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JACC Vol. 26, No. 2
August 1995:547-52
547
EDITORIAL
Physician Use of Beta-Adrenergic Blocking Therapy:
A Changing Perspective*
H A R O L D L. KENNEDY, MD, MPH, ROBERT S. ROSENSON, MD
Chicago, Illinois
Although the merit of beta-adrenergic blocking therapy in the
treatment of cardiovascular disease has steadily evolved since
its clinical introduction ~30 years ago (1,2), it remains somewhat enigmatic as to why these therapeutic agents are not
prescribed more widely by North American physicians (3). This
physician resistance to utilizing beta-blocker therapy, in our
opinion, is multifaetorial and has resulted from a combination
of both scientific and commercial events that occurred in North
America during the past two decades. This scientific landscape
is now changing, and it is appropriate to examine the factors
that color physicians' attitudes regarding this therapeutic class
of drugs.
Initially, investigative studies and clinical trials of betablocker therapy were slow to emerge. In part, this resulted
from the slow genesis and refinement of scientific methodology
regarding clinical trials (4), and in part because the clinical
introduction of beta-blocker therapy was simultaneously accompanied by (at least in North America) an insidious medical
concern regarding the adverse effects of beta-blocker therapy
(5-7). Despite multicenter randomized clinical trials that definitively established tile importance of beta-blocker therapy as
an independent preventive therapy in both ischemic heart
disease and hypertension for decreasing all-cause mortality,
cardiovascular mortality and sudden death (2,8-10), physician
prescription of such therapy in North America has remained
unexpectedly low (3). These practice attitudes have evolved for
several reasons; prominent among them is a sense of physician
skepticism concerning the benefits of beta-blocker therapy and
an exaggerated concern for their adverse effects. After three
decades of clinical investigation and >55 trials of beta-blocker
therapy involving as many as 53,000 patients (11-13), it is both
appropriate and timely for physicians to reflect and critically
examine the data that established the merit of beta-blocker
*Editorials published in the Journal o1'the American College of Cardiology
reflect the views of the authors and do not necessarily represent the views oF
JACC or the American College of Cardiology.
From the Section of Cardiology, Rush Heart Institute, Department of
Internal Medicine, Rush Medical College, Rush-Presbyterian-St. Luke's Medical
Center, Chicago, Illinois.
Manuscript received July 13, 1994; revised manuscript received March 9,
1995, accepted March 14, 1995.
Address for correspondence: Dr. Harold L. Kennedy, The Cardiovascular
Research Foundation, St. Anthony's Medical Center, 10004 Kennedy Road,
Suite 160B, Saint Louis, Missouri 63128.
©1995 by the American College of Cardiology
therapy in cardiovascular diseases and perhaps reflect on their
personal perspective and temerity (if any) in prescribing such
therapy.
Ethcacy of Beta-Blocker Therapy
Beta-blocker therapy has been shown to be eiticacious 1) as
primary preventive therapy in hypertensive patients to reduce
cardiovascular events and all-cause death (10); 2) as a secondary preventive therapy in acute and post-myocardial infarction
patients to decrease myocardial reinfarction, total mortality,
cardiovascular mortality and sudden death (11-13); 3) as a
moderately to highly effective ai~tiarrhythmic agent for ventricular arrhythmias when used as monotherapy or adjuvant
combined therapy for specific patient subsets (14-18); 4) in
preventing postoperative atrial fibrillation or flutter in patients
undergoing coronary artery bypass graft surgery (19,20); 5) in
the prevention of sudden death in patients with congenital long
QT syndrome (21,22); 6) in improving "~ystolicdysfunction m
idiopathic dilated and ischemic cardiomyopathy (23-27); and
7) in the therapy of various systemic disease states where
adrenergic activity itself is deleterious (e.g., thyrotoxicosis,
Marfan syndrome, dissecting aortic aneurysm, esophageal varices, essential tremor, alcohol withdrawal) (28-31). Additional
cardiovascular preventive benefit seems intuitive from experimental and clinical data, which have shown that beta-blocker
therapy 1) decreases platelet aggregation (32-34); 2) decreases
plaque rupture (32); 3) decreases mean blood velocity and thus
reduces shear stress in vascular dissection (28,32); 4) decreases
endothelial permeability to mherogenic low density lipoproteins (35); a,ad 5) decreases atheroma formation in animals
(32,35). Although these antiatherogenic effects of beta-blocker
pharmacologic action are apparent, definitive clinical evidence
of this benefit is not forthcoming because no large clinical trial
directly assessing long-term beta-blocker therapy on atherosclerosis has been performed nor is planned (36).
Beta-blocker therapy has also been shown to have favorable
effects on the autonomic nervous system by increasing heart
rate variability indexes that are secondary to increased vagal
tone, attenuating vagal withdrawal and reducing sympathetic
beta-receptor stimulation or a combination of such effects
(37-39). Moreover, in myocardial failure, where elevated
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548
KENNEDY AND ROSENSON
PHYSICIAN USE OF BETA-BLOCKERS
catecholamine levels have been associated with myofibrillar
degeneration and cardiomyopathy (40,x, down-regulation (reduced numbers) of betal-receptors (41,42) and alteration in
the G protein complex important in coupling beta-receptors to
adenylate cyclase (43), it seems rational that beta-adrenergic
blockade would be beneficial (24).
