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JACC Vol. 25, No. 6
May 1995:1327-32
1327
MYOCARDIAL INFARCTION
Treatment With Beta-Adrenergic Blocking Agents After Myocardial
Infarction: From Randomized Trials to Clinical Practice
SAMI VISKIN, MD,* ILAN KITZIS, MD,? ELI LEV, MD, ZEEV ZAK, MD, KARIN HELLER, MD,
Y A E L V I L L A , MSc,~ A L E J A N D R O
BERNARD
BELHASSEN,
ZAJARIAS, MD,§ SHLOMO
LANIADO, MD, FACC,
MD, F A C C
Tel Aviv, Israel; Syracuse, New York; and Mexico City, Mexico
Objectives. Our aim was to determine the percent of patients
with myocardial infarction who are treated with beta-adrenergic
blocking agents in dosages proved to be effective in preventing
death after a heart attack.
Background. In the prospective randomized trials showing that
beta-blocker treatment improves survival rates after myocardial
infarction, relatively high dosages of these agents were used.
However, it is not known whether these dosages are used in
current clinical practice.
Methods. In a retrospective analysis of clinical data from 606
consecutive survivors of myocardial infarction at four university
hospitals in three countries, we assessed the number of infarct
survivors receiving prospectively defined "effective dosages" of
beta-blockers. We defined these dosages as those that demonstrated improved survival rates of infarct survivors who received
active drug in large, prospective, double-blind, placebo-controlled
trials.
Results. Only 58% of infarct survivors with no contraindications to beta-blockers received these drugs at the time of hospital
discharge, and only 11% received dosages equivalent to >50% of
the effective dosages. Independent predictors of failure to prescribe beta-blockers to infarct survivors without contraindications
to these drugs were the use of diuretic agents, transient heart
failure, impaired left ventricular function and increased patient
age. Among patients receiving beta-blockers, only the use of
propranoiol predicted prescription of a low beta-blocker dosage.
Conclusions. Failure to prescribe beta-blockers after myocardial infarction is common but in most cases is not due to clear
contraindications. Many patients not receiving beta-blockers belong to subgroups that would derive the greatest benefit from such
treatment. Finally, even when beta-blockers are prescribed, the
dosages used are considerably lower than those proved to be
effective in preventing death after myocardial infarction.
(J Am Coil Cardioi 1995;25"1327-32)
Prospective randomized trials have shown that beta-blockers
improve the long-term prognosis of patients with myocardial
infarction (1): mortality, cardiac death and sudden cardiac
death are reduced by 21%, 24% and 30%, respectively (1,2). In
addition, treatment with beta-blockers reduces the risk of
reinfarction by 25% (1). Therefore, infarct survivors who have
no specific contraindications to beta-blockers should routinely
be offered such therapy (3,4).
However, although data on the beneficial effects of betablockers have existed for almost 2 decades (5), many infarct
survivors are not being treated with these agents. A recent
survey of medical practices in 16 hospitals in Massachusetts (6)
and two multicenter trials in the United States (7) and Europe
(8) demonstrated that only 44% to 56% of patients were
receiving beta-blocker therapy after a myocardial infarction.
These numbers are surprising because clear contraindications
to such treatment were found in only 18% of patients enrolled
in prospective beta-blocker trials (9,10).
Although several studies have found predictors of failure to
prescribe beta-blockers, including impaired left ventricular
ejection fraction (11), evidence of heart failure (6,11) and
increased patient age (6,12,13), we know of no published data
on the dosages of beta-blockers generally prescribed after a
myocardial infarction. Such data are important because trials
showing improvement in survival rates with beta-blocker treatment invariably used relatively high dosages (9,14-16). Therefore, the aim of this study was to analyze the percent of infarct
survivors who receive beta-blockers in dosages comparable to
those proved to be effective in improving long-term survival.
From the Departmentsof Cardiologyand EmergencyMedicine,SouraskyTel AvivMedicalCenter and SacklerSchoolof Medicineand :]:Departmentof
Statistics, Tel AvivUniversity,Tel Aviv. Israel; +State Universityof New York
Health Science Center, Syracuse, New York: and §lnstituto Nacional de
Cardiologialgnacio Chavez,MexicoCity,Mexico.Dr. Viskinis a recipientof a
fellowship from the American PhysiciansFellowship for Medicine in Israel.
