Atenolol use and clinical outcomes after thrombolysis for acute myocardial infarction: the GUSTO-I experience

Abstract

Objectives. We assessed the use and effects of acute intravenous and later oral atenolol treatment in a prospectively planned post hoc analysis of the GUSTO-I dataset.Background. Early intravenous beta blockade is generally recommended after myocardial infarction, especially for patients with tachycardia and/or hypertension and those without heart failure.Methods. Besides one of four thrombolytic strategies, patients without hypotension, bradycardia or signs of heart failure were to receive atenolol 5 mg intravenously as soon as possible, another 5 mg intravenously 10 min later and 50 to 100 mg orally daily during hospitalization. We compared the 30-day mortality of patients given no atenolol (n = 10,073), any atenolol (n = 30,771), any intravenous atenolol (n = 18,200), only oral atenolol (n = 12,545) and both intravenous and oral drug (n = 16,406), after controlling for baseline differences and for early deaths (before oral atenolol could be given).Results. Patients given any atenolol had a lower baseline risk than those not given atenolol. Adjusted 30-day mortality was significantly lower in atenolol-treated patients, but patients treated with intravenous and oral atenolol treatment vs. oral treatment alone were more likely to die (odds ratio, 1.3; 95% confidence interval, 1.0 to 1.5; p = 0.02). Subgroups had similar rates of stroke, intracranial hemorrhage and reinfarction, but intravenous atenolol use was associated with more heart failure, shock, recurrent ischemia and pacemaker use than oral atenolol use.Conclusions. Although atenolol appears to improve outcomes after thrombolysis for myocardial infarction, early intravenous atenolol seems of limited value. The best approach for most patients may be to begin oral atenolol once stable.

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1998;32;634-640
J. Am. Coll. Cardiol.
Investigators
Kerry L. Lee, Eric J. Topol, Paul W. Armstrong, for the GUSTO-I
David Naylor, Robert M. Califf, Frans van de Werf, Amanda L. Stebbins,
Matthias Pfisterer, Jafna L. Cox, Christopher B. Granger, Sorin J. Brener, C.

myocardial infarction: the GUSTO-I experience
Atenolol use and clinical outcomes after thrombolysis for acute
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Atenolol Use and Clinical Outcomes After Thrombolysis for Acute
Myocardial Infarction: The GUSTO-I Experience
MATTHIAS PFISTERER, MD, JAFNA L. COX, MD,* CHRISTOPHER B. GRANGER, MD,†
SORIN J. BRENER, MD,‡ C. DAVID NAYLOR, MD,* ROBERT M. CALIFF, MD,†
FRANS VAN DE WERF, MD,§ AMANDA L. STEBBINS, MS,† KERRY L. LEE, PHD,†
ERIC J. TOPOL, MD,‡ PAUL W. ARMSTRONG, MD,? FOR THE GUSTO-I INVESTIGATORS
Basel, Switzerland, Ontario and Edmonton, Canada, Durham, North Carolina, Cleveland, Ohio and Leuven, Belgium
Objectives. We assessed the use and effects of acute intravenous
and later oral atenolol treatment in a prospectively planned post
hoc analysis of the GUSTO-I dataset.
Background. Early intravenous beta blockade is generally
recommended after myocardial infarction, especially for patients
with tachycardia and/or hypertension and those without heart
failure.
Methods. Besides one of four thrombolytic strategies, patients
without hypotension, bradycardia or signs of heart failure were to
receive atenolol 5 mg intravenously as soon as possible, another
5 mg intravenously 10 min later and 50 to 100 mg orally daily
during hospitalization. We compared the 30-day mortality of
patients given no atenolol (n ? 10,073), any atenolol (n ? 30,771),
any intravenous atenolol (n ? 18,200), only oral atenolol (n ?
12,545) and both intravenous and oral drug (n ? 16,406), after
controlling for baseline differences and for early deaths (before
oral atenolol could be given).
