95% CI, 0.754–1.048]; P = 0.16).
A subgroup analysis determined that patients who underwent revas-
cularization conferred more benefit from lower doses than doses >
50% of the target dose (HR, 0.649 [95% CI, 0.472–0.891], 0.546
[95% CI, 0.403–0.740], and 0.768 [95% CI, 0.563–1.048]; P = 0.037
for the > 0% to 12.5%, > 12.5% to 25%, and > 25% to 50% doses,
respectively). No differences in benefit were observed among differ-
ent doses in nonrevascularized patients. Subgroup analyses found no
interaction with the effect of β-blocker dose and survival on the basis
of β-blocker agent (metoprolol vs carvedilol), type of MI (STEMI vs
non-STEMI), or LVEF (> vs < 40%).
The Early Beta-blocker Administration before Primary
PCI in Patients with ST-elevation Myocardial Infarction (EARLY-
BAMI) trial was a prospective, international, multicenter, random-
ized, placebo-controlled, double-blind trial that studied the role of
intravenous β-blockade before PCI in 683 patients presenting with
a STEMI.36 The primary objective of the study was 30-day infarct
size evaluated through CMR. Patients presenting within 12 hours of
symptom onset were randomized to intravenous metoprolol or pla-
cebo. Of note, the results of METOCARD-CINC were not available
at the time this study was designed. Patients in the metoprolol group
received 5 mg of intravenous metoprolol during ambulance transit
and another 5 mg immediately before PCI initiation in the catheter-
ization laboratory. A 10 mg dose was selected due to the increased
risk of cardiogenic shock observed in the COMMIT trial with 15 mg
of intravenous metoprolol. All participants were to receive oral meto-
prolol, at a dose recommended by their physician, 12 hours post-
PCI and upon discharge. Participants also received unfractionated
heparin, aspirin, and clopidogrel or ticagrelor. Key exclusion criteria
included, but were not limited to, Killip class III and IV, systolic BP
< 100 mm Hg, heart rate < 60 beats per minute, type II and III atrio-
ventricular block, previous MI, and asthma. Baseline characteristics
were similar between groups with the exception of more patients in
the placebo group undergoing coronary artery bypass graft surgery
(7% vs 3.6%; P = 0.049) and a lower heart rate in the metoprolol
group (74.35 ± 13.71 vs 78.68 ± 15.69; P < 0.001). The average age
was 62.4 years, and 74.8% of the patients were male. One-half of the
patients presented with an anterior MI. At baseline, 18.8% of partici-
pants were on a β-blocker, and 73% were discharged on a β-blocker.
Mean time from onset of symptoms to first medical contact was
similar between the 2 groups (135.5 minutes vs 147.8 minutes;
P = 0.880). Of the patients randomized to intravenous metoprolol,
81.1% received the 10 mg target dose. CMR was performed in 66%
of those enrolled. No differences were noted in mean (± SD) infarct
size (15.3 ± 11% vs 14.9 ± 11.5%; P = 0.616) or LVEF (51.0 ± 10.9%
vs 51.7 ± 10.8%; P = 0.683) between those receiving metoprolol or
placebo, respectively. There was no difference in the rate of major
adverse cardiac events (ie, cardiac death, nonfatal reinfarction, or
target vessel revascularization) at 30 days between the metoprolol
(6.2%) and placebo groups (6.9%; P = 0.72). Subgroup analyses
were performed based on the location of infarct, time to presenta-
tion, and the presence of an occluded vessel, but these were not deter-
mined to affect infarct size. This study was limited by the larger than
anticipated dropout rate of 34% before CMR imaging. Patients who
died before undergoing CMR could have led to a selection bias of
patients with smaller infarcts.
Huang et al37 conducted a meta-analysis to evaluate the role
of β-blockers in patients post-MI who underwent PCI. Data from 10
observational studies and from over 40,000 patients were included.
The duration of follow-up varied between studies and ranged from
Cardiology in Review  •  Volume 26, Number 3, May/June 2018 β-Blocker Use and Outcomes in ACS
0.5 to 4 years. Of the studies that reported which agent was used,
carvedilol was the most commonly prescribed. β-Blocker use was
associated with a significant reduction in all-cause death (unadjusted
relative risk, 0.58, 95% CI, 0.48–0.71; adjusted HR, 0.76, 95% CI,
0.62–0.94). This benefit was only observed in those with a reduced
EF, with low rates of other secondary prevention drugs (eg, ACEIs/
angiotensin II receptor blockers and antiplatelet therapy), or pre-
sentation with non-STEMI. Authors concluded that the diminished
effect of β-blockers in the general MI population may be due to
advancement in other treatment options.
