Download Benefit of Immediate Beta-Blocker Therapy on Mortality in Patients

Benefit of Immediate Beta-Blocker Therapy on
Mortality in Patients With ST-Segment Elevation
Myocardial Infarction*
Michael M. Hirschl, MD1; Christian G. Wollmann, MD2; Friedrich Erhart, MD3; Walter Brunner,
MD4; Franz Pfeffel, MD5; Martin Gattermeier, MD6; Friedrich Steger, MD7; Harald Mayr, MD2
Objectives: Despite the recommendations to initiate β-blockade
to all patients with an ST-segment elevation myocardial infarction,
data concerning the timing of the administration of β-blockers are
controversially discussed. In view of these controversies, we analyzed the effect of immediate vs. delayed β-blockade on all-cause
mortality of patients with ST-segment elevation myocardial infarction in the Lower Austrian Myocardial Infarction Network.
Design: Nonrandomized, prospective observational cohort study.
Setting: Myocardial infarction network including the out-of-hospital emergency services, five primary-care hospitals and a percutaneous coronary intervention-capable hospital in the western part
of Lower Austria.
Patients: The data of all patients with ST-segment elevation myocardial infarction defined according to the American Heart Association criteria and treated according to the treatment protocol
*See also p. 1566.
1
Department of Internal Medicine, Landesklinikum Waldviertel Zwettl, Austria.
2
3rd Medical Department, Landesklinikum St.Pölten-Lilienfeld, Austria.
3Department of Internal Medicine, Landesklinikum Mostviertel Amstetten,
­Austria.
4
Department of Internal Medicine, Landesklinikum Mostviertel Melk, Austria.
5
Department of Internal Medicine, Landesklinikum Lilienfeld, Austria.
6Department of Internal Medicine, Landesklinikum Mostviertel Waidhofen/
Ybbs, Austria.
7Department of Internal Medicine, Landesklinikum Mostviertel Scheibbs, Austria.
Supported, in part, by the Karl Landsteiner Institute of Coronary Artery
Disease and Heart Rhythm Disturbances (St.Pölten, Austria).
Dr. Hirschl has board membership with Takeda Pharma. Dr. Wollmann has
board membership with St. Jude Medical. Dr. Mayr has board membership
with Medtronic.
Dr. Hirschl lectured for Servier Austria, Takeda Pharma, and Actelion.
Drs. Wollmann and Mayr are consultants for Biotronik, Boston Scientific,
Medtronic, and St Jude Medica. Dr. Wollmann received travel support
from Biotronik, Boston Scientific, Medtronic, and St. Jude Medical.
The remaining authors have disclosed that they do not have any potential
conflicts of interest.
For information regarding this article, E-mail: [email protected]
Copyright © 2013 by the Society of Critical Care Medicine and Lippincott
Williams & Wilkins
DOI: 10.1097/CCM.0b013e31827caa64
1396
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of the network were consecutively collected. For the purpose of
survival analyses, the baseline survival time was set to 48 hours
after the first electrocardiogram, and in all patients with recurrent
MI within the observational period, only the first MI was regarded.
Interventions: The treatment protocol recommended either the
immediate oral administration of 2.5 mg bisoprolol (within 30 min
after the first electrocardiogram) or 24 hours after acute myocardial infarction (delayed β-blockade).
Measurements and Main Results: In total, out of the 664 patients
with ST-segment elevation myocardial infarction, 343 (n = 52%)
received immediate β-blockade and 321 (48%) received delayed
β-blockade. The probability of any death (baseline survival time: 48
hours after first electrocardiogram; 640 patients) was 19.2% in the
delayed treatment group and 10.7% in the immediate treatment
group (p = 0.0022). Also the probability of cardiovascular mortality
was significantly lower in the immediate β-blocker treatment group
(immediate treatment group: 9 (5.2%); delayed treatment group:
30 (13.4%); p = 0.0002). Multivariable Cox regression analysis
identified immediate β-blocker therapy to be independently
protective against death of any cause (odds ratio: 0.55, p = 0.033).
Conclusion: Immediate β-blocker administration in the emergency
setting is associated with a reduction of all-cause and cardiovascular mortality in patients with ST-segment elevation myocardial
infarction and seems to be superior to a delayed β-blockade in our
patient cohort. (Crit Care Med 2013; 41:1396–1404)
Key Words: acute myocardial infarction; betablocker; mortality;
reperfusion.