Results. Patients given any atenolol had a lower baseline risk
than those not given atenolol. Adjusted 30-day mortality was
significantly lower in atenolol-treated patients, but patients
treated with intravenous and oral atenolol treatment vs. oral
treatment alone were more likely to die (odds ratio, 1.3; 95%
confidence interval, 1.0 to 1.5; p ? 0.02). Subgroups had similar
rates of stroke, intracranial hemorrhage and reinfarction, but
intravenous atenolol use was associated with more heart failure,
shock, recurrent ischemia and pacemaker use than oral atenolol
use.
Conclusions. Although atenolol appears to improve outcomes
after thrombolysis for myocardial infarction, early intravenous
atenolol seems of limited value. The best approach for most
patients may be to begin oral atenolol once stable.
(J Am Coll Cardiol 1998;32:634–40)
©1998 by the American College of Cardiology
Several therapies improve survival after acute myocardial
infarction (MI), including aspirin (1), thrombolytics (2),
angiotensin-converting enzyme inhibitors for patients with
impaired left ventricular function (3) and beta-adrenergic
blocking agents (4). An overview of 28 randomized trials of
early beta blockade in acute MI found a significant, 14%
reduction in mortality during the first week (5). In the largest
study, the First International Study of Infarct Survival (ISIS-1)
trial (conducted before the use of thrombolysis) (6), intrave-
nous, then oral atenolol treatment reduced mortality by 15%
compared with no atenolol (p ? 0.04). Most of the reduction
occurred on the first day, and patients randomized to atenolol
had fewer suspected cardiac ruptures (7). In the Thrombolysis
in Myocardial Infarction (TIMI) phase II trial (8), patients
randomized to acute intravenous metoprolol had less early
reinfarction and recurrent ischemia than patients treated with
delayed oral metoprolol, but ventricular function and mortality
did not differ, although the power to detect such differences
was small. There was also a trend towards reduced intracranial
hemorrhage with intravenous metoprolol (9). In a much
smaller study, although early intravenous treatment with a
beta-blocking or a specific bradycardic agent and thrombolysis
was safe, this strategy appeared not to enhance myocardial
salvage or preservation of left ventricular function (10).
Despite these inconclusive results, early intravenous beta
blockade is generally recommended after MI, especially for
patients with tachycardia or hypertension and those without
heart failure (11). The aim of this study was to describe the use
and effects of acute intravenous and later oral atenolol in
patients also treated with thrombolytics. The analysis plan was
to compare outcomes according to use of any atenolol, and use
of intravenous atenolol, with and without adjustment for
From the Division of Cardiology, University Hospital Basel, Basel, Switzer-
land; *Institute for Clinical Evaluative Sciences, North York, Ontario, Canada;
†Duke Clinical Research Institute, Durham, North Carolina; ‡Cleveland Clinic
Foundation, Cleveland, Ohio; §University Hospital Gasthuisberg, Leuven, Bel-
gium; ?Department of Medicine, University of Alberta, Edmonton, Canada.
Funded by a combined grant from ICI Pharma (Wilmington, DE), Bayer (New
York, NY), CIBA-Corning (Medfield, MA), Genentech (South San Francisco,
CA) and Sanofi Pharmaceuticals (Paris, France).
Manuscript received February 10, 1998; revised manuscript received May 5,
1998, accepted May 20, 1998.
Address for correspondence: Dr. Christopher B. Granger, Duke Clinical
Research Institute, 2024 West Main Street, Bay A-1, Durham, North Carolina
27705. E-mail: grang001@mc.duke.edu.
JACC Vol. 32, No. 3
September 1998:634–40
634
©1998 by the American College of Cardiology
Published by Elsevier Science Inc.
0735-1097/98/$19.00
PII S0735-1097(98)00279-4
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confounding factors. This was a prospectively planned, obser-
vational analysis of the Global Utilization of Streptokinase and
TPA (alteplase) for Occluded Coronary Arteries (GUSTO-I)
data (12).
