- Email: [email protected]
Esmolol in acute ischemic syndromes
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 coronary 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 contraindication 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 admission. The primary efficacy outcome was a composite event consisting of any of the following that occurred during the index hospitalization: death, myocardial (re)infarction, recurrent ischemia, or arrhythmia as well as silent myocardial ischemia 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%), arrhythmias (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% receiving 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 contraindications 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 relative or absolute contraindications. In addition, between 5% and 10% of patients who are “-blocker eli-
From the aSt Louis University Health Sciences Center, St Louis, Mo, bUniversity of Louisville, Louisville, Ky, cUniversity of California, San Diego, San Diego, Calif, dUniversity of Missouri, Columbia, Mo, and eBaxter Pharmaceutical Products Inc, New Providence, 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: [email protected] 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 regarding 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 syndromes11,12 and left ventricular systolic dysfunction.13-17 The safety and efficacy of intravenous esmolol 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
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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 unstable angina/non-Q-wave myocardial infarction with relative 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 institution before patient enrollment. Saint Louis University was the Clinical Coordinating Center. Electrocardiograms and ambulatory 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 anginatype 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 sublingual nitroglycerin and/or nitroglycerin spray therapy, and either positive creatine kinase (CK), CK-MB enzymes, or concomitant electrocardiographic changes: ST-segment depression (⬎0.5 mm), T-wave inversion of ⱖ1 mm, or transient (⬍20 minutes) ST-segment elevation. At least 1 relative contraindication to -blockade was necessary for the patient to be enrolled. Relative contraindications included documented 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, insulin-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, verapamil). All patients gave written voluntary informed consent before random assignment in the study. Patients were excluded from the study for severe bradycardia (heart rate ⬍55 beats/min), hypotension (systolic blood pressure ⬍100 mm Hg unresponsive to fluids), prolonged electrocardiographic PR segment (ⱖ0.30 seconds), secondor third-degree AV block or junctional rhythm, acute bronchospastic episode, severe congestive heart failure, history of uncontrolled diabetes, and pregnancy. Because of the difficulty in interpreting Holter recordings, patients with atrial
fibrillation/flutter, bundle branch block, preexcitation syndrome (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. Because of a previously identified interaction between intravenous 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 confirmation of enrollment and provided security against potential randomization bias. Random assignment was stratified by the type of presenting acute ischemic syndrome (ie, acute transmural myocardial infarction or unstable angina/non-Qwave 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-pressure 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 medical 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 calciumchannel 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 individual 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 investigator to slow heart rate response. The use of intravenous 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 discontinuation of esmolol and the initiation of intravenous calciumchannel blockers. After random assignment, patients in the treatment arm of the study were given a bolus dose of 500 g/kg intravenous
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esmolol administered slowly over 1 minute. This was immediately 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 titration 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 failure (evidenced by new rales greater than one third of posterior 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 intravenous esmolol infusion was discontinued. If symptoms resolved 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 intravenous 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 discretion of the individual investigator in the event of recurrent 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 administration 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 assignment 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 independent, blinded assessment by cardiologists. Serial cardiac enzymes (total CK, CK-MB) were obtained at baseline/study entry 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 recurrent ischemic chest pain and/or myocardial (re)infarction
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manifested by pain of ⱖ20 minutes duration or ⱖ2 recurrent episodes occurring within a 30-minute period. To define procedure-related myocardial infarctions, serial enzymes and electrocardiograms were also collected for all patients undergoing percutaneous or surgical coronary revascularization procedures.
End points The primary efficacy outcome was a composite event consisting of any of the following that occur during the index hospitalization: (1) death, (2) nonfatal myocardial (re)infarction, (3)recurrent ischemia, (4) nonfatal cardiac arrest, (5) nonfatal ventricular tachycardia or fibrillation, or (6) silent myocardial ischemia episodes assessed by ambulatory electrocardiographic monitoring in the 24 hours after random assignment. Myocardial ischemic episodes on ambulatory electrocardiographic monitoring were defined according to the initial randomization group. For patients admitted with STsegment 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 protocol 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 before 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 overall ␣-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 reinfarction, (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
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initial observation in the esmolol group: (1) development of new congestive heart failure (new rales greater than one third of posterior lung fields, new third heart sound, or new radiographic evidence of pulmonary edema), (2) advanced second- or third-degree heart block, (3) occurrence of new bronchospastic episode, (4) systolic blood pressure ⬍90 mm Hg unresponsive to volume replacement, or (5) severe bradycardia (⬍50 beats/min). One-tailed tests at an overall ␣ level of 0.05 were used. The sample size was planned to be 250 patients per treatment group, which, with a primary efficacy outcome of ⱖ0.70 in the control group, would have had a power ⱖ0.9 to detect a 20% reduction of this outcome in the esmolol group, with an ␣-level of ⬍0.05. Because of patient recruitment problems, the study was terminated after 109 patients were enrolled. Therefore, the results from this study were considered exploratory, not confirmatory. Because of the small sample size, the planned analyses were not performed. Instead, the Fisher exact procedure was used on each efficacy outcome individually as well as on the composite outcome as a whole, with no adjustment for the ␣-level. For the 6-week follow-up efficacy data, the Fisher exact procedure was used on cardiac hospitalization for cardiac causes and the composite end point, and the 2 procedure was used for anginal status. No probability value was calculated for the other 2 end points at 6-week follow-up (death and myocardial infarction or reinfarction) because there was no occurrence in either treatment group.
