Esmolol in acute ischemic syndromes

Rita G. Mitchell, RN, MSN,a Marcus F. Stoddard, MD,b Ori Ben-Yehuda, MD,c Kul B. Aggarwal, MD,d
Kent S. Allenby, MD,e Raul A. Trillo, MD,e Ruth Loyd, MS,e Cheng-Tao Chang, PhD,e and
Arthur J. Labovitz, MD,a for the EMIT Investigators

Background ␤-Blockers have been shown to reduce both morbidity and mortality rates in patients with acute coro-
nary syndromes. However, because of potential side effects, their use is limited in patients who might benefit the most
from such therapy. It was thought that the use of an ultra-short-acting intravenous ␤-blocker might produce similar results
with fewer complications in those patients with relative contraindications to ␤-blocker therapy.
Methods Accordingly, we evaluated the use of esmolol in patients with acute coronary syndromes and relative con-
traindication to ␤-blocker therapy in a prospective randomized trial. One hundred eight patients at 21 sites received an
infusion of intravenous esmolol or standard therapy on admission and were followed for 6 weeks from the day of admis-
sion. The primary efficacy outcome was a composite event consisting of any of the following that occurred during the in-
dex hospitalization: death, myocardial (re)infarction, recurrent ischemia, or arrhythmia as well as silent myocardial isch-
emia assessed by ambulatory electrocardiographic monitoring. Safety end points including hypotension,
bradyarrhythmias, new or worsening congestive heart failure, and bronchospasm were also recorded.
Results Event rates for primary end points were similar in the 2 groups: death (2% in the standard care group vs 4%
in the group receiving esmolol), myocardial (re)infarction (4% standard vs 7% esmolol), ischemia (12% vs 13%), arrhyth-
mias (4% vs 2%), and silent ischemia (13% vs 15%). There was a higher incidence of transient hypotension in the group
receiving esmolol (2% vs 16%), but all such events were noted to resolve after discontinuation of the esmolol infusion.
There were no additional differences in safety end points: bradycardia (2% for those receiving standard care vs 9% re-
ceiving esmolol), new congestive heart failure (10% vs 16%), bronchospasm (0% vs 7%), and heart block (2% vs 2%).
Conclusions The use of an ultra-short-acting ␤-blocker such as esmolol might offer an alternative to patients with con-
traindications to standard ␤-blocker therapy. Although this trial had limited power to detect safety and efficacy differences
between the 2 therapies, it was observed that safety end points, which occurred during esmolol administration, resolved
readily when the infusions were decreased or discontinued. Additional testing is needed to substantiate these findings.
(Am Heart J 2002;144:e9.)

The use of intravenous ␤-blockers in the acute
phases of myocardial infarction and unstable angina
has been shown to reduce in-hospital morbidity and
mortality rates.1-7 Despite the demonstrated efficacy of
intravenous ␤-blockers, their use has been observed to
be limited in patients with acute myocardial infarction
and unstable angina.5,8 The limited use of intravenous
␤-blockers in patients with acute ischemic syndromes
appears to be largely attributable to preexisting rela-
tive or absolute contraindications. In addition, be-
tween 5% and 10% of patients who are “␤-blocker eli-
From the aSt Louis University Health Sciences Center, St Louis, Mo, bUniversity of Louis-
ville, Louisville, Ky, cUniversity of California, San Diego, San Diego, Calif, dUniversity
of Missouri, Columbia, Mo, and eBaxter Pharmaceutical Products Inc, New Provi-
dence, NJ.
Submitted April 9, 2001; accepted February 27, 2002.
Reprint requests: Arthur J. Labovitz, MD, Saint Louis University Health Sciences Center,
3635 Vista at Grand Ave, St Louis, MO 63110-1250.
E-mail: labovitz@slu.edu
Copyright 2002, Mosby, Inc. All rights reserved.
1097-6744/2002/$35.00 ⫹ 0 4/90/126114
doi:10.1067/mhj.2002.126114
gible” have side effects such as hypotension or
bradycardia during initiation of therapy, necessitating
premature discontinuation of ␤-blocker treatment.3,4,9
The availability of an intravenous ultra-short-acting
␤-blocker, esmolol, may alleviate clinical concerns re-
garding the potential to precipitate and sustain
␤-blocker-associated adverse side effects.