Methods
Patient population. The methods, results and clinical def-
initions for GUSTO-I have been published (12). Briefly, 41,021
patients within 6 h of symptom onset with ST-segment eleva-
tion were randomly assigned to receive streptokinase (1.5
million U) with subcutaneous heparin (12,500 U) twice daily
beginning 4 h after the start of thrombolysis, streptokinase (1.5
million U) with intravenous heparin, accelerated alteplase with
intravenous heparin or combined alteplase (1.0 mg/kg, up to
90 mg) and streptokinase (1 million U) with intravenous
heparin. All patients received 160 to 325 mg of aspirin daily.
The primary end point of the study was all-cause mortality at
30 days.
Use of atenolol. The protocol recommended that patients
without hypotension, bradycardia or signs of heart failure be
given atenolol (Tenormin?, ICI Pharma, Wilmington, DE)
5 mg intravenously over 5 min as soon as possible after
enrollment, followed 10 min later by another 5 mg intrave-
nously over 5 min. Oral atenolol (50 mg given 10 min after the
last intravenous dose, followed by 50 to 100 mg daily) was to be
given if no contraindications existed. All other medications and
invasive procedures were prescribed at the discretion of the
physician.
Atenolol subgroups. Five main subgroups were established
for this analysis: patients receiving no atenolol, patients receiv-
ing any intravenous atenolol, patients receiving only oral
atenolol and patients receiving both intravenous and oral
atenolol. Groups were further defined by inclusion of only
patients “eligible” for atenolol, inclusion of only patients who
received oral atenolol the day of or the day after enrollment
(days 0 or 1) and inclusion of only patients who survived for at
least 24 or 48 h after entry. Eligible patients were those who
had a heart rate ?55 beats/min, systolic blood pressure
?90 mm Hg and Killip class I or II at entry, and who did not
develop congestive heart failure or cardiogenic shock during
the first 24 h after enrollment. Atenolol initiation after hospital
discharge was not collected.
Statistical analysis. This was a prospectively planned, ob-
servational analysis. Baseline characteristics were summarized
by frequencies and percentages for categorical variables and by
the median, 25th and 75th percentiles for continuous variables.
When predicting 30-day mortality, we used a validated
model to adjust for baseline differences (13). To control for the
confounding issue of early deaths (occurring before oral
atenolol could be given), patients dying within 24 and 48 h of
entry were separately removed and the analyses repeated.
Likewise, an event such as cardiogenic shock, which indepen-
dently predicts mortality, might be a reason for, rather than a
result of, withholding atenolol. When predicting 30-day mor-
tality or the nonuse of atenolol, we adjusted for these two types
of confounding variables by repeating the analyses after ex-
cluding patients who developed cardiogenic shock within 24 h
of enrollment. To account for the greater opportunity for
atenolol use among survivors, another adjustment was per-
formed in which we included only patients who received
atenolol during the first 2 days.
For the prediction of intracranial hemorrhage, adjustments
for differences in baseline predictors were made with another
validated predictive model (14).
To allow comparison with the TIMI-II population, we used
their criteria to identify a low-risk cohort (8). Patients in this
group had no previous infarction, location of infarction other
than anterior, systolic blood pressure ?100 mm Hg, heart rate
under 100 beats/min and no atrial fibrillation, presented in
Killip class I or II and were under 70 years old.
This observational study represents an ancillary analysis of
the GUSTO-I database, which has undergone multiple com-
parisons. To minimize the risk of applying “significance” to
differences possibly due to chance alone, p values in the 0.01 to
0.05 range should be interpreted as only suggestive of statisti-
cal significance.
Results
Atenolol use. Of the 41,021 patients enrolled in GUSTO-I,
24.8% received no atenolol and 75.2% received any atenolol:
44.5% received any intravenous atenolol and 30.7% received it
orally only. Patients who received both intravenous and oral
atenolol had their first oral dose earlier than did patients given
oral atenolol alone. Of patients who received both intravenous
and oral atenolol, 92% received the first oral dose by the end
of the day after enrollment. In contrast, only 68% of patients
managed solely with oral atenolol had received the drug within
this interval.
Baseline characteristics. In general, patients receiving
atenolol had lower-risk features at baseline, including younger
age, higher systolic blood pressure and lower Killip class
(Table 1). With regard to MI location, patients receiving
atenolol were at higher risk, owing to a greater incidence of
anterior MI compared with patients not receiving atenolol.