Results The analysis was performed on an intention-to-treat basis (ie, 2 patients who were randomly assigned to but did not receive esmolol were analyzed as part of the esmolol treatment group). One hundred eight randomly assigned patients were enrolled between September 1997 and February 1999. Sixty-six men and 42 women, with a mean age of 59.2 years, were evaluated. Fifty-five patients were randomly assigned to receive intravenous esmolol with standard care, and 53 received standard care. Table I summarizes the baseline clinical and demographic characteristics of the 2 study groups. The treatment arms were well matched with respect to age, race, and electrocardiographic criteria. Sixtyone percent of the men were assigned to the standard care arm and the 69% of the women received esmolol. Relative contraindications to -blockers were similar in both subsets, with bradycardia, mild congestive heart failure, and bronchospastic disease being the most frequent. The occurrence of in-hospital events was similar in both groups, as demonstrated in Table II. A comparison of other indicators showed no significant difference between the 2 groups. The mean number of hours in the ICU/CCU was 63.0 for those in the esmolol group and 72.4 for those receiving standard care alone. The number of cardiac catheterizations (71% in the esmolol group vs 69% in the standard care group),
Table I. Baseline clinical and demographic characteristics of the study group Variable
Esmolol (n ⴝ 55)
Standard (n ⴝ 53)
Male (%) 26 40 Race White 35 35 Black 18 11 Other 2 7 Age (y) 58.1 (31.7-88.3) 60.4 (35.0-84.4) Heart rate (beats/min) 81.0 (58-125) 78.7 (56-109) Systolic blood pressure (mm Hg) 128.1 (95-200) 130.7 (97-197) Relative contraindication Left ventricular dysfunction 12 14 Mild CHF 18 15 Bronchospastic disease 20 11 Prolonged PR interval 1 0 IDDM 9 11 Hypotension 14 15 Bradycardia 17 19 Calcium-channel blockers 12 9 ECG criteria ST elevation (%) 23 21 non-ST elevation 32 32 CHF, Congestive heart failure; IDDM, insulin-dependent diabetes mellitus; ECG, electrocardiogram.
Table II. Summary of study end points Esmolol Standard (n ⴝ 55) (n ⴝ 52) In-hospital end points (%) Death Nonfatal reinfarction Recurrent ischemia Nonfatal cardiac arrest Nonfatal V Tach or fibrillation Silent myocardial ischemic episode Composite end points 6-week end point (post index hospitalization) (%) Death Myocardial infarction Cardiac rehospitalization Anginal status Class I Class II Class III Class IV CHF status Class I Class II Class III Class IV
P
2 (3.64) 1 (1.92) 1.000 4 (7.27) 2 (3.85) .679 7 (12.73) 6 (11.54) 1.000 0 (0.00) 0 (0.00) N/A 1 (1.82) 2 (3.85) .611 8 (14.81) 7 (13.46) 1.000 17 (30.91) 14 (26.92) .676 n ⫽ 55 n ⫽ 53 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 8 (14.55) 5 (9.43) n ⫽ 42 n ⫽ 39 34 (80.95) 34 (87.18) 4 (9.52) 2 (5.13) 2 (4.76) 2 (5.13) 2 (4.76) 1 (2.56) n ⫽ 42 n ⫽ 38 22 (52.38) 29 (76.32) 11 (26.19) 3 (7.89) 5 (11.90) 6 (15.79) 4 (9.52) 0 (0.00)
N/A N/A .394 .828
.024
angioplasties (36% vs 49%), stent placements (32% vs 40%), rotational atherectomies (4% vs 0%), and coronary artery bypass graft surgeries (18% vs 26%) was similar for both groups.