Brookline,Massachusetts.
Manuscript receivedJuly 14, 1994;revisedmanuscriptreceivedDecember9.
1994, acceptedDecember15, 1994.
*Presentaddressand addressfor correspondence:Dr. SamiViskin,Department of Cardiology,ElectrophysiologyDivision. Universityof California, San
Francisco, 500 Parnassus Avenue,Box 1354,San Francisco,California94143.
©1995 by the AmericanCollegeof Cardiology
Methods
We reviewed the files of consecutive patients discharged
with a diagnosis of acute myocardial infarction from one
American, one Mexican and two Israeli hospitals. The patients
had been treated in wards of Internal Medicine and Cardiology
at the State University of New York Health Science Center,
0735-1097/95/$950
0735-1097(94)00552-2
1328
V1SKIN ET AL.
BETA BLOCKERS AFTER MYOCARDIAl_ INFARCTION
Syracuse, New York (166 patients), lnstituto Nacional de
Cardiologia Ignacio Chavez, Mexico City, Mexico (71 patients), the Chaim Sheba Medical Center, Tel-Hashomer,
Israel (113 patients) and the Souras~-Tel Aviv Medical Center, Tel Aviv, Israel (256 patients) during the last 6 months of
1993.
Definitions. We defined contraindication to beta-blocker
treatment according to the criteria used in the large prospective studies on beta-blocker treatment after myocardial infarction (9,10,14,15). Thus, the presence of any of the following
classified a patient as having contraindications: 1) a diagnosis
(or clinical signs) of asthma or chronic obstructive lung disease; 2) heart failure not controlled with diuretic drugs (furosemide >80 mg/day) or with digoxin and diuretic drugs (any
dosage); 3) the presence of atrioventricular (AV) block of any
degree, heart rate <50 beats/min or systolic blood pressure
<100 mm Hg (unless transient) before treatment with betablockers.
The type and daily dosage of beta-blocker recommended at
the time of hospital discharge were recorded as a percent on
the basis of the "effective dosage." We defined "demonstrated
effective dosages," (or, in short, "effective dosages") of betablockers as the dosages used in large prospective double-blind
placebo-controlled beta-blocker trials that demonstrated improved survival in the patients receiving active drug. Accordingly,
we defined "effective dosages" as follows: propranolol, 160 m~'
day (9,15); metoprolol, 200 mg/day (14), or atenolol, 100 mg/day
(17). We found no patients receiving timolol, sotalol, pindolol,
practolol, oxprenolol or acebutolo[ at the time of hospital discharge.
Statistics. The following variables were analyzed for their
value in predicting absence of beta-blocker treatment among
patients without contraindications to beta-blockers: age, gender, hospital from which the patients were discharged, infarct
location, Q wave infarction, left ventricular ejection fraction,
results of coronary angiography, revascularization procedures,
lowest heart rate recorded, presence of arrhythmias, pulmonary edema, heart failure and hypotension at any time during
the hospital stay and use of other medication (diuretic drugs,
calcium channel blocking agents, vasodilators, digoxin, nitrates, aspirin or anticoagulant agents). Univariate predictors
were examined by chi-square test for discrete variables and
t test or analysis of variance for continuous variables. The
results are given as odd ratio and p values. In addition to the
variables mentioned, the type of beta-blocker used was tested
for prediction of the dosage of beta-blocker (expressed as
percent of effective dosage) prescribed. Pearson correlation
was performed to evaluate the relation between two continuous variables. Multivariate predictors of failure to prescribe
beta-blockers were selected by logistic regression; stepwise
regression was used to define the most important independent
predictor of the dosage of beta-blocker prescribed. Statistical
significance was defined as a p value <0.05.