T
he American Heart Association (AHA) recommends
the initiation of β-blockade to all patients with an
ST-segment elevation myocardial infarction (STEMI)
without contraindications to β-blocking agents (1). Based on
these guidelines, application of β-blockers is an essential part
in the out-of-hospital treatment of STEMI patients in our rural
MI network. However, the timing of the administration of
β-blockers is controversially discussed especially if β-blockers
should be given within the first 24 hours after acute MI (2, 3).
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Feature Articles
In contrast to the current recommendations, some recent trials evaluating the effect of early β-blocker treatment failed to
demonstrate a decrease of mortality in patients with STEMI (4,
5). In view of these recent controversies, we analyzed our data
of the Lower Austrian Myocardial Infarction network with
regard to the effect of immediate vs. delayed β-blocker treatment on mortality of patients with STEMI.
METHODS
Study Design
Patients for this analysis were drawn from the database of
the Lower Austrian Myocardial Infarction Network, which
included patients presented with the primary diagnosis of a
STEMI according to the AHA criteria. As we established the
Network, numerous hypothesis were a priori defined and evaluated by the local Ethical Committee. The observation period
was a priori defined from June 2006 to December 2010. The
treatment protocol of the network was defined prior to the
start of data collection and included unambiguous guidelines
concerning reperfusion strategies, platelet inhibition, anticoagulation, and concomitant β-blocker therapy (the detailed
protocol of the network is described in detail in the following
paragraphs). The application of β-blockers was recommended
either immediately after diagnosis of a STEMI (defined within
the first 30 min after STEMI was confirmed with a 12-lead
electrocardiogram [ECG]) or after 24 hours of the acute event.
However, as the final decision depends on the physician on
duty, the characteristic of the study is nonrandomized, prospective, and observational. The hypothesis was to evaluate the
effect of immediate vs. delayed β-blockade on all-cause mortality of patients with STEMI in our network.
Patient Characteristics
The data of all patients with STEMI diagnosed out-of-hospital
by an emergency physician or by a physician in one of the primary-care hospitals between June 1, 2006, and December 31,
2010, were consecutively collected and retrospectively analyzed.
All patients gave their informed consent to use their data for
study purposes. The study was approved by the Ethical Committee of the Government of the Federal State of Lower Austria.
Diagnosis and Treatment Protocol
All patients with STEMI diagnosed out-of-hospital or in one of
the primary care hospitals within the Lower Austrian Myocardial Infarction Network were included. The network consisted
of five emergency medical services (EMS) and five primary
care hospitals located in the western part of Lower Austria. The
EMS in Austria consisted of a physician with a specific education in emergency medicine and two paramedics. The percutaneous coronary intervention (PCI) center is located in the
center of the network and the average distance from the EMS
stations to the PCI center was 82 km. STEMI was defined as 1)
anterior MI: greater than or equal to 2 mm ST-segment elevation in greater than or equal to 2 of the leads I, aVL, and V1–V6;
or 2) inferior MI: greater than or equal to 1 mm ST-segment
Critical Care Medicine
elevation in greater than or equal to 2 leads II, III, aVF, and
V5–V6. The reperfusion strategy depended on the time interval between onset of symptoms and first medical contact. If the
time interval was below 120 minutes, a thrombolytic treatment
was given and the patient was transferred to the PCI center.
In all other cases, patients were transferred directly to primary
PCI with a treatment delay of less than 120 minutes from the
first medical contact. The diagnosis of a STEMI was assessed
by the physician of the EMS or the primary care hospital and
confirmed by the cardiologist at the PCI center.
Reperfusion Protocol
Patients without thrombolysis received the following medication given in the ambulance: 250 mg aspirin, 600 mg clopidogrel, a bolus of bivalirudin (0.1 mg/kg), followed by a
continuous infusion of bivalirudin (0.25 mg/kg/hr). The emergency physician used this predefined treatment protocol in all
patients with STEMI. Patients eligible for thrombolysis received
rtPa according to the guidelines, 250 mg aspirin, 300 mg clopidogrel, and weight-adjusted unfractioned heparin.
β-Blockade
The use of bisoprolol (2.5 mg oral) immediately after diagnosis
of the STEMI was recommended by protocol. Administration
of bisoprolol by the emergency physician either out-of-hospital
or in the emergency department of the primary care hospital has to be done within 30 minutes after confirmation of an
acute STEMI by the first ECG. Contraindications for the use of
bisoprolol were systolic blood pressure less than 100 mm Hg,
bradycardia (HR less than 60/min), AV-block II° or III°, and
clinical signs of heart failure (rales over both lungs, cyanosis).