The use of intravenous esmolol in acute ischemic
syndromes has been limited by studies of small sample
sizes.10-17 These preliminary studies, however, have
demonstrated that intravenous esmolol is associated
with infarct size reduction in an animal model10 and is
well tolerated in patients with acute ischemic syn-
dromes11,12 and left ventricular systolic dysfunc-
tion.13-17 The safety and efficacy of intravenous esmo-
lol compared with standard long-acting intravenous
␤-blockers has not been evaluated in randomized trials.
The Multicenter Study of Expanded Utilization of
Intravenous Beta-Blocker Therapy in Acute Ischemic
Syndromes: The Esmolol Myocardial Ischemia Trial
(EMIT) was a randomized study designed to assess the

108 Mitchell et al
safety, tolerability, and clinical efficacy of the addition
of intravenous esmolol to “standard care” therapy as
compared with “standard care” therapy alone, which
did not include intravenous ␤-blockers, among patients
with acute transmural myocardial infarct and/or unsta-
ble angina/non-Q-wave myocardial infarction with rela-
tive contraindications to ␤-blocker therapy.
Methods
Participating sites and investigators
Patients were enrolled at 21 sites in the United States. Full
institutional review board approval was obtained at each in-
stitution before patient enrollment. Saint Louis University was
the Clinical Coordinating Center. Electrocardiograms and am-
bulatory electrocardiograms were analyzed at the core labs at
the Clinical Coordinating Center.
Patient selection, recruitment, and random
assignment
Patients who were examined at the hospital within 12
hours of chest pain, who met criteria for acute transmural
myocardial infarction (ie, ST-segment elevation) or unstable
angina/non-Q-wave myocardial infarction (ie, non-ST-segment
elevation), were considered for enrollment in the study.
Acute transmural myocardial infarction was defined as angina-
type chest discomfort of ⬎20 minutes duration, unresponsive
to sublingual nitroglycerin and/or nitroglycerin spray therapy,
and new or presumably new ST-segment elevation of ⬎10
mm in at least 2 of the 3 inferior leads (II, III, aVF), in at
least 2 contiguous precordial leads (V1-V6), or in leads I and
aVL. Unstable angina/non-Q-wave myocardial infarction was
defined as symptoms of cardiac ischemia (angina or anginal
equivalent) lasting at least 5 minutes, unrelieved by sublin-
gual nitroglycerin and/or nitroglycerin spray therapy, and ei-
ther positive creatine kinase (CK), CK-MB enzymes, or con-
comitant electrocardiographic changes: ST-segment
depression (⬎0.5 mm), T-wave inversion of ⱖ1 mm, or tran-
sient (⬍20 minutes) ST-segment elevation. At least 1 relative
contraindication to ␤-blockade was necessary for the patient
to be enrolled. Relative contraindications included docu-
mented left ventricular dysfunction, mild congestive heart
failure, history of bronchospastic airway disease (without
acute bronchospasm), prolonged electrocardiographic PR
interval (⬎0.25 seconds and ⬍0.30 seconds), controlled, in-
sulin-requiring diabetes mellitus, hypotension (systolic blood
pressure ⱖ100 mm Hg but 108 mm Hg), bradycardia (heart
rate ⱖ55 but 68 beats/min), and concomitant use of AV
node-blocking calcium-channel blockers (ie, diltiazem, vera-
pamil). All patients gave written voluntary informed consent
before random assignment in the study.
Patients were excluded from the study for severe bradycar-
dia (heart rate ⬍55 beats/min), hypotension (systolic blood
pressure ⬍100 mm Hg unresponsive to fluids), prolonged
electrocardiographic PR segment (ⱖ0.30 seconds), second-
or third-degree AV block or junctional rhythm, acute bron-
chospastic episode, severe congestive heart failure, history of
uncontrolled diabetes, and pregnancy. Because of the diffi-
culty in interpreting Holter recordings, patients with atrial
American Heart Journal
November 2002
fibrillation/flutter, bundle branch block, preexcitation syn-
drome (ie, Wolff-Parkinson-White syndrome), and permanent
ventricular pacemakers were also excluded. Also excluded
were patients for whom surgical revascularization (coronary
artery bypass grafting) was planned at the time of screening.