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Table III. Safety end points
CHF Hypotension Bronchospasm AV block Bradycardia
Esmolol (%)
Standard (%)
P
7 18* 9* 2 9*
8 2 0 2 2
NS ⬍.01 ⬍.01 NS NS
AV block, Atrioventricular block. *Resolved within 30 minutes of discontinuation of infusion
Safety of the -blocker therapy was evaluated by attainment 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 discontinued 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 numbers 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 standard 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 bronchospastic 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 esmolol -blocker group compared with 1.92% of the standard care cohort (P ⫽ .206). In 18.2% of the patients receiving esmolol, an episode of hypotension (systolic blood pressure ⬍90 mm Hg unresponsive to volume replacement) was noted compared with 1.9% of the control group. This difference 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, systolic blood pressure increased above 90 after discontinuation of esmolol. A hypotensive episode was reported in 1 patient who continued to have chest pain throughout his hospitalization despite high doses of intravenous nitroglycerin. This patient, who had diffuse 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
patients who received standard care. The 2 groups were similar in the number of readmissions to the hospital for recurrent cardiac events (18.0% vs 12.0%). There were no additional deaths or myocardial infarctions reported in either group.
Discussion -Blockers are underutilized after an episode of acute myocardial ischemia, despite their proven advantages. A retrospective study of 201,752 Medicare patients showed that only 34% of patients with a diagnosis 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 myocardial infarction.5 The major reason for limited use of intravenous -blockers have included classically defined 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 patients 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 ventricular 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 patients. Although this study was not powered to evaluate differences in clinical outcomes, the incidence of adverse clinical events in the 2 groups was similar. The incidence of hypotension was greater in the esmolol treatment group but was readily reversible by titration 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
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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 myocardial 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 candidates for standard -blocker therapy. The only statistically significant safety end point was noted to be hypotension when compared with patients not receiving -blocker therapy. Additional study is needed in a larger population to substantiate these findings.
References 1. Yusuf S, Wittes J, Friedman L. Overview of results of randomized clinical trials in heart disease, I: treatment following myocardial infarction. JAMA 1988;260:2088-93. 2. ISIS-I (First International Study of Infarct Survival) Collaborative Group. Randomized trial of intravenous atenolol among 16,027 cases of suspected acute myocardial infarction: ISIS-I. Lancet 1986;12:57-65. 3. MIAMI Trial Research Group. Patient population. Am J Cardiol 1985;56:10-4G. 4. Hjalmarson A, Herlitz J, Malek I. Effect on mortality of metoprolol in acute myocardial infarction: a double-blind randomized trial. Lancet 1981;8251:823-7. 5. Rogers WJ, Bowlby JL, Chandra NC, et al. Treatment of myocardial in the United States (1990 to 1993): observations from the National Registry of Myocardial Infarction. Circulation 1994;90: 2103-14. 6. ACC/AHA Task Force. Guidelines for the early management of patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on assessment of diagnostic and therapeutic cardiovascular procedures (subcommittee to develop guidelines for the early manage-
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Background -Blockers have been shown to reduce both morbidity and mortality rates in patients with acute coronary 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 contraindication 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 admission. The primary efficacy outcome was a composite event consisting of any of the following that occurred during the index hospitalization: death, myocardial (re)infarction, recurrent ischemia, or arrhythmia as well as silent myocardial ischemia 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%), arrhythmias (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% receiving 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 contraindications 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 relative or absolute contraindications. In addition, between 5% and 10% of patients who are “-blocker eli-
From the aSt Louis University Health Sciences Center, St Louis, Mo, bUniversity of Louisville, Louisville, Ky, cUniversity of California, San Diego, San Diego, Calif, dUniversity of Missouri, Columbia, Mo, and eBaxter Pharmaceutical Products Inc, New Providence, 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: [email protected] 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 regarding 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 syndromes11,12 and left ventricular systolic dysfunction.13-17 The safety and efficacy of intravenous esmolol 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