Clinical outcomes. Unadjusted clinical outcomes, includ-
ing mortality, generally were better for patients treated with
atenolol than for those who were not (Table 2). A higher
proportion of patients who received no atenolol died, and their
deaths occurred earlier: half of the deaths among such patients
occurred within 21 h of entry, and the median time to death
Abbreviations and Acronyms
GUSTO-I ? Global Utilization of Streptokinase and TPA
(alteplase) for Occluded Coronary Arteries (trial)
ISIS-1
? First International Study of Infarct Survival
MI
? myocardial infarction
TIMI
? Thrombolysis In Myocardial Infarction (trial)
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was 23 h earlier for patients who received intravenous and oral
atenolol than for those given only oral drug.
Overall stroke and intracranial hemorrhage rates were
lower among patients given atenolol; however, the rates of
intracranial hemorrhage did not differ between patients who
received any intravenous atenolol (0.64%) and those who
received oral drug alone or no atenolol (0.67%). Even among
patients who presented with marked hypertension (entry sys-
tolic blood pressure ?160 mm Hg), intravenous atenolol use
did not confer a lower risk of intracranial hemorrhage (1.3%
for any intravenous atenolol vs. 1.4% for patients not given
intravenous atenolol). After adjustment for baseline differ-
ences, the use of intravenous atenolol was not associated with
any difference in the rate of intracranial hemorrhage (p ?
0.81).
The reinfarction rate was similar between patients given
intravenous atenolol (3.9%) vs. no intravenous atenolol (4.1%,
p ? 0.61) and between patients given intravenous and oral
(3.8%) vs. oral atenolol alone (4.2%, p ? 0.07). Among
patients given atenolol beginning the day of or after enroll-
ment, 3.8% suffered a reinfarction compared with 3.7% of
patients not given early treatment (odds ratio 1.02, 95%
confidence interval 0.90 to 1.15). Recurrent ischemia occurred
more often among patients given atenolol, although the timing
of ischemia relative to the start of atenolol use was not
recorded.
Table 1. Baseline Clinical Features
Atenolol Use
None
(n ? 10,073)
Any
(n ? 30,771)
Any I.V.
(n ? 18,200)
Oral only
(n ? 12,545)
I.V. and Oral
(n ? 16,406)
Age (yr)
Female sex
Systolic blood pressure (mm Hg)
Heart rate (beats/min)
Killip class
I or II
III or IV
Location of infarction
Anterior
Inferior
Previous hypertension
Previous infarction
Thrombolytic assignment
Streptokinase-subcutaneous heparin
Streptokinase-intravenous heparin
Accelerated alteplase
Combination
65 (57, 73)
29
121 (108, 140)
72 (60, 87)
60 (51, 69)
24
130 (115, 145)
74 (63, 85)
60 (50, 68)
23
130 (118, 148)
76 (66, 88)
61 (53, 69)
25
128 (110, 140)
70 (60, 80)
59 (50, 68)
23
131 (119, 148)
76 (66, 88)
94.3
5.7
99.1
0.9
99.2
0.8
98.9
1.1
99.4
0.6
37.1
59.9
35
20
39.7
56.7
39
15
43.7
52.7
39
15
34.0
62.5
39
16
43.6
52.7
39
14
25.2
25.6
24.9
24.3
23.9
25.3
25.4
23.9
25.0
25.7
24.8
24.5
26.0
24.8
26.2
23.1
25.1
25.7
24.9
24.3
Data presented are percent of patients or median (25th, 75th percentiles). I.V. ? intravenous.
Table 2. Major Clinical Outcomes
Atenolol Use
None
(n ? 10,073)
Any
(n ? 30,771)
Any I.V.