Patients with known or suspected drug or alcohol abuse
were not included because of the potential for problems
with patient follow-up. Patients with serious advanced illness
were not studied. Patients who had received ␤-blockers
within 24 hours of screening were not included to prevent
contamination of results from previous ␤-blocker use. Be-
cause of a previously identified interaction between intrave-
nous calcium-channel blockers and esmolol, patients who
had received intravenous calcium-channel blockers within 48
hours of screening were not considered for participation.
Eligible subjects were randomly assigned by means of a
telephone, computer-driven response system on a 24-hour
“on-demand” basis. This telephone system ensured proper
sequence allocation and immediate coordinating center con-
firmation of enrollment and provided security against poten-
tial randomization bias. Random assignment was stratified by
the type of presenting acute ischemic syndrome (ie, acute
transmural myocardial infarction or unstable angina/non-Q-
wave myocardial infarction as determined by the screening
electrocardiogram). On the basis of the telephone random
assignment, consented patients were randomly assigned to 1
of 2 treatment groups: (1) intravenous esmolol for 16 to 30
hours plus “standard medical therapy,” followed by oral
metoprolol, or (2) “standard therapy” alone, which did not
include planned intravenous ␤-blockers.
Study procedures
Patients were observed for a period of 30 minutes before
random assignment. During this period, a limited physical
examination, pretrial medication history, chest radiograph,
and screening electrocardiogram were obtained. A rate-pres-
sure product (RPP) was calculated (systolic blood pressure ⫻
heart rate) by use of readings obtained during the baseline
period. At the investigator’s clinical discretion, standard med-
ical therapies for patients with acute coronary ischemia were
initiated for all patients during this time. This included
thrombolytic therapy, intravenous heparin, aspirin, nitrates,
and narcotics. Among patients not previously taking calcium-
channel blockers, the use of short-acting dihydropyridine
agents were discouraged. For patients previously receiving
calcium-channel blockers, it was suggested that attempts be
made to discontinue their use at the discretion of the individ-
ual investigator. Oral calcium-channel blockers were allowed
in patients with refractory angina as clinically indicated. In
addition, oral AV node-blocking calcium-channel blockers (ie,
diltiazem or verapamil) could be used in the “standard care
only” group if they were believed to be necessary by the in-
vestigator to slow heart rate response. The use of intrave-
nous calcium-channel blockers was prohibited in patients
receiving esmolol. If the investigator deemed it necessary to
use intravenous calcium-channel blockers, a washout period
of no less than 60 minutes was required between the discon-
tinuation of esmolol and the initiation of intravenous calcium-
channel blockers.
After random assignment, patients in the treatment arm of
the study were given a bolus dose of 500 ␮g/kg intravenous
American Heart Journal
Volume 144, Number 5
esmolol administered slowly over 1 minute. This was immedi-
ately followed by a maintenance infusion of 50 ␮g/kg/min,
with titration in increments of 50 ␮g/kg/min every 5 to 15
minutes. Measurement of heart rate and blood pressure,
along with chest auscultation, were done before each titra-
tion of esmolol. This regimen was followed until one of the
following conditions was met: (1) the attainment of a target
RPP decrement of 30% from baseline, (2) a peak dose of 300
␮g/kg/min drug administration, or (3) development of a
safety end point. A 30% decrement in RPP has historically
been used to indicate an appropriate reduction in heart rate
and blood pressure. A safety end point was considered to
have been met if the subject had new congestive heart fail-
ure (evidenced by new rales greater than one third of poste-
rior lung fields, new third heart sound, or new radiographic
evidence of pulmonary edema), second- or third-degree heart
block, bronchospastic episode, systolic blood pressure ⬍90
mm Hg unresponsive to fluids, or severe bradycardia ⬍50
beats/min. Intravenous esmolol dosage was decrementally
adjusted to one-half the current dose if a safety end point
was met. If symptoms persisted for ⬎30 minutes, the intrave-
nous esmolol infusion was discontinued. If symptoms re-
solved within 30 minutes, attempts were made to increase
the esmolol infusion rate to a previously tolerated dose. The
protocol infusion of intravenous esmolol was maintained for
a period of 16 to 30 hours after initiation of therapy. Blood
pressure, heart rate, and chest auscultation were performed
throughout the maintenance infusion.