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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 unstable angina/non-Q-wave myocardial infarction with relative 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 institution before patient enrollment. Saint Louis University was the Clinical Coordinating Center. Electrocardiograms and ambulatory 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 anginatype 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 sublingual nitroglycerin and/or nitroglycerin spray therapy, and either positive creatine kinase (CK), CK-MB enzymes, or concomitant electrocardiographic changes: ST-segment depression (⬎0.5 mm), T-wave inversion of ⱖ1 mm, or transient (⬍20 minutes) ST-segment elevation. At least 1 relative contraindication to -blockade was necessary for the patient to be enrolled. Relative contraindications included documented 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, insulin-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, verapamil). All patients gave written voluntary informed consent before random assignment in the study. Patients were excluded from the study for severe bradycardia (heart rate ⬍55 beats/min), hypotension (systolic blood pressure ⬍100 mm Hg unresponsive to fluids), prolonged electrocardiographic PR segment (ⱖ0.30 seconds), secondor third-degree AV block or junctional rhythm, acute bronchospastic episode, severe congestive heart failure, history of uncontrolled diabetes, and pregnancy. Because of the difficulty in interpreting Holter recordings, patients with atrial
fibrillation/flutter, bundle branch block, preexcitation syndrome (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. Because of a previously identified interaction between intravenous 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 confirmation of enrollment and provided security against potential randomization bias. Random assignment was stratified by the type of presenting acute ischemic syndrome (ie, acute transmural myocardial infarction or unstable angina/non-Qwave 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-pressure 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 medical 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 calciumchannel 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 individual 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 investigator to slow heart rate response. The use of intravenous 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 discontinuation of esmolol and the initiation of intravenous calciumchannel blockers. After random assignment, patients in the treatment arm of the study were given a bolus dose of 500 g/kg intravenous
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esmolol administered slowly over 1 minute. This was immediately 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 titration 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 failure (evidenced by new rales greater than one third of posterior 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 intravenous esmolol infusion was discontinued. If symptoms resolved 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 intravenous 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 discretion of the individual investigator in the event of recurrent 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 administration 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 assignment 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 independent, blinded assessment by cardiologists. Serial cardiac enzymes (total CK, CK-MB) were obtained at baseline/study entry 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 recurrent ischemic chest pain and/or myocardial (re)infarction
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manifested by pain of ⱖ20 minutes duration or ⱖ2 recurrent episodes occurring within a 30-minute period. To define procedure-related myocardial infarctions, serial enzymes and electrocardiograms were also collected for all patients undergoing percutaneous or surgical coronary revascularization procedures.
End points The primary efficacy outcome was a composite event consisting of any of the following that occur during the index hospitalization: (1) death, (2) nonfatal myocardial (re)infarction, (3)recurrent ischemia, (4) nonfatal cardiac arrest, (5) nonfatal ventricular tachycardia or fibrillation, or (6) silent myocardial ischemia episodes assessed by ambulatory electrocardiographic monitoring in the 24 hours after random assignment. Myocardial ischemic episodes on ambulatory electrocardiographic monitoring were defined according to the initial randomization group. For patients admitted with STsegment 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 protocol 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 before 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 overall ␣-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 reinfarction, (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
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initial observation in the esmolol group: (1) development of new congestive heart failure (new rales greater than one third of posterior lung fields, new third heart sound, or new radiographic evidence of pulmonary edema), (2) advanced second- or third-degree heart block, (3) occurrence of new bronchospastic episode, (4) systolic blood pressure ⬍90 mm Hg unresponsive to volume replacement, or (5) severe bradycardia (⬍50 beats/min). One-tailed tests at an overall ␣ level of 0.05 were used. The sample size was planned to be 250 patients per treatment group, which, with a primary efficacy outcome of ⱖ0.70 in the control group, would have had a power ⱖ0.9 to detect a 20% reduction of this outcome in the esmolol group, with an ␣-level of ⬍0.05. Because of patient recruitment problems, the study was terminated after 109 patients were enrolled. Therefore, the results from this study were considered exploratory, not confirmatory. Because of the small sample size, the planned analyses were not performed. Instead, the Fisher exact procedure was used on each efficacy outcome individually as well as on the composite outcome as a whole, with no adjustment for the ␣-level. For the 6-week follow-up efficacy data, the Fisher exact procedure was used on cardiac hospitalization for cardiac causes and the composite end point, and the 2 procedure was used for anginal status. No probability value was calculated for the other 2 end points at 6-week follow-up (death and myocardial infarction or reinfarction) because there was no occurrence in either treatment group.