However, the final decision to give bisoprolol depended on the
emergency physician on duty. If the patient did not receive bisoprolol within the first 30 minutes after the primary ECG, the
protocol recommended bisoprolol 24 hours after the first ECG.
Patients who remained free of any β-blocker treatment were
excluded from further analysis, as well as patients who received
bisoprolol outlying the defined timing of the protocol.
Management at the PCI Center
After arrival in the emergency department of the PCI center,
patients without thrombolytic treatment were transferred
immediately to the catheterization suite. Coronary angiography
was performed to identify the infarct-related artery. In case of a
PCI, either a bolus of bivalirudin was given (0.5 mg/kg) followed
by an increase of the continuous infusion (1.75 mg/kg/hr) or a
bolus of unfractioned heparin was given (60 IU/kg; maximum
dose of 4000 IU) intravenously followed by a continuous
infusion of 1000 IU/hr in the emergency service. Additionally,
abciximab was administered (dose: bolus: 0.25 mg/kg followed
by a continuous infusion [dose: 0.125 μg/kg/min]) until the
guide wire was removed.
Outcome Parameters
The primary outcome parameter was all-cause mortality in patients with immediate vs. delayed β-blocker therapy.
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Secondary parameters included cardiovascular death 30 days
and 1 year after MI. The effect of β-blockers on two predefined
subgroups was also investigated: elderly patients aged over 70
years and patients with greater than or equal to two criteria
for an increased risk of shock according to current guidelines
(1). Criteria for an increased risk of shock included age greater
than 70 years, symptoms greater than 12 hours, systolic blood
pressure less than 120 mm Hg, heart rate greater than 110 bpm.
Safety parameters were the frequency of congestive heart failure
(Killip class III or IV), cardiogenic shock, and bradyarrhythmia
with the need of intervention or cardiopulmonaryresuscitation
due to ventricular fibrillation within the first 24 hours.
Fatal events were retrieved from the Statistical Department
of the Austrian government, which collected the causes of
death of all patients who died in a hospital in Austria. Patients
who died from noncardiovascular cause were considered event
free until death. The data of all patients were consecutively
registered in the database of the Lower Austrian Myocardial
Infarction Network. Individual patient data were handled in
a blinded fashion, and the registry was performed according
to the Helsinki criteria. The preclinical data were noted in an
established STEMI record by the emergency physician on duty.
The data from the preclinical records, as well as from the clinical records, were transferred into the MI network database.
Data Collection and Analysis
Analysis of data with regard to outcome parameters and protocol adherence were performed by two physicians (a cardiologist and an emergency physician) blinded to treatment.
Normal distributed continuous data were reported as mean
± sd, and not normally distributed continuous data were
reported as quartiles, minimum, and maximum. Categorical variables were compared using the chi-square and Fisher’s
exact test, where appropriate. Normal distributed continuous
variables were compared using the Student t test. Nonparametric Mann-Whitney U tests were conducted to compare not
normally distributed parameters.
Cardiovascular death, stroke, re-infarction in follow-up,
and the need for revascularization in follow-up were defined
as major cardiac adverse events (MACE).
Multivariable regression analyses were performed using Cox
proportional hazard models to compare survival outcomes in
patients with and without β-blocker treatment. Adjustment
was performed for early β-blocker treatment, Clopidogrel and
Metoprolol in Myocardial Infarction Trial shock index greater
than or equal to 2 (including age greater than 70 yr, symptoms
more than 12 hr, systolic blood pressure less than 120 mm Hg,
and heart rate greater than 110 bpm), treatment only with
drug-eluting stent, history of MI and/or PCI, and number of
cardiovascular risk factors greater than or equal to 2 (including hypertension, diabetes, dyslipidemia, current smoking,
family history of coronary artery disease). Kaplan–Meier survival curves using the log rank test were calculated for survival with and without β-blocker therapy. In order to reduce
potential bias (e.g., potential advantage in survival of patients
who received delayed β-blocker treatment), only patients who
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survived the first 48 hours were counted for survival analyses.
A p value less than 0.05 for two-sided comparisons was considered statistically significant.
Statistical analyses with impact on main results were verified by a statistician of the Institute of Biostatistics and Clinical
Research, University of Münster, Germany. Analyses were
performed using the statistical software package IBM SPSS
Statistics 20 (IBM Corporation, Armonk, NY).