If the esmolol infusion did not require protocol-mandated
drug discontinuation; 12.5 to 25 mg of oral metoprolol was
administered 30 minutes before discontinuation of the intra-
venous esmolol infusion. Metoprolol was titrated as clinically
tolerated up to a dose of 100 mg a day for a minimum of 6
weeks.
Patients randomly assigned to the control arm of the study
were treated with standard therapies that did not include
intravenous ␤-blockers. Routine use of oral ␤-blockers during
the study period was strongly discouraged but left to the dis-
cretion of the individual investigator in the event of recur-
rent ischemia unresponsive to other medical therapies. Oral
␤-blockers were prohibited during the first 24 hours of the
study while data on silent ischemia were being collected by
the Holter monitor. Patients assigned to the standard care
group were assessed every 15 minutes during the administra-
tion and titration of the standard care medications until
symptom resolution or development of a safety end point.
Electrocardiograms were obtained at screening and during
the baseline observation period and repeated at 12 hours, 24
hours, 3 days, and on the day of discharge. A Holter monitor
was applied to the patient immediately after random assign-
ment and before initiation of esmolol infusion (if applicable).
Holter monitoring continued for a total of 24 hours from the
time the Holter was applied. Electrocardiograms and Holter
tapes were forwarded to the core laboratories for indepen-
dent, blinded assessment by cardiologists. Serial cardiac en-
zymes (total CK, CK-MB) were obtained at baseline/study en-
try and 8 and 16 hours after the baseline sample was
obtained.
Serial enzymes and electrocardiograms were collected in
the event of clinically suspected myocardial ischemia or re-
current ischemic chest pain and/or myocardial (re)infarction
Mitchell et al 109
manifested by pain of ⱖ20 minutes duration or ⱖ2 recurrent
episodes occurring within a 30-minute period. To define pro-
cedure-related myocardial infarctions, serial enzymes and
electrocardiograms were also collected for all patients under-
going percutaneous or surgical coronary revascularization
procedures.
End points
The primary efficacy outcome was a composite event con-
sisting of any of the following that occur during the index
hospitalization: (1) death, (2) nonfatal myocardial (re)infarc-
tion, (3)recurrent ischemia, (4) nonfatal cardiac arrest, (5)
nonfatal ventricular tachycardia or fibrillation, or (6) silent
myocardial ischemia episodes assessed by ambulatory electro-
cardiographic monitoring in the 24 hours after random as-
signment. Myocardial ischemic episodes on ambulatory elec-
trocardiographic monitoring were defined according to the
initial randomization group. For patients admitted with ST-
segment elevation, a recurrent myocardial ischemic event
was defined as new ST-segment elevation of ⱖ1 mm or new
ST-segment depression of ⱖ1 mm, after return to ST-segment
“isoelectric” point and lasting ⱖ1 minute in duration, with or
without concomitant ischemic chest pain. Patients enrolled
with ST-segment depression were noted to have recurrent
myocardial ischemia if they had new ST-segment depression
or elevation ⱖ1 mm after the return of the ST segment to
isoelectric baseline and lasting ⱖ1 mm in duration with or
without concomitant ischemic chest pain.
Secondary end points were assessed during a follow-up
phone call 6 weeks after random assignment. The points
evaluated were death, myocardial infarction, rehospitalization
for cardiac causes, and classification of anginal status and
congestive heart failure status as defined by the New York
Heart Association (NYHA) functional capacity classification.