Results The analysis was performed on an intention-to-treat basis (ie, 2 patients who were randomly assigned to but did not receive esmolol were analyzed as part of the esmolol treatment group). One hundred eight randomly assigned patients were enrolled between September 1997 and February 1999. Sixty-six men and 42 women, with a mean age of 59.2 years, were evaluated. Fifty-five patients were randomly assigned to receive intravenous esmolol with standard care, and 53 received standard care. Table I summarizes the baseline clinical and demographic characteristics of the 2 study groups. The treatment arms were well matched with respect to age, race, and electrocardiographic criteria. Sixtyone percent of the men were assigned to the standard care arm and the 69% of the women received esmolol. Relative contraindications to -blockers were similar in both subsets, with bradycardia, mild congestive heart failure, and bronchospastic disease being the most frequent. The occurrence of in-hospital events was similar in both groups, as demonstrated in Table II. A comparison of other indicators showed no significant difference between the 2 groups. The mean number of hours in the ICU/CCU was 63.0 for those in the esmolol group and 72.4 for those receiving standard care alone. The number of cardiac catheterizations (71% in the esmolol group vs 69% in the standard care group),
Table I. Baseline clinical and demographic characteristics of the study group Variable
Esmolol (n ⴝ 55)
Standard (n ⴝ 53)
Male (%) 26 40 Race White 35 35 Black 18 11 Other 2 7 Age (y) 58.1 (31.7-88.3) 60.4 (35.0-84.4) Heart rate (beats/min) 81.0 (58-125) 78.7 (56-109) Systolic blood pressure (mm Hg) 128.1 (95-200) 130.7 (97-197) Relative contraindication Left ventricular dysfunction 12 14 Mild CHF 18 15 Bronchospastic disease 20 11 Prolonged PR interval 1 0 IDDM 9 11 Hypotension 14 15 Bradycardia 17 19 Calcium-channel blockers 12 9 ECG criteria ST elevation (%) 23 21 non-ST elevation 32 32 CHF, Congestive heart failure; IDDM, insulin-dependent diabetes mellitus; ECG, electrocardiogram.
Table II. Summary of study end points Esmolol Standard (n ⴝ 55) (n ⴝ 52) In-hospital end points (%) Death Nonfatal reinfarction Recurrent ischemia Nonfatal cardiac arrest Nonfatal V Tach or fibrillation Silent myocardial ischemic episode Composite end points 6-week end point (post index hospitalization) (%) Death Myocardial infarction Cardiac rehospitalization Anginal status Class I Class II Class III Class IV CHF status Class I Class II Class III Class IV
P
2 (3.64) 1 (1.92) 1.000 4 (7.27) 2 (3.85) .679 7 (12.73) 6 (11.54) 1.000 0 (0.00) 0 (0.00) N/A 1 (1.82) 2 (3.85) .611 8 (14.81) 7 (13.46) 1.000 17 (30.91) 14 (26.92) .676 n ⫽ 55 n ⫽ 53 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 8 (14.55) 5 (9.43) n ⫽ 42 n ⫽ 39 34 (80.95) 34 (87.18) 4 (9.52) 2 (5.13) 2 (4.76) 2 (5.13) 2 (4.76) 1 (2.56) n ⫽ 42 n ⫽ 38 22 (52.38) 29 (76.32) 11 (26.19) 3 (7.89) 5 (11.90) 6 (15.79) 4 (9.52) 0 (0.00)
N/A N/A .394 .828
.024
angioplasties (36% vs 49%), stent placements (32% vs 40%), rotational atherectomies (4% vs 0%), and coronary artery bypass graft surgeries (18% vs 26%) was similar for both groups.
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Table III. Safety end points
CHF Hypotension Bronchospasm AV block Bradycardia
Esmolol (%)
Standard (%)
P
7 18* 9* 2 9*
8 2 0 2 2
NS ⬍.01 ⬍.01 NS NS
AV block, Atrioventricular block. *Resolved within 30 minutes of discontinuation of infusion
Safety of the -blocker therapy was evaluated by attainment 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 discontinued 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 numbers 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 standard 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 bronchospastic 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 esmolol -blocker group compared with 1.92% of the standard care cohort (P ⫽ .206). In 18.2% of the patients receiving esmolol, an episode of hypotension (systolic blood pressure ⬍90 mm Hg unresponsive to volume replacement) was noted compared with 1.9% of the control group. This difference 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, systolic blood pressure increased above 90 after discontinuation of esmolol. A hypotensive episode was reported in 1 patient who continued to have chest pain throughout his hospitalization despite high doses of intravenous nitroglycerin. This patient, who had diffuse 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
patients who received standard care. The 2 groups were similar in the number of readmissions to the hospital for recurrent cardiac events (18.0% vs 12.0%). There were no additional deaths or myocardial infarctions reported in either group.
Discussion -Blockers are underutilized after an episode of acute myocardial ischemia, despite their proven advantages. A retrospective study of 201,752 Medicare patients showed that only 34% of patients with a diagnosis 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 myocardial infarction.5 The major reason for limited use of intravenous -blockers have included classically defined 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 patients 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 ventricular 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 patients. Although this study was not powered to evaluate differences in clinical outcomes, the incidence of adverse clinical events in the 2 groups was similar. The incidence of hypotension was greater in the esmolol treatment group but was readily reversible by titration 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
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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 myocardial 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 candidates for standard -blocker therapy. The only statistically significant safety end point was noted to be hypotension when compared with patients not receiving -blocker therapy. Additional study is needed in a larger population to substantiate these findings.
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