RESULTS
General Characteristics
In total, 664 patients with STEMI were analyzed; 52% (n =
343) received immediate β-blocker treatment and 48% (n =
321) received a delayed β-blockade. About 38 patients had to
be excluded due to lack of any β-blocker therapy (n = 21) or
the administration of β-blocker (n = 17) at a time point which
was not in accordance to the treatment protocol. Reasons for
the lack of β-blocker or out-of-protocol treatment were cardiac
arrest prior to application (n = 4), signs of cardiogenic shock
(n = 3), prolonged hypotension (n = 9), bradycardia with the
need to intervention (n = 8), unconsciousness of the patient
(n = 2), vomiting (n = 9), lack of adherence to the protocol by
the physician on duty (n = 3). Three patients were treated for
recurrent infarction within the observational period. Only the
first MI was counted for survival.
The baseline characteristics of all patients included in the
study, as well as the characteristics of the patients counted for
survival analyses, are illustrated in Table 1. Except for age, no
differences were observed between both treatment groups.
Systolic and diastolic blood pressures and heart rate were significantly higher in patients treated with β-blocker (Table 1).
The different time intervals, reperfusion strategies, number
of affected coronary vessels, number of stents implanted, and
the percentage of drug-eluting stents did not differ between
the both treatment groups (Table 2). The application of the
β-blocker was done within the time interval of first ECG and
departure from the site of operation. The average time interval
was 12 minutes with a 95% confidence interval (CI) of 8.4–
16.6 minutes in the early β-blocker group. The time interval
between first ECG and departure was 11 minutes (95% CI,
7.6–16.3 min).
Mortality Data
The follow-up duration was 31 months (interquartile range:
8–44 months). When analyzing only patients within survival
analyses, the probability of a fatal event was 19.2% in the group of
patients with delayed β-blocker therapy and 10.7% in the group
with immediate β-blocker therapy (Table 3). The cardiovascular
mortality after 30 days and after 1 year was lower in the immediate
β-blocker treatment group (30-day cardiovascular mortality:
immediate β-blocker: 0.9%; delayed β-blocker: 4.3%, p = 0.0058;
1-year cardiovascular mortality: immediate β-blocker: 1.9%
delayed β-blocker: 8.1%, p = 0.0003; Table 3).
Figure 1 shows the probability of survival starting 48 hours
after first ECG. Log-rank test revealed a significant lower
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Feature Articles
Table 1. General Characteristic of All Patients With ST-Segment Elevation Myocardial
Infarction With (+) and Without (–) β-Blocker
All Patients
Variable
Total
All,
n = (%)
BBL (–),
n (%)
BBL (+),
n (%)
664 (100)
321 (100)
343 (100)
Age (yr)
64 ± 13
66 ± 13
63 ± 13
Male gender
462 (70)
219 (68)
Systolic blood pressure
(mm Hg, mean ± sd;
n = 346)
138 ± 31
Diastolic blood pressure
(mm Hg, mean ± sd;
n = 342)
Heart rate (bpm,
mean ± sd; n = 660)
Patients Within Survival Analyses
p
All,
n (%)
BBL (–),
n (%)
BBL (+),
n (%)
p
640 (100)
302 (100)
338 (100)
0.015
64 ± 13
65 ± 13
63 ± 13
0.054
243 (71)
NS
447 (70)
207 (69)
240 (71)
NS
129 ± 32
146 ± 28
<0.001*
139 ± 31
131 ± 31
146 ± 28
<0.001*
81 ± 18
77 ± 17
85 ± 18
<0.001*
82 ± 18
78 ± 17
85 ± 18
<0.001*
79 ± 20
75 ± 20
82 ± 19
<0.001*
78 ± 19
75 ± 19
82 ± 19
<0.001*
Hypertension
388 (59)
176 (55)
212 (62)
NS
376 (59)
166 (55)
210 (63)
NS
Dyslipidemia
219 (33)
97 (31)
122 (36)
NS
214 (34)
94 (31)
120 (36)
NS
Current smoker
222 (36)
98 (33)
124 (39)
NS
220 (37)
97 (16)
123 (21)
NS
Diabetes mellitus
118 (18)
59 (19)
59 (17)
NS
112 (18)
53 (18)
59 (18)
NS
Previous myocardial
infarction
40 (6)
23 (7)
17 (5)
NS
38 (6)
21 (7)
17 (5)
NS
Previous percutaneous
coronary
intervention
50 (8)
27 (8)
23 (7)
NS
48 (8)
25 (8)
23 (7)
NS
NS = not significant.