Statistical analysis
The primary efficacy outcome was predefined in the proto-
col as a composite event consisting of the occurrence of (1)
death, (2) nonfatal infarction or reinfarction, (3) recurrent
ischemia, (4) nonfatal cardiac arrest, (5) nonfatal ventricular
tachycardia or fibrillation, or (6) silent myocardial ischemia
defined by ambulatory electrocardiographic monitoring be-
fore hospital discharge. The main analysis of this outcome
was planned to compare its frequency in the esmolol and
control groups by use of a ␹2 test. The frequency of each
component was also to be compared between groups, with
an adjustment for multiple comparisons to maintain the over-
all ␣-level for these tests at 0.05.
At the 6-week follow-up contact, data were collected on
the occurrence of (1) death, (2) myocardial infarction or rein-
farction, (3) hospitalization for cardiac causes, (4) anginal
status defined by the NYHA functional capacity classification,
and (5) functional capacity defined by NYHA classification.
The frequency of these events between esmolol and control
groups was to be compared by use of the log rank test and
Kaplan-Meier estimates of distribution of time to events.
The primary safety outcome was a predefined composite
event consisting of occurrence and persistence of any of the
following for ⬎30 minutes in the standard care group or for
⬎30 minutes after a reduction of the esmolol dose or after
 American Heart Journal
110 Mitchell et al
November 2002

initial observation in the esmolol group: (1) development of

Table I. Baseline clinical and demographic characteristics of
new congestive heart failure (new rales greater than one
the study group
third of posterior lung fields, new third heart sound, or new
radiographic evidence of pulmonary edema), (2) advanced Esmolol Standard
second- or third-degree heart block, (3) occurrence of new Variable (n ⴝ 55) (n ⴝ 53)
bronchospastic episode, (4) systolic blood pressure ⬍90 mm
Hg unresponsive to volume replacement, or (5) severe brady- Male (%) 26 40
cardia (⬍50 beats/min). One-tailed tests at an overall ␣ level Race
of 0.05 were used. White 35 35
The sample size was planned to be 250 patients per treat- Black 18 11
Other 2 7
ment group, which, with a primary efficacy outcome of
Age (y) 58.1 (31.7-88.3) 60.4 (35.0-84.4)
ⱖ0.70 in the control group, would have had a power ⱖ0.9 Heart rate (beats/min) 81.0 (58-125) 78.7 (56-109)
to detect a 20% reduction of this outcome in the esmolol Systolic blood pressure (mm Hg) 128.1 (95-200) 130.7 (97-197)
group, with an ␣-level of ⬍0.05. Relative contraindication
Because of patient recruitment problems, the study was Left ventricular dysfunction 12 14
terminated after 109 patients were enrolled. Therefore, the Mild CHF 18 15
results from this study were considered exploratory, not con- Bronchospastic disease 20 11
firmatory. Because of the small sample size, the planned anal- Prolonged PR interval 1 0
yses were not performed. Instead, the Fisher exact procedure IDDM 9 11
Hypotension 14 15
was used on each efficacy outcome individually as well as on
Bradycardia 17 19
the composite outcome as a whole, with no adjustment for
Calcium-channel blockers 12 9
the ␣-level. For the 6-week follow-up efficacy data, the Fisher ECG criteria
exact procedure was used on cardiac hospitalization for car- ST elevation (%) 23 21
diac causes and the composite end point, and the ␹2 proce- non-ST elevation 32 32
dure was used for anginal status. No probability value was
calculated for the other 2 end points at 6-week follow-up CHF, Congestive heart failure; IDDM, insulin-dependent diabetes mellitus; ECG,
electrocardiogram.
(death and myocardial infarction or reinfarction) because
there was no occurrence in either treatment group.