JACC Vol. 25, No. 6
May 1995:1327-32
Results
Patient characteristics. During the study period, 606 patients (mean [+_SD] age 64 +_ 14 years) were discharged after
a myocardial infarction. Of these, 69% were male and 78%
were <75 years old; in 31%, the infarct involved the anterior
wall, in 59% it was inferior or inferoposterolateral and in 9%
it was not localized. A Q wave infarction occurred in 45% of
patients. Transient complications among infarct survivors included bradyarrhythmias in 22%, atrial or ventricular tachyarrhythmias in 16%, hypotension in 10%, heart failure in 21%,
pulmonary edema in 14% and cardiogenic shock in 2%.
Data on left ventricular ejection fraction were available for
54% of patients. The mean ejection fraction was 45 _+ 19%;
90% and 71% of infarct survivors, respectively, had an ejection
fraction >30% and >40%. Cardiac catheterization was performed during the hospital stay for myocardial infarction in
49% of patients: Single-, double- and triple-vessel coronary
disease was found in 41%, 29% and 23%, respectively, of these
patients, and normal coronary arteries were reported in 6%.
During the hospital stay for infarction, coronary bypass surgery
was performed in 7% of infarct survivors (14% of those
undergoing catheterization); coronary angioplasty was attempted in 15% and was successful in 12% (29% and 23%,
respectively, of those undergoing catheterization).
Treatment with beta-blockers after myocardial infarction.
Contraindications to treatment with beta-blockers were
present in 18% of infarct survivors. They included bronchial
asthma or chronic obstructive lung disease in 7%, heart failure
controlled only with the use of >80 mg of furosemide daily or
the use of digoxin in 7%, sinus bradycardia in 4%, AV block in
5% and hypotension at the time of hospital discharge in 5%.
Many patients had more than one contraindication.
Only 51% of all infarct survivors received beta-blocker
treatment at the time of hospital discharge. Moreover, only 6%
of all infarct survivors received an effective dosage of these
drugs (Fig. 1). The percent of infarct survivors receiving
beta-blockers was similar in all four hospitals (48%, 53% and
57% in the Israeli, the American and the Mexican hospitals,
respectively; p = NS). However, the type of beta-blocker used
varied among hospitals: Metoprolol was used in >85% of
treated patients in the American and Mexican hospitals,
whereas propranolol was the drug most commonly used (63%
of treated patients) in the two Israeli hospitals. Atenolol was
given to 26%, 11% and 5% of patients receiving beta-blockers
in the Israeli, American and Mexican hospitals, respectively.
The mean daily dosages used were 105 _+ 56 mg of metoprolol,
50 _+ 34 mg of propranolol and 65 + 57 mg/day of atenolol.
Except for atenolol, which tended to be used in a higher dosage
in the American hospital (111 _+ 122 mg/day, p : 0.05), the
dosage of beta-blockers prescribed for infarct survivors was
similar in the four hospitals studied (p = 0.2 and p = 0.13 for
propranolol and metoprolol, respectively).
Although 82% of infarct survivors had no contraindications
to beta-blocker treatment, only 58% of this group received
beta-blockers. Moreover, most patients receiving beta-blockers
JACC Vol. 25. No. 6
May 1995:1327-32
50
VISKIN ET AL.
BETA-BLOCKERS AFFER MYOCARDIAL INFARCTION
1329
Table 1. Predictors of Treatment With Beta-Blockers Among
Infarct Survivors Without Contraindications
T 49
45
Variable
•
40
Odds Ratio (95% confidence limits)
All Patients
Univariate Analysis
~J Patients Without
35
Contraindications
3O
24.9
~25
22
19.3
a. 2 0
Use of diuretic drugs
Transient heart failuret
Age >70 years
LVEF not measured
Use of calcium channel blockers
Pulmonary edema
LVEF <30%
15
10
7.9
5
2.8
3.3
Successful PTCA
Electrical complications
Female gender
0.25 (0.15-0.42)*
0.27 (0.16-0.47)*
0.30 (0.20-0.44)*
0.45 (0.31-0.64)*
0.45 (0.3l-0.66)*
0.33 (0.16-0.69):[:
0.32 (0.11-0.87)§
0.60 (0.34-1.05)[[
0.62 (0.38-1.04)1[
0.69 (0.47-1.03)11
Multivariate Analysis (logistic regression)
0
0
1--25
26--50
51--75
>75
Percentage of Effective Dosage (%)
Figure 1. Distribution of infarct survivors according to the dosage of
beta-blocker prescribed at the time of hospital discharge. Dosages of
beta-blockers are shown as percent of effective dosage (see Methods
for definition of effective dosage). Solid bars = all patients surviving a
myocardial infarction; open bars - all infarct survivors who had no
contraindications to beta-blocker treatment.