(n ? 18,200)
Oral only
(n ? 12,545)
I.V. and Oral
(n ? 16,406)
30-day mortality
Stroke
Intracranial hemorrhage
Reinfarction
Recurrent ischemia
Congestive heart failure
Shock
Ventricular tachycardia
Ventricular fibrillation
Asystole
High-degree AV block
Tamponade
Time to death (h)
16.5
2.0
0.9
3.7
15.5
22.7
12.4
9.6
9.9
11.8
13.8
1.5
3.8
1.3
0.6
4.1
21.3
14.1
3.9
5.1
5.7
3.7
6.5
0.5
4.6
1.4
0.6
3.9
22.0
15.3
4.5
5.4
5.8
4.4
5.6
0.6
2.7
1.1
0.5
4.2
20.4
12.3
3.1
4.6
5.4
2.8
7.8
0.5
3.1
1.3
0.6
3.8
22.1
14.3
3.3
4.7
5.4
3.3
4.9
0.5
18.8 (3.7, 77.8)79.1 (23.3, 187.6) 62.4 (17.2, 166.2)113 (40.8, 227.5)94.0 (35.3, 195)
Data presented are percent of patients or median (25th, 75th percentiles). AV ? atrioventricular; I.V. ? intravenous.
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The highest incidence of ventricular tachycardia, ventricu-
lar fibrillation and asystole occurred in patients receiving no
atenolol. Intravenous and oral atenolol use was not associated
with a lower incidence of ventricular arrhythmias than oral
atenolol alone, but was associated with a higher incidence of
asystole.
Suspected cardiac tamponade occurred less often among
patients given intravenous atenolol (0.6%) than among pa-
tients given no intravenous atenolol (0.9%, p ? 0.0001), but
the incidence was similar compared with patients given only
oral atenolol (0.5%).
When early intravenous atenolol was compared with early
(within the first 24 h) oral atenolol use, there were increased
rates of congestive heart failure (14.3% vs. 10.7%, p ? 0.01),
cardiogenic shock (3.3% vs. 2.2%, p ? 0.01), recurrent isch-
emia (22.1% vs. 18.9%, p ? 0.01) and the need for pacing
(6.0% vs. 4.0%, p ? 0.01).
Adjusted mortality. The use of any atenolol conferred a
mortality risk fivefold lower than if no atenolol had been given
(Table 3). A significantly lower mortality persisted after ad-
justment for baseline differences, after exclusion of early
deaths and when only “atenolol-eligible” patients were consid-
ered. This pattern persisted for the use of any intravenous
atenolol and for only oral atenolol.
There was a higher unadjusted mortality for patients who
received intravenous and oral atenolol than for those given
early oral atenolol alone. The increased risk of death persisted
after adjustment for baseline characteristics and after exclu-
sion of patients dying within 24 hours of enrollment. After the
removal of patients dying during the first 48 hours, the higher
mortality among patients receiving intravenous atenolol was of
decreased, borderline significance (p ? 0.02). After adjusting
for baseline differences and including only patients given oral
atenolol begun the day of or after enrollment, the likelihood of
dying by 30 days did not differ significantly between patients
given intravenous and oral atenolol and those given only oral
atenolol (p ? 0.15).
Early intravenous vs. oral atenolol treatment in clinical
subgroups. The point estimate suggesting slight harm with the
use of acute intravenous atenolol vs. oral atenolol alone was
similar for the overall group, for patients with systolic blood
pressure ?140 mm Hg (or pulse ?90) and Killip class I at entry
and for patients who underwent thrombolysis within 2 h of
symptom onset (Fig. 1). “Low-risk” patients were of such low
risk (only 7 deaths of 462 patients) that modeling was not
performed. Baseline characteristics associated with early death
after intravenous atenolol were similar to baseline character-
istics associated with early death overall (Table 4).
Discussion
The use of atenolol in 75% of patients in GUSTO-I, and of
intravenous atenolol in 44%, is similar to that of previous trials
in which beta blockade was protocol-mandated for all eligible
patients (8). This represents a much higher rate of use than in
recent United States registry data, which show that only 36%
of patients with acute MI receive oral beta-blockers and only
17% are given intravenous drug after thrombolytic therapy
(15).