Table II. Summary of study end points

Results
The analysis was performed on an intention-to-treat Esmolol Standard
(n ⴝ 55) (n ⴝ 52) P
basis (ie, 2 patients who were randomly assigned to
but did not receive esmolol were analyzed as part of
In-hospital end points (%)
the esmolol treatment group). One hundred eight ran- Death 2 (3.64) 1 (1.92) 1.000
domly assigned patients were enrolled between Sep- Nonfatal reinfarction 4 (7.27) 2 (3.85) .679
tember 1997 and February 1999. Sixty-six men and 42 Recurrent ischemia 7 (12.73) 6 (11.54) 1.000
women, with a mean age of 59.2 years, were evalu- Nonfatal cardiac arrest 0 (0.00) 0 (0.00) N/A
Nonfatal V Tach or fibrillation 1 (1.82) 2 (3.85) .611
ated. Fifty-five patients were randomly assigned to re- Silent myocardial ischemic episode 8 (14.81) 7 (13.46) 1.000
ceive intravenous esmolol with standard care, and 53 Composite end points 17 (30.91) 14 (26.92) .676
received standard care. Table I summarizes the base- 6-week end point (post index
line clinical and demographic characteristics of the 2 hospitalization) (%) n ⫽ 55 n ⫽ 53
study groups. Death 0 (0.00) 0 (0.00) N/A
Myocardial infarction 0 (0.00) 0 (0.00) N/A
The treatment arms were well matched with respect Cardiac rehospitalization 8 (14.55) 5 (9.43) .394
to age, race, and electrocardiographic criteria. Sixty- Anginal status n ⫽ 42 n ⫽ 39 .828
one percent of the men were assigned to the standard Class I 34 (80.95) 34 (87.18)
care arm and the 69% of the women received esmolol. Class II 4 (9.52) 2 (5.13)
Class III 2 (4.76) 2 (5.13)
Relative contraindications to ␤-blockers were similar in
Class IV 2 (4.76) 1 (2.56)
both subsets, with bradycardia, mild congestive heart CHF status n ⫽ 42 n ⫽ 38 .024
failure, and bronchospastic disease being the most fre- Class I 22 (52.38) 29 (76.32)
quent. Class II 11 (26.19) 3 (7.89)
The occurrence of in-hospital events was similar in Class III 5 (11.90) 6 (15.79)
Class IV 4 (9.52) 0 (0.00)
both groups, as demonstrated in Table II. A compari-
son of other indicators showed no significant differ-
ence between the 2 groups. The mean number of
hours in the ICU/CCU was 63.0 for those in the esmo- angioplasties (36% vs 49%), stent placements (32% vs
lol group and 72.4 for those receiving standard care 40%), rotational atherectomies (4% vs 0%), and coro-
alone. The number of cardiac catheterizations (71% in nary artery bypass graft surgeries (18% vs 26%) was
the esmolol group vs 69% in the standard care group), similar for both groups.
American Heart Journal
Volume 144, Number 5
Table III. Safety end points
Esmolol (%) Standard (%)
CHF 7 8
Hypotension 18*
Bronchospasm 9*
AV block 2 2
Bradycardia 9*
AV block, Atrioventricular block.
*Resolved within 30 minutes of discontinuation of infusion
Safety of the ␤-blocker therapy was evaluated by at-
tainment of safety end points (Table III). Nine patients
in the esmolol group met a protocol-specified safety
end point for which the esmolol was discontinued. At
the discretion of the investigator, esmolol was also dis-
continued in 3 patients for other reasons: confusion
and restlessness, an episode of ventricular tachycardia,
and no coronary artery disease identified upon cardiac
catheterization.
Congestive heart failure was noted in similar num-
bers in both groups, as evidenced by new rales greater
than one third of posterior lung fields (7.3% of patients
receiving esmolol vs 5.8% of patients receiving stan-
dard care), new third heart sound (0.0% vs 1.9%), and
new radiographic evidence of pulmonary edema (9.1%
vs 1.9%). Second- or third-degree heart block occurred
in both groups at a rate of 1.8% and 1.9%. A new bron-
chospastic event was observed in 9.1% of the esmolol
treatment group but was not noted in those patients
receiving standard care (P ⫽ .037). Severe bradycardia
(heart rate ⬍50 mm Hg) was noted in 9.1% of the es-
molol ␤-blocker group compared with 1.92% of the
standard care cohort (P ⫽ .206).