received a dosage significantly lower than those proved to be
effective in preventing death (Fig. 1): Sixty-seven percent of
infarct survivors without contraindications to beta-blockers
(and 61% of those <70 years old) received a dosage equivalent
to -<25% of the effective dosage of beta-blockers, whereas a
dosage equivalent to >50% of the effective dosage was given to
only 11% of infarct survivors without contraindications to
beta-blockers regardless of age.
Use of diuretic agents was the most important independent
predictor of failure to prescribe beta-blockers to infarct survivors without contraindications to beta-blockers (Table 1).
Other variables representing left ventricular dysfunction (transient or compensated heart failure, left ventricular ejection
fraction <30% or pulmonary edema during the hospital stay)
also predicted failure to prescribe beta-blockers at the time of
hospital discharge (Table 1). Of note, persistent left heart
failure despite treatment would classify a patient as having
contraindications to beta-blockers.
We found no significant correlation between any of the
variables predicting failure to prescribe beta-blockers (Table 1)
and the beta-blocker dosage actually prescribed (Table 2). By
Pearson analysis, no correlation was found between the last
heart rate recorded and the dose of beta-blocker prescribed.
The only independent variable that predicted use of low (or
high) beta-blocker dosage was the type of beta-blocker used
(Table 2): The mean dosage of propranolol was equivalent to
<33% of the effective dosage, whereas patients receiving
metoprolol received (on average) the equivalent of 50% of the
effective dosage. Finally, the only variable that predicted the
use of propranolol (rather than metoprolol or atenolol) was
the use of diuretic drugs.
Age >70 years
Use of diuretic drugs
0.62 (0.50-0.87):I:
0.66 (0.50-0.88)~:
0.76 (0.62-0.93)§
0.64 (0.4%0.88)§
LVEF <30%
Transient heart failure
An odds ratio value <1 denotes that the respective variable predicted failure
to prescribe beta-blockers: *p < 0.0001. tPersistent heart failure despite
treatment would classify a patient as having a contraindication to beta-blocker
therapy. ;p < 0.005. §p < 0.05. liP - 0.07; all other variables tested (see
Methods) did not significantly predict the use of beta-blockers. LVEF = left
ventricular ejection fraction; PTCA - percutaneous transluminal coronary
angioplasty.
Discussion
Although beta-blockers should be part of the standard
long-term treatment after a myocardial infarction (3,4),
roughly 50% of >600 patients surviving a myocardial infarction in three countries were discharged without such treatment. These figures are similar to those reported in multicenter trials (7,8). However, the main finding in our study is
that failure to recommend beta-blockers at the time of hospital
discharge is typically not due to clear contraindications. More-
Table 2. Percent of Effective Dosage of Beta-Blockers Administered
to Infarct Survivors Without Contraindications
Percent of Effective Dosage* (mean _+ SD)
Univariate Analysis
City
Tct Aviv
Syracuse, New York
Mexico City
Type of beta-blocker
Metoprolol
Propranolol
Atenolol
42 _+27]
60 -+ 55
44 _+ 18]
p < 0.01
p < 0.05
52 _+ 28]
31 _+ 21
65 + 571
p < 0.0005
p < 0.0005
Multivariate Analysis (stepwise regression)
Type of beta-blocker
p < 0.0001
*See Methods for definition of effective dosage. No other variable tested
(Table 1) correlated significantlywith the prescribed dosage of beta-blocker.
1330
V1SKIN ET AL.
BETA-BLOCKERS A F T E R M Y O C A R D I A L INFARCTION
over, many of the patients not receiving beta-blockers belong
to patient subgroups that would derive the greatest benefit
from such treatment. Finally, even when beta-blockers are
prescribed, the dosages used are considerably smaller than
those proved to be effective by prospective trials, with only 6%
of infarct survivors receiving effective dosages.