probability of death in patients with early β-blocker treatment
(p < 0.001; Fig. 1). Analysing all-cause mortality with regard
to different reperfusion strategies, the decrease of mortality of
the immediate β-blocker group was consistent in the group of
patients who were treated with primary PCI (delayed β-blocker
treatment: n = 25, immediate β-blocker treatment: n = 12;
p = 0.009). No significant differences of all-cause mortality were
observed in the other groups (delayed β-blockade vs. immediate β-blockade: no intervention: 7 vs. 2 patients, p = 0.067;
thrombolysis: 9 vs. 5 patients, p = not ­significant [NS]; coronary
artery bypass graft: 0 vs. 2 patients, p = NS) The use of immediate β-blocker therapy was not associated with an increase of
all-cause mortality in patients with an increased risk for cardiogenic shock (shock criteria ≥ 2; p = NS, Fig. 2). In patients
older than 70 years, survival was not different in this patient
group with or without immediate β-blocker therapy (log-rank
0.23). Overall 24 patients (15 males, 57%; mean age 75 ± 9 years
[median 78; range 61–88]) died within the first 48 hours after
the first ECG (immediate β-blocker group: 5, delayed β-blocker
group: 19). All patients died related to the MI.
Major Adverse Cardiovascular Events
The number of any major cardiac adverse events was significantly lower in patients with immediate β-blocker therapy
Critical Care Medicine
compared with those with a delayed β-blocker therapy (immediate β-blocker group: 52; delayed β-blocker group: 71; p =
0.01; Table 4). The percentage of cardiovascular death was significantly lower in the immediate β-blocker group (2.9%) compared with the delayed β-blocker group (9.2%), but there were
no significant differences between both groups concerning reinfarction, the need for revascularization, and for stroke within
the observational period (Table 4).
Discharge Data
Table 5 summarizes the average length of stay and the drug
therapy of both groups at the time of discharge from the hospital. Analysis included the percentage of patients with aspirin, clopidogrel, statin therapy and renin-angiotensin-system
blockade. No significant differences were observed between
both groups. The discharge dose of bisoprolol was nearly identical between both groups.
Safety Parameters
Figure 3 illustrates the frequency of STEMI-related compli­
cations within the first 24 hours after MI. The percentage of
congestive heart failure (Killip class III or IV), cardiogenic
shock, and ventricular fibrillation was not significantly different
between both groups. Hypotensive episodes and bradycardia
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Table 2. Time Intervals, Reperfusion Strategy and Angiographic Data in All Patients
With ST-Segment Elevation Myocardial Infarction Without β-Blocker Therapy (–) and
With Immediate β-Blocker Therapy (+)
All Patients
Variable (No. Valid
Cases)
Onset pain to first
electrocardiogram
(min, median [first, third
quartile]; n = 507)
All
BBL (–)
Patients Within Survival Analyses
BBL (+)
p
All
BBL (–)
BBL (+)
111 [57,216] 103 [56,208] 120 [57,225] NSa 111 [57,216] 101 [56,200] 120 [57,226]
First electrocardiogram to PCI 94 (67,143) 95 (66,149) 94 [68,136.5] NSa
(min, median [first, third
quartile]; n = 525)
p
NSa
94 (67,143)
95 (65,149)
94 (68,137)
NSa
25 (4%)
12 (4%)
13 (4%)
NSb
Reperfusion strategy (n = 664)
27 (4%)
14 (4%)
13 (4%)
114 (17%)
62 (19%)
52 (15%)
113 (18%)
61 (20%)
52 (15%)
38 (6%)
15 (5%)
23 (7%)
38 (6%)
15 (5%)
23 (7%)
393 (59%)
185 (8%)
208 (61%)
379 (59%)
175 (58%)
204 (60%)
Coronary artery bypass graft
(n)
21 (3%)
10 (3%)
11 (3%)
21 [3%]
10 [3%]
11 [3%]
No intervention (n)
71 (11%)
35 (11%)
36 (11%)
No. of vessels (mean ± sd,
n = 648)
1.8 ± 0.9
1.8 ± 0.9
Total no. of stents (mean ± sd,
n = 664)
1.3 ± 1.0
Bare metal stents (n)
Drug-eluting stents (n)
Thrombolysis (n)
Thrombolysis with PCI (n)
Thrombolysis with
delayed PCI (n)
Primary PCI (n)
NSb
64 (10%)
29 (10%)
35 (10%)
1.8 ± 0.9
a
NS
1.8 ± 0.9
1.8 ± 0.9
1.8 ± 0.9
NSa
1.3 ± 1.0
1.3 ± 1.0
NSa
1.3 ± 1.0
1.3 ± 1.0
1.3 ± 1.0
NSa
109 (17%)
57 (18%)
52 (15%)
NSb
107 (17%)
55 (18%)
52 (16%)
NSb
402 (61%)
186 (59%)
216 (64%)
493 (62%)
180 (60%)
213 (64%)
20 (3%)
9 (3%)
11 (3%)
19 (3%)
8 (3%)
11 (3%)
Type of stent (n = 657)
Bare metal stent+drug-eluting
stent (n)
NS = not significant; PCI = percutaneous coronary intervention.