In 18.2% of the patients receiving esmolol, an epi-
sode of hypotension (systolic blood pressure ⬍90 mm
Hg unresponsive to volume replacement) was noted
compared with 1.9% of the control group. This differ-
ence was statistically significant (P ⫽ .008). Episodes
of hypotension were reported in 11 patients. Three of
these patients were not taking esmolol at the time of
the hypotension. In 6 of the reported episodes, sys-
tolic blood pressure increased above 90 after discon-
tinuation of esmolol. A hypotensive episode was re-
ported in 1 patient who continued to have chest pain
throughout his hospitalization despite high doses of
intravenous nitroglycerin. This patient, who had dif-
fuse disease and was not a candidate for thrombolytic
agents, was admitted with inferior changes and later
had an anterior extension that ultimately led to his
death.
At the time of the 6-week follow-up, 68.0% of those
patients in the esmolol arm were receiving continuing
treatment with ␤-blockers compared with 46.9% of the
Mitchell et al 111
patients who received standard care. The 2 groups
were similar in the number of readmissions to the hos-
P pital for recurrent cardiac events (18.0% vs 12.0%).
There were no additional deaths or myocardial infarc-
NS tions reported in either group.
2 ⬍.01
0 ⬍.01
NS
2 NS Discussion
␤-Blockers are underutilized after an episode of
acute myocardial ischemia, despite their proven advan-
tages. A retrospective study of 201,752 Medicare pa-
tients showed that only 34% of patients with a diagno-
sis of acute myocardial infarction received ␤-blockers
but demonstrated a 40% lower mortality rate for those
patients who did receive ␤-blockers.8 In the National
Registry of Myocardial Infarction (NRMI), intravenous
␤-blockers were used in 17% of thrombolytic-treated
patients and in 36% of all patients with acute myocar-
dial infarction.5 The major reason for limited use of
intravenous ␤-blockers have included classically de-
fined relative or absolute contraindications. In the
Metoprolol In Acute Myocardial Infarction (MIAMI)
trial, patients screened for enrollment were ineligible
for random assignment because of contraindications to
␤-blockade: heart rate 65 beats/min (20.3%), systolic
blood pressure 105 mm Hg or left ventricular failure
with rales ⬎10 cm (12.1%), and presence of chronic
obstructive lung disease (3.1%).3 In addition, between
5% and 10% of patients who are “␤-blockers eligible”
have side effects such as hypotension or bradycardia
during initiation of therapy, necessitating premature
discontinuation of ␤-blocker treatment.3,4,9
The use of an ultra-short-acting ␤-blocker such as
esmolol would theoretically expand the group of pa-
tients eligible to receive ␤-blocker therapy in acute
ischemic syndromes by limiting any untoward adverse
events. Studies evaluating the use of esmolol in acute
ischemic syndromes have been limited. Early studies
demonstrated reduction in infarct size in an animal
model.10 Esmolol has been shown to be well tolerated
in acute ischemic syndromes in patients with left ven-
tricular dysfunction.13,15,16
Although class effect cannot be assumed, the EMIT
study sought to demonstrate that an ultra-short-acting
␤-blocker could be used safely in this group of pa-
tients. Although this study was not powered to evalu-
ate differences in clinical outcomes, the incidence of
adverse clinical events in the 2 groups was similar.
The incidence of hypotension was greater in the esmo-
lol treatment group but was readily reversible by titra-
tion of the drug.
Conclusions
In patients at risk for complications secondary to the
use of ␤-blockers, an ultra-short-acting ␤-blocker such
as esmolol may offer an alternative. Because of the

112 Mitchell et al
small number of subjects, the study had limited power
to detect important safety and efficacy differences, and
it would be imprudent to make claims regarding the
efficacy of esmolol use in patients with acute myocar-
dial ischemia. The importance of ␤-blocker use in this
population has been well documented. Esmolol was
generally well tolerated in the patient population with
relative contraindications to ␤-blockers and therefore
offers an alternative to those patients who are not can-
didates for standard ␤-blocker therapy. The only statis-
tically significant safety end point was noted to be hy-
potension when compared with patients not receiving
␤-blocker therapy. Additional study is needed in a
larger population to substantiate these findings.
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3. MIAMI Trial Research Group. Patient population. Am J Cardiol
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4. Hjalmarson A, Herlitz J, Malek I. Effect on mortality of metoprolol
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