What are effective dosages of beta-blockers? We defined as
effective only those dosages proved to be effective in reducing
mortality in prospective, randomized, double-blind placebocontrolled trials (9,14,15). It is possible that lesser dosages are
also effective in prolonging survival after infarction, but this
hypothesis remains to be proved.
According to our definition, dosages of metoprolol,
200 rag/day (14), and propranolol, 160 rag/day (15), represented effective doses. However, higher dosages of propranolol
(180 to 240 rag/day) were prescribed to the majority of patients
in the Beta-blocker Heart Attack Trial (9). Thus, we may have
overestimated the low percent of patients receiving effective
dosages of propranolol in our study.
Nine percent of patients in our study received atenolol. For
these patients, we considered effective a dosage of 100 rag/day,
a regimen that has been found (17) to have effects on the
1-year survival of infarct survivors comparable to those of
160 mg/day of propranolol. However, those data come from a
small study with a high withdrawal rate (17). Also, 100 rag/day
of atenolol decreased the 1-year cardiovascular mortality in the
ISIS-I study (18), but the randomization period in that study
was limited to the in-hospital period. In fact, only 35% of
patients in ISIS-1 received long-term treatment with betablockers. Therefore, our definition of 100 rag/day of atenolol as
effective dosage was based mainly on published data on
"equipotency" with propranolol and metoprolol (19-21).
However, these equipotency data were derived from the drugs'
effects on blood pressure (19) and on tachycardia (induced by
exercise [19,20] or isoproterenol infusion [21]) and do not
necessarily apply to postinfarction patients.
Why are so many infarct survivors discharged without
beta-blocker therapy? Only a minority of infarct survivors
have clear contraindications to beta-blocker treatment. Such
patients comprised only 18% of our study group and of those
in the largest beta-blocker trials (9,10). If diabetes and peripheral vascular disease are added to the list of contraindications,
up to 27% of infarct survivors may be considered to have
contraindications (22). However, published data suggest that
infarct survivors with these conditions should not be deprived
of the potential benefits of beta-blocker treatment. Although
some studies (10,14) excluded patients with severe intermittent
claudication, peripheral vascular disease itself was not a contraindication to enrollment in large beta-blocker trials (9,14).
Yet symptomatic deterioration of peripheral vascular disease
as a reason for drug discontinuation was not more common in
patients receiving beta-blockers than in those receiving placebo (9,14,23). Moreover, reduction of mortality and reinfarction rates by beta-blocker treatment appears to be especially
pronounced in diabetic patients (24-27).
In our study, only 58% of infarct survivors without contra-
JACC VoI. 25, No. 6
May 1995:1327-32
indications to beta-blockers were receiving these drugs. Predictors of failure to prescribe beta-blockers included the
presence of impaired left ventricular function (as indicated by
treatment with diuretic agents, transient or controlled heart
failure or left ventricular ejection fraction <30%) and increased patient age. It is plausible that physicians avoid
recommending beta-blockers to patients with impaired left
ventricular function and to elderly patients, mainly because of
their concern for potential iatrogenic complications. These
observations deserve further comment.
Infarct survivors with impaired left ventricular function
are less likely to receive beta-blockers. Is that justifiable? Our
results are in accordance to the report by Lichstein et al. (11)
on the use of beta-blockers in a multicenter trial. In that study
(11), the percent of infarct survivors receiving beta-blockers
ranged from 57% among patients with good left ventricular
function to 21% among patients with a left ventrieular ejection
fraction <30%.
The danger of causing overt heart failure with beta-blockers
appears to be overestimated: The rate of precipitation of heart
failure of enough severity to warrant drug discontinuation was
<5% in the large beta-blocker trials (9,10,14). Even among
infarct survivors with marked cardiomegaly (28) or with a
history of congestive heart failure (23), clinical heart failure
was rarely precipitated (in 8% and 15% of patients, respectively) and was not more common than in patients treated with
placebo (23,28). In fact, some data (11) suggest that betablocker treatment of postinfarction patients with impaired
ejection fraction may prevent, rather than precipitate, the
development of clinical heart failure. Finally, by withholding
beta-blocker treatment from patients with impaired left ventricular function, we may be depriving the very patients who
have the most to gain from such therapy (2,28,29). The large
prospective beta-blocker trials did not provide data on the
ejection fraction of randomized patients (9,10,14). However,
other variables that correlate with large infarcts (i.e., higher
serum enzyme levels [14] or cardiomegaly [9,10] invariably
correlated with a greater absolute reduction in mortality with
beta-blocker therapy (9,10,14). For example, in the Norwegian
Multicenter Study, 2 lives were saved for each 100 patients with
normal heart size treated with timolol, whereas among patients
with cardiomegaly, 10 lives were saved per 100 patients treated
(28).