a
Mann-Whitney U test.
b
Chi-square test.
were more frequently noted in patients with a delayed β-blocker
treatment (17 vs. 5, p = 0.008; 41 vs. 14, p < 0.001).
0.95]; drug-eluting stent: hazard ratio 0.47 [95% confidence
limits: 0.28, 0.79]).
Multivariable Survival Analysis
After adjustment for early β-blocker treatment, COMMIT-shock
index ≥ 2 (including age > 70 yr, symptoms > 12 hr, systolic blood
pressure < 120 mm Hg, heart rate > 110 bpm), treatment only
with drug-eluting stent, number of cardiovascular risk factors
greater than or equal to 2 (including arterial hypertension, diabetes, dyslipidemia, current smoking, family history of CAD), and
history of MI and/or PCI, multivariable Cox regression analysis
revealed a COMMIT shock index greater than or equal to 2 and
history of MI and/or PCI as predictors for death of any cause
(Table 6). Immediate β-blocker therapy and the use of only
drug-eluting stent reduced the risk for death of any cause
(β-blocker: hazard ratio 0.55 [95% confidence limits: 0.32,
DISCUSSION
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Although treatment with β-blocker improves long-term
outcomes in patients with acute MI, the beneficial effect of
immediate or early treatment in the acute phase of STEMI is
unclear. The question whether early β-blocker treatment is
helpful or harmful is not answered yet. The COMMIT trial
found that intravenous followed by oral metoprolol was
harmful during the initial 24 hours with a significant increase
in the risk of shock (6). However, the applicability of this
trial to European or North American practice is limited, as
patients with PCI were excluded and 54% were treated with
thrombolysis. Due to the combination of the primary use
of an intravenous β-blocker formulation and completely
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Table 3. 30-Day
and 1-Year All-Cause and Cardiovascular Mortality in Patients With
ST-Segment Elevation Myocardial Infarction Without β-Blocker Therapy (–) and With
Immediate β-Blocker Therapy (+)
Overall,
n (Probability of
Event %)
Total
638
β-Blocker (–),
n (Probability of
Event %)
301
β-Blocker (+),
n (Probability of
Event %)
p (LogRank)
337
30-d cardiovascular mortality
16 (2.52%)
13 (4.34%)
3 (0.89%)
0.0058
1-yr cardiovascular mortality
29 (4.81%)
23 (8.14%)
6 (1.88%)
0.0003
Total cardiovascular mortality
39 (9.13%)
30 (13.41%)
9 (5.17%)
0.0002
Total
640
302
338
30-d all-cause mortality
17 (2.67%)
14 (4.66%)
3 (0.89%)
0.0033
1-yr all-cause mortality
38 (6.23%)
28 (9.79%)
10 (3.23%)
0.0006
Total all-cause mortality
62 (14.85%)
41 (19.19%)
21 (10.73%)
0.0022
Probability of fatal events expressed as %.
different reperfusion strategies, it seems difficult to apply these
data for recommendations in a complete different setting. In
contrast, Yusuf et al (7) demonstrated a significant reduction
of mortality if β-blockers were used early in the treatment
of acute MI. Similar results from a German MI registry have
been recently published (8). The authors demonstrated a
significant decrease in hospital mortality in patients with
STEMI with and without reperfusion therapy. The benefit was
even greater in high-risk patients with STEMI such as elderly
patients and patients without reperfusion therapy. However,
acute β-blocker therapy was defined within a maximum time
range of 48 hours. In contrast, a recently published analysis of
the data of the NCDR Action Registry-GWTG demonstrated
that in high-risk patients for shock β-blocker therapy resulted
in an increased number of patients with shock or death (4).