The use of atenolol in GUSTO-I was associated with
decreased mortality, stroke, shock and arrhythmias, but in-
creased recurrent ischemia and reinfarction. The interpreta-
tion of these data is confounded in that patients treated with
Table 3. 30-day Mortality
Comparison
Odds Ratio (95%
Confidence Interval) Chi-squarep
Any atenolol vs. no atenolol
Unadjusted
Including only “atenolol-
eligible”*
Adjusted
Adjusted, removing
deaths within 24 h
Adjusted, removing
deaths within 48 h
Any intravenous atenolol vs.
no atenolol
Unadjusted
Including only “atenolol-
eligible”*
Adjusted
Oral atenolol alone vs. no
atenolol
Unadjusted
Including only “atenolol-
eligible”*
Adjusted
Adjusted, removing
deaths within 24 h
Adjusted, removing
deaths within 48 h
Intravenous and oral
atenolol vs. oral
atenolol alone
Unadjusted
Adjusted
Adjusted, removing
deaths within 24 h
Adjusted, removing
deaths within 48 h
Adjusted, removing
deaths within 48 h,
and including only
patients first given
oral atenolol on day 1
(n ? 15,171)
Adjusted, removing
patients developing
shock within 48 h
(n ? 28,273)
Adjusted, including only
patients first given
oral atenolol on day 1
or 2 (n ? 22,790)
0.20 (0.19–0.22)
0.29 (0.26–0.32)
1,600
441
? 0.0001
? 0.0001
0.33 (0.31–0.36)
0.48 (0.43–0.54)
616
161
? 0.0001
? 0.0001
0.53 (0.46–0.60) 95
? 0.0001
0.50 (0.46–0.54)
0.64 (0.57–0.71)
287
63
0.0001
0.0001
0.71 (0.65–0.78) 58 0.0001
0.14 (0.14–0.16)
0.22 (0.19–0.26)
1,395
403
? 0.0001
? 0.0001
0.22 (0.19–0.25)
0.34 (0.29–0.40)
650
202
? 0.0001
? 0.0001
0.39 (0.33–0.47)121
? 0.0001
1.2 (1.0–1.3)
1.2 (1.1–1.5)
1.3 (1.1–1.6)
50.03
0.0001
0.001
15
10
1.3 (1.0–1.5)50.02
1.1 (0.87–1.4)0.60.4
1.1 (0.95–1.4) 9.70.002
1.3 (1.1–1.5) 2.0 0.15
*Atenolol-eligible: heart rate ?55 beats/min, systolic blood pressure
?90 mm Hg, Killip class I or II, and no evidence of congestive heart failure or
cardiogenic shock at presentation.
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atenolol were generally less ill at presentation and may have
had greater preservation of left ventricular function. Because
there was a delay in beginning atenolol (especially oral ateno-
lol) after enrollment and a very high proportion of deaths
(19% of the eventual 30-day mortality) occurred within 4 h
after randomization (16), atenolol was used more often in
survivors unrelated to any treatment effect. The reduction in
adverse events seen with atenolol use, then, may have been due
to lower baseline risk, longer survival time, the beneficial
effects of atenolol or to a combination of these factors.
To address the issue of differences in baseline risk, vali-
dated risk-adjustment models were applied. Another way to
adjust for baseline differences was to include only patients who
were “atenolol-eligible.” To adjust for the confounding influ-
ence of early death (reducing the opportunity for use of
atenolol), we excluded all patients who died early and included
only patients who began atenolol treatment within 2 days of
enrollment.
Mortality. Studies conducted before thrombolytic therapy
came into use have shown a 15% to 25% reduction in mortality
with the use of a variety of beta-blockers after acute myocar-
dial infarction (4–6). Although nonrandomized, the current
observational study reinforces these findings and extends them
into the thrombolytic era. The markedly lower mortality seen
with atenolol use was highly significant even after adjustment
for confounding factors.