Should elderly patients be treated with beta-blockers after
myocardial infarction? Physicians seem to be reluctant to
prescribe beta-blockers to elderly patients (6,12). In our study
only 38% of infarct survivors without contraindications to
beta-blockers who were ->70 years old received these agents,
whereas 68% of similar younger patients received such treatment.
Although the value of beta-blockers for improving survival
in elderly infarct survivors remains to be proved (prospective
beta-blocker trials excluded patients >70 (9,14,15) or 75
(10,16,30) years old, subgroup analysis of most prospective
trials does not suggest a decreased benefit from beta-blockade
with increasing age (9,10,14,16). In fact, it is the youngest
JACC Vol. 25, No. 6
May 1995:1327-32
patients (those <50 [2], <60 [23] or <65 [14] years old) who
may, because of their generally good prognosis, derive the
smallest benefit from beta-blocker treatment. Finally, use of
beta-blockers was the best predictor of survival among patients
who were >70 years of age at the time of myocardial infarction
in a nonrandomized study (12), and a trend toward increased
survival with beta-blocker use was also reported for patients
>75 years old (13).
Bradycardia and symptomatic peripheral vascular disease
seem to be the only adverse effects of beta-blockers more
common with increasing age (31). Therefore, with close followup, increased age should not be viewed as a contraindication to
beta-blockade (31).
Only a minority of infarct survivors receive effective dosages of beta-blockers. To our knowledge, there have been no
previous published data on the dosages of beta-blockers commonly prescribed after infarction. Our observation that only
6% of patients received a dosage equivalent to those proved
effective in preventing death after infarction should be confirmed by further studies.
The only independent predictor of prescription of a low
dosage was the type of beta-blocker used: Patients receiving
propranolol received a significantly lower dosage. This trend
was apparently influenced by the dose of beta-blockers available in tablets: A 10 mg tablet of propranolol is equivalent to
only 6% of the effective dosage (32). In contrast, patients
receiving the smallest metoprolol dose available in tablets (i.e.,
50 mg [32]) are receiving 25% of the effective daily dosage. Our
study did not examine why physicians prefer one beta-blocker
over another. It is possible that propranolol was preferred for
patients conceived to be at higher risk for adverse effects, as
suggested by the more common use of propranolol (rather
than other beta-blockers) among patients receiving diuretic
agents.
Limitations and clinical implications of our study. Our
study focused on the clinical practices of four hospitals in three
countries, and the data may not apply to the treatment of
infarct survivors elsewhere. However, the percent of infarct
survivors receiving beta-blockers in our study was very similar
to that reported in large studies (7,8,33). Also, we limited our
evaluation of drug treatment to that recommended at the time
of hospital discharge; thus, it is possible that more betablockers were given during follow-up visits. However, in the
European Cooperative Study (8), the percent of infarct survivors receiving beta-blockers at 3 months and 1 year after
infarction was essentially that reported at the time of hospital
discharge. In addition, a recent survey of treatment practices in
England (22), indicated that family physicians were administering beta-blockers to only 39% of infarct survivors without
contraindications. Therefore, we believe that our results regarding the underuse of beta-blockers after myocardial infarction represent common clinical practice and identify a major
gap between what we have learned from prospective trials and
current treatment of patients. This gap ought to be closed by
continuing medical education. Alternatively, prospective studies should be made of infarct survivors randomized to receive
VISK1N ET AL.
BETA-BLOCKERS AFTER MYOCARDIAL INFARCTION
1331
either the "effective dosage" defined by large clinical trials or
the relatively low dosage of beta-blockers commonly used.
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