However, this analysis included STEMI and NSTEMI patients,
and the early use of β-blocker was defined as within the first
24 hours after acute MI. Therefore, it remains unanswered
whether immediate β-blocker treatment may be helpful for
patients with STEMI. To our knowledge, our analysis is the
first comparing the immediate use of β-blockers (i.e., within
30 min after diagnosis of STEMI was confirmed by ECG out
of hospital) with an administration of β-blockers after the
first day of STEMI.
We found a significant association between the immediate
β-blocker treatment and all-cause mortality in the multivariate
regression analysis. The reduction of mortality remained until
1 year after the acute event and included not only all-cause
mortality but also cardiovascular mortality. The decrease was
most pronounced in the primary PCI group. An important
cause of concern using β-blocker is the possible development
of serious complications such as congestive heart failure,
bradyarrythmia, or even more important cardiogenic shock.
However, the rate of complications such as heart failure or
cardiogenic shock did not increase in patients with immediate
β-blocker therapy during our observational study. These
Figure 1. All-cause mortality in patients with ST-segment elevation
myocardial infarction with (BBL: Yes) or without (BBL: No) immediate
β-blocker therapy. ECG = electrocardiogram.
Figure 2. All-cause mortality in patients with an increased risk for cardiogenic shock (possible risk factors ≥ 2) with (BBL: Yes) or without (BBL:
No) immediate β-blocker therapy. ECG = electrocardiogram.
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Table 4. Major
Adverse Cardiovascular Events Within the Survival Analysis
Overall patients,
n (%)
Variable
β-Blocker (–) Patients,
n (%)
β-Blocker (+) Patients,
n (%)
p
Total patients
640 (100)
302 (100)
338 (100)
Major cardiac adverse
events (≥1)
122 (19.1)
71 (23.5)
52 (15.4)
0.01
Cardiovascular death
37 (5.8)
28 (9.2)
10 (2.9)
0.001
Stroke
15 (2.3)
7 (2.3)
8 (2.4)
NS
Reinfarction
32 (5)
20 (6.6)
12 (3.5)
NS
Revascularization
38 (5.9)
16 (5.3)
22 (6.5)
NS
NS = not significant.
Table 5. Discharge
Data of Patients Without (–) and With (+) Immediate β-Blocker Therapy
Variable
Overall,
n (%)
β-Blocker (–),
n (%)
β-Blocker (+),
n (%)
p
Total
664
321
343
Length of stay (d) (median)
5.8 (4.6)
5.9 (4.7)
5.8 (4.9)
NS
Aspirin (%)
640 (96)
314 (98)
326 (95)
NS
Clopidogrel (%)
574 (86)
280 (88)
294 (86)
NS
Statin therapy (%)
519 (78)
248 (77)
271 (79)
NS
Renin-angiotensin system blockade
(%)
343 (52)
167 (52)
176 (51)
NS
4.6 (2.1)
4.6 (1.8)
4.7 (2.4)
NS
Bisoprolol dose at discharge
(mg) (median)
NS = not significant.
findings demonstrate the safe use of β-blockers in the outof-hospital setting if the contraindications were carefully
considered. The subgroup analysis of patients with an
increased risk for shock (possible shock criteria ≥2) illustrates
that immediate β-blocker
therapy had no adverse effect
on the rate of cardiogenic
shock. Even in patients older
than 70 years, the immediate
use of β-blockers was not
associated with an adverse.
These findings are especially
important for the emergency
services, as it demonstrates
the safety of immediate use
of β-blockers in patients with
STEMI.
We assume that the timing of β-blocker administration in patients with STEMI
is crucial with regard to a
possible benefit on mortality.
Beta-blockers reduce the heart
rate and left ventricular work
Figure 3. Complications within the first 24 hr after acute myocardial infarction in both treatment groups.
CPR = cardiopulmonary resuscitation; VF = ventricular fibrillation.
load with the result of a lower
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June 2013 • Volume 41 • Number 6
Feature Articles
Table 6. Predictors
for Death of Any Cause Using Cox Regression Analysis (n = 640)
p
Hazard Ratio
95% Confidence Interval
Immediate β-blocker-therapy
0.0331
0.554
0.322–0.954
History of percutaneous coronary intervention
and/or myocardial infarction
0.0585
1.835
0.978–3.443
CVRF ≥ 2
0.9183
1.028
0.611–1.729
COMMIT-Shock Index ≥ 2
0.0013
2.399
1.407–4.090
Drug-eluting stent only
0.0044
0.474
0.283–0.792
Variables
Cardiovascular risk factor (CVRF) = arterial hypertension, hypercholesterolemia, diabetes mellitus, current smoking, family history of coronary artery disease.
Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT)-Shock Index = age > 70 yr, symptoms > 12 hr, systolic blood pressure < 120 mm Hg, heart
rate > 110 bpm.
oxygen demand of the myocardium (9). The effect becomes
even more important if the myocardium is ischemic. Due to
these favorable effects, the immediate use of β-blockers may
lead to a less widespread infarction (10). Our results are consistent with data from a previous study, which demonstrated
a reduced rate of reinfarction and recurrent chest pain in
STEMI patients receiving intravenous metoprolol 2 hours
after the diagnosis (11). However, this study was performed
in the thrombolytic era and may be therefore not representative for the current STEMI management. Another more recent
study investigated the use of β-blocker prior to primary coronary angioplasty in patients with acute MI (12). The probability of 1-year all-cause mortality of 3.2% in this previous study
was identical to the mortality of 3.2% in our group of patients
receiving β-blocker therapy immediately.
The discrepancy to other previously published data demonstrating a harmful effect of β-blocker therapy may be
explained by the different timing of β-blocker administration. If β-blockers are given as early as possible, the protective
effect on the ischemic myocardium may be the crucial cause
for the reduced mortality in patients with STEMI. In contrast,
a delayed administration of β-blockers may have no effect on
infarct size, as the necrosis has been determined especially if
β-blockers are given later than 12 hours after the acute event.
In these patients, the adverse hemodynamic effects may outweigh the beneficial effects of β-blocker therapy and may lead
to hypotension, congestive heart failure, and cardiogenic shock.
These potential complications have a negative effect of shortand long-term mortality in STEMI patients. Our assumptions are in line with previously published data of Sharma et
al (13), who demonstrated a significantly smaller elevation
of creatine-kinase-muscle-brain after primary angioplasty in
patients receiving β-blockers prior to the procedure compared
with those receiving no β-blocker treatment. These data have
been recently confirmed by experimental data demonstrating a
larger myocardial salvage if intravenous metoprolol was given
prior to coronary reperfusion (14). Further recently ongoing
studies such as the METOCARD-CNIC trial may provide further confirmation that the application of β-blockers prior to
reperfusion may be associated with reduced infarct size and
better prognosis of STEMI patients (15).
Critical Care Medicine
Limitations
Despite these favorable data of imme­diate β-blocker administration in STEMI patients, some caveats of our study have to
be mentioned. As the design of the study is observational, some
selection effects by confounders have to be taken into account.
To reduce the bias due to possible confounders, we decided
to exclude patients from survival analyses who died within
48 hours. The decision was made to ensure comparability of the
different patients groups. The assumption is that patients dying
within the first 48 hours have died independently of immediate or delayed β-blocker treatment, e.g., death occurred prior
to a sufficient β-blocker effect. However, our data demonstrate
clearly that the excluded patients exhibited similar general characteristics and vascular risk factors as the analyzed group of
STEMI patients. Even the inclusion of these early died patients
did not change the favorable effect of immediate β-blocker
treatment on survival of STEMI patients. Therefore, the results
of our study seem to be representative for patients with STEMI
receiving β-blocker treatment. A second limitation is the lack
of the exact time point of the β-blocker application in the outof-hospital setting. However, by analyzing the out-of-hospital
recordings, we could determine two undisputable time points,
that is, the writing of the first ECG and the time of departure
from the site of operation. As drug treatment is usually done
prior to departure, a very tight time frame could be identified
within β-blockade was established. The mean time interval
between first ECG and β-blocker application was at least within
12 minutes and 95% of all patients received the β-blocker
within a time range between 8 and 16 minutes. As the time
frame is very small, the observed differences of the β-blocker
application should not have a considerable effect on the outcome parameters.
CONCLUSION
In summary, immediate β-blocker administration in the emergency setting of the Lower Austrian Myocardial Infarction
Network seems to be associated with a reduction of all-cause
and cardiovascular mortality in patients with STEMI. Immediate β-blocker administration could be superior to a delayed
β-blockade in these patients with acute STEMI. Our data confirm the recommendations concerning the use of β-blockers
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in patients with acute MI. The establishment of β-blockade
should be an essential part of the emergency treatment of
patients with STEMI in the out-of-hospital setting, as the benefit seems to outweigh potential complications of β-blockers in
our patient cohort. The findings of our study should be confirmed in a prospective randomized controlled trial.
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