The mortality reductions presented here are larger than
those previously reported. The treatment effects may have
been exaggerated because the untreated cohort likely consisted
of three subpopulations that post hoc adjustments could not
adequately tease out: low-risk individuals for whom treatment
was deliberately withheld (biasing against an effect of ateno-
lol), otherwise eligible patients whose physicians were uncer-
tain about the efficacy of early atenolol with thrombolysis (the
group with whom a reasonably unbiased comparison is possi-
ble) and very high-risk patients who were deemed too sick to
receive atenolol (biasing towards an exaggerated treatment
effect). This caveat notwithstanding, the results are direction-
ally consistent with previous descriptions and are consistent
with the short-term mortality reduction from an overview of
almost 30,000 patients across 28 trials (4).
Given the acceptance of the general benefit of beta block-
ade after MI, the most important unresolved clinical issue may
be whether patients benefit from acute intravenous beta block-
ade (beyond oral therapy). The TIMI-IIb trial compared early
intravenous, then oral, metoprolol vs. a strategy of significantly
delayed oral metoprolol (at 6 days). Although acute intrave-
nous and oral metoprolol conferred a lower risk of reinfarction
and recurrent ischemia in the TIMI-II study (8), the lower
event rate occurred only during the first week. Because oral
metoprolol use did not begin until day 6 in the comparison
group, however, their higher ischemic event rate may reflect
the delay until oral metoprolol use rather than the lack of
immediate intravenous metoprolol. An incremental benefit of
immediate intravenous atenolol in addition to oral drug, vs.
slightly later oral drug alone, was not seen in GUSTO-I
patients after adjusting for differences in baseline characteris-
tics and excluding early cardiogenic shock. In TIMI-II, pro-
Figure 1. Odds ratios and 95% confidence intervals for
30-day mortality, adjusted for baseline characteristics
and excluding deaths within 24 h, for selected patient
subgroups who received intravenous and oral atenolol
vs. oral atenolol alone. Hypertension was defined as
systolic blood pressure ?140 mm Hg or pulse ?90 at
enrollment, with Killip class I. Low-risk was defined as
location of infarction other than anterior, Killip class I
or II, heart rate ?100, age ?70 years, no atrial fibrilla-
tion and no previous infarction at enrollment (8).
“Treated within 2 hours” refers to thrombolytic therapy.
Table 4. Baseline Characteristics by Intravenous Atenolol Use and Time of Death
Intravenous Atenolol,
Lived ?48 H
(n ? 328)
Intravenous Atenolol,
Lived ?48 H
(n ? 17,711)
No Intravenous Atenolol,
Lived ?48 H
(n ? 1129)
Age (yr)
Systolic blood pressure (mm Hg)
Heart rate, median (beats/min)
Killip class
I or II
III or IV
Location of infarction
Anterior
Inferior
71 (63, 78)
130 (110, 145)
82 (70, 97)
59 (50, 68)
130 (118, 148)
76 (66, 88)
72 (64, 78)
110 (99, 130)
81 (65, 100)
93.6
6.4
99.3
0.7
81.5
18.5
59.5
35.4
43.3
53.1
55.9
40.6
Data presented are percent of patients or median (25th, 75th percentiles).
638
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ATENOLOL USE AFTER ACUTE MYOCARDIAL INFARCTION
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spectively defined subgroup analysis suggested that patients
presenting within 2 h of symptom onset had greater benefit
from intravenous metoprolol; we could not replicate this
finding. TIMI-II also identified a “low-risk” group that ap-
peared to derive greater benefit. In GUSTO-I, this subgroup
(see Methods) had such low mortality that the effect of early
intravenous atenolol could not be meaningfully measured.
Although the American College of Cardiology/American
Heart Association Guidelines recommend the use of intrave-
nous beta-blockers for patients with hypertension and/or tachy-
cardia in the absence of congestive heart failure (11), we could
not show that this subgroup benefited.
Stroke. Although the TIMI-II study found a trend (p ?
0.11) toward reduced intracranial hemorrhage among patients
assigned to intravenous metoprolol (9), we were unable to
show such an association after adjusting for baseline charac-
teristics. Even for patients presenting with hypertension, the
rates of intracranial hemorrhage were the same regardless of
use of early intravenous atenolol.