Summary
During this decade, many trials investigated the role of
early intravenous β-blockade in patients undergoing PCI.33,36,38 The
METOCARD-CNIC and EARLY-BAMI trials both randomized
STEMI patients to intravenous metoprolol or control group before
PCI, but found conflicting outcomes.33,36 Variations between the 2 tri-
als should be considered. A lower intravenous metoprolol dose was
administered in EARLY-BAMI, and patients were permitted to be on
β-blocker therapy before enrollment. On the contrary, prior β-blocker
use was not permitted in METOCARD-CNIC. METOCARD-CNIC
also only included those with anterior wall MI, and thus, many of
these patients had a larger infarct size. METOCARD-CNIC was not
double-blinded or placebo-controlled and had a relatively small sam-
ple size (n = 270), but EARLY-BAMI utilized a double-blinded, pla-
cebo-controlled design and studied over twice as many patients. It is
imperative to note that METOCARD-CNIC did not include patients
with Killip Class III to IV, so the results of this trial should not be
extrapolated to this population, especially considering the net hazard
experienced by patients with Killip Class III in the early metoprolol
group of COMMIT.
The trials in the 2010s are among the most recent trials evalu-
ating β-blockers in ACS and include standard medical therapies such
as ACEi, statins, and P2Y12 inhibitors. Unfortunately, the data are
limited by study design, which was aimed at determining changes in
infarct size rather than patient outcomes.
THROUGH THE DECADES: WHERE WE’VE COME
FROM AND WHERE WE ARE TODAY
Context is vitally important in any science to accurately inter-
pret and apply clinical data. Contextualizing β-blocker therapy for
the treatment of ACS is no exception—in fact, failure to do so can
result in gross misinterpretation and misapplication of β-blockers
in AMI in current medical practice. Although certain patient pop-
ulations undoubtedly benefit from long-term β-blocker therapy
(eg, reduced LV function), others remain in question and require
patient-specific decision making. It is evident from available trial data
that in the setting of hemodynamic instability or cardiogenic shock,
signs of HF, or bradycardia, early β-blocker therapy has consistently
proven to be potentially harmful.3,30,39 On the contrary, patients with
AMI with a reduced EF who do not have signs of HF have a clear
mortality benefit from long-term β-blocker therapy (class I level A
recommendation in current guidelines).3
Although the use of β-blockers in ACS is uniformly recog-
nized and accepted as a standard of care, the benefits of β-blockers
in the current era of ACS management remain in question in patients
without LV dysfunction or ventricular arrhythmias. Large, random-
ized, placebo-controlled trials, such as COMMIT, TIMI-IIB, and
GUSTO-I, which showed benefit with β-blockers in the reperfusion
era, included few patients who received PCI, which has been shown
to reduce infarct size and blunt the sympathetic response more so
than thrombolytic therapy, subsequently reducing the incidence of
catecholamine-mediated adverse effects.40 In addition, many of the
β-blocker trials that we base current recommendations on were
© 2018 Wolters Kluwer Health, Inc. All rights reserved. www.cardiologyinreview.com | 165
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
conducted before the widespread implementation of high potency
statins and P2Y12 inhibitors. High intensity statins, which have been
shown to reduce cardiovascular mortality, recurrent MI, and stroke
in patients with an ACS, may also reduce rates of sudden cardiac
death.41,42 Third generation P2Y12 inhibitors (ie, ticagrelor and pra-
sugrel) seem to reduce infarct size and microvascular obstruction
more than clopidogrel.43 One can only assume that as medical thera-
pies continue to advance (eg, proprotein convertase subtilisin/kexin
type 9 [PCSK9] inhibitors, anti-inflammatory therapies, etc.), similar
trends may be observed. Taken altogether, the beneficial effects of
β-blockers in ACS may be blunted in the context of faster, more com-
plete reperfusion strategies and better medical therapies. In support
of this, a meta-analysis of patients with ACS but without LV dysfunc-
tion compared trials in the prereperfusion era and postreperfusion
era, and showed no mortality benefit of β-blockers in the reperfusion
era.44 In addition, a national cohort study of over 160,000 patients
presenting with an AMI between 2007 and 2013 failed to show a dif-
ference in 1-year mortality in patients receiving a β-blocker without
LV dysfunction or HF.45
CONCLUSION
β-blocker use in ACS has evolved considerably throughout the
decades. The role of β-blocker therapy in ACS is to reduce myocardial
oxygen demand and arrhythmias by blunting catecholamine-mediated
adverse effects. Although early trials of β-blockers showed a mortality
benefit, more recent trials have failed to replicate these results.
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