Recurrent ischemia and reinfarction. We found no conclu-
sive evidence of protection against in-hospital reinfarction with
the use of any atenolol, although the wide confidence intervals
do not rule out the potential for a clinically important reduc-
tion in event rates. Recurrent ischemia was more common
among patients who received atenolol, but the timing of
recurrent ischemia was not recorded. Although impossible to
prove, this association may simply reflect the use of atenolol to
manage the recurrent ischemia.
Tamponade. Consistent with the lower incidence of sus-
pected tamponade associated with the use of early intravenous
atenolol in ISIS-1 (6), a lower incidence of tamponade was
seen with intravenous atenolol use in GUSTO-I, although the
absolute difference was small (0.6% vs. 0.9% for no intrave-
nous drug, p ? 0.0001). A theoretical appeal of early intrave-
nous beta blockade is the potential to reduce the incidence of
cardiac rupture, which contributes to the increased risk of early
death associated with thrombolysis (2). The prompt adminis-
tration of a more potent thrombolytic regimen may itself be
associated with less “early hazard,” however, and this may
lessen any relative beneficial effect of very early beta blockade
on mortality (16).
Risk of intravenous atenolol. After adjustment for baseline
differences and control for timing of death, the point estimate
still suggested slight harm with acute intravenous atenolol use.
Thus, although the limits of the analysis are substantial, the
results suggest that oral beta-blockers should be the standard
of care and that early intravenous atenolol seems of limited
value.
Limitations. This study is limited by its observational na-
ture. Interpretation of the effect of atenolol on outcomes is
confounded by the nonrandomized assignment of such ther-
apy. Enrollment of patients into GUSTO-I was based on their
eligibility for thrombolytic therapy, and baseline characteristics
were those at the time of randomization. The decision to give
or withhold atenolol was made some time after randomization,
when the status of the patient may have changed. Thus, the risk
adjustments herein pertain to the time of randomization to
reperfusion regimen and not necessarily to the time of the
decision about atenolol use.
Even more uncertain is the influence of early deaths on the
results. A clinician observing a patient after randomization
may have delayed the decision to begin atenolol pending
clinical findings or for logistical reasons; patients dying during
this period are counted in the “no atenolol” group. Although
eliminating early deaths using various criteria can give a
perspective on the effect of this issue, there is no completely
satisfactory approach. Additionally, although more than 41,000
patients were enrolled in GUSTO-I, once subgroups are
examined the power to detect meaningful differences in out-
comes is limited. The limited power is compounded by even
fewer events in the analyses from which early deaths are
removed. Moreover, a major portion of the benefit of intrave-
nous atenolol may be in the reduction of deaths during the first
24 h. Therefore, removing the patients with early death from
the analysis may remove the ability to detect an early beneficial
effect.
Given these limitations, although this report can provide a
detailed account of the clinical outcomes of patients selected
for atenolol therapy, it cannot provide definitive evidence
about whether and which type of beta-blocker therapy should
be used. Rather, observations about differences in outcome
with and without atenolol should be interpreted in light of
other sources of evidence and used only to generate hypothe-
ses.
Clinical implications. These observational GUSTO-I data
do not corroborate reports that early beta blockade reduces
the risk of intracranial hemorrhage, but are entirely consistent
with available randomized evidence regarding reduced risk of
cardiac rupture and death with this therapy. Use of beta-
blockers is thus unequivocally beneficial for patients who have
received thrombolytic therapy. However, a large, randomized
trial still is required to determine the optimal timing and route
of such therapy. Until then, data from this analysis of more
than 41,000 patients with MI show that the addition of routine
intravenous atenolol adds only limited value to a strategy of
early oral atenolol given once the patient is stable.
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September 1998:634–40
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1998;32;634-640
J. Am. Coll. Cardiol.
Investigators
Kerry L. Lee, Eric J. Topol, Paul W. Armstrong, for the GUSTO-I
David Naylor, Robert M. Califf, Frans van de Werf, Amanda L. Stebbins,
Matthias Pfisterer, Jafna L. Cox, Christopher B. Granger, Sorin J. Brener, C.

myocardial infarction: the GUSTO-I experience
Atenolol use and clinical outcomes after thrombolysis for acute
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