Recent clinical data on patients with idiopathic cardiomyopathy have shown that left ventricular dysfunction is improved by beta-blocker therapy by ameliorating both increased
neuroendocrine activation and decreased myocardial substrate
utilization (43) and by blocking sympathetic-induced immune
abnormalities that reduce cell-mediated immunity and circulating T cells (44). These latter data support preliminary
observations from the Metoprolol Dilated Cardiomyopathy
(MDC) trial (45,46), which found beneficial improvement
of ejection fraction in those patients without betat-autoantibodies on metoprolol. In the largest (641 patients) prospective randomized heart failure mortality study of betablocker therapy published to date, the Cardiac Insufficiency
Bisoprolol Study (CIBIS) (27) disclosed in subgroup analysis a
survival benefit of bisoproiol in patients with a diagnosis of
primary dilated cardiomyopathy. Nonetheless, as recognized
by ~xperts in the field, previous randomized trials of betablocker therapy in congestive heart failure (MDC and CIBIS)
have been underpowered and have not used proper dosage in
appropriate subsets of patients; therefore, definitive recommendations have not been established (47).
Renewed Interest in Beta-Blocker Therapy
Renewed interest in the merit of beta-blocker therapy for
cardiovascular diseases has emerged predominantly during the
past 5 years as a result of diverse clinical developments. One
surprising development was the findings of the Cardiac Arrhythmia Suppression Trial (CAST) (48,49), which disclosed
that class I antiarrhythmic agents were harmful to postmyocardial infarction patients for the treatment of asymptomatic or mildly symptomatic ventricular arrhythmias. These
presumed proarrhythmic events heightened the anxiety of
many physicians in prescribing any and all antiarrhythmic
agents and necessitated a search for efficacious and safe
long-term sudden death preventive agents to be used in
post-myocardial infarction patients (50). Whereas physician
antiarrhythmic drug interest subsequently refocused on the
class III agents sotalol and amiodarone (51-57), there also
clearly emerged renewed interest in beta-blocker monotherapy
for such patients (17,18,50).
Another development influencing the perspective of betablocker therapy has resulted from the enlarging population of
patients with congestive heart failure and their need for
efficacious pharmacologic therapy. Congestive heart failure
affects between 1 and 2 million U.S. adults and has a 5- to
10-year mortality rate ranging from 10% to 70% dependent on
age and severity, and more than half of the mortality in North
America is by sudden death (58,59). In such patients the
benefit of beta-blocker therapy was suggested by data from the
JACC Vol. 26, No. 2
August 1995:547-52
Beta-Blocker Heart Attack Trial (BHAT) (60), which showed
beta-blocker therapy in post-myocardial infarction patients
with a history of congestive heart failure to be associated with
the greatest freedom from cardiovascular events and sudden
death. These findings were further supported by multivariate
analyses of the data of the Multicenter Diltiazem PostInfarction Trial (61) and CAST (62), both of which found
beta-blocker therapy to be an independent and significant
factor associated with less occurrence of new or worsened
congestive heact failure in post-myocardial infarction patients
with an ejection fraction <-40% or a history of congestive heart
failure. Moreover, since 1975 there has been accruing evidence
that beta-01ocker therapy beneficially improves systolic dysfunction in patients with idiopathic dilated cardiomyopathy
(23-27,43,45). The attributes of beta-blocker therapy for both
ischemic and idiopathic cardiomyopathy appear promising
enough that the Department of Veterans Affairs Cooperative
Studies Program and the National Heart, Lung, and Blood
Institute are jointly commencing a clinical trial in 1995, the
Beta-Blocker Evaluation of Survival Trial (BEST), to ,totermine whether beta-blocker therapy in addition to standard
medical therapy prolongs the lives of patients with congestive
heart failure.
Finally, the development and emergence of modern epidemiologic techniques of meta-analysis have also emphasized the
merits of beta-blocker therapy by calling attention to the large
number of randomized long- and short-term clinical trials of
beta-blocker therapy, the strength of the observations and the
conclusiveness of the data (I1-13). The consensus from such
meta-analyses indicates that patients with coronary artery
disease receiving beta-blocker agents without intrinsic sympathomimetic activity consistently benefit from statistically significant reductions in all-cause mortality, cardiovascular mortality, nonfatal cardiac arrest and sudden death, cardiac rupture,
ventricular fibrillation and myocardial reinfarction (11-13).
Physician Nonuse of Beta-Blocker Therapy
The reawakening of interest in beta-blocker therapy for
preventing cardiovascular events and sudden death and improving the prognosis of patients with congestive heart failure
has focused attention on the relative nonuse of beta-blocker
therapy by North American and English-speaking physicians
(3). As shown in Table 1, the optional utilization of betablocker therapy during the past decade by North American
physicians in post-myocardial infarction and congestive heart
failure populations in published clinical trials is dramatically
lower than that in similar investigation~in Scandinavian populations (52,61-71). Low utilization of beta-blocker therapy
also exists in clinical trials reported from western European
countries and Mexico (Table 1) (53,72-76). Whereas the use of
beta-blocker therapy in the studies shown in Table 1 was an
optional choice of individual physicians, a marked disparity in
prescribed beta-blocker therapy from North American studies
(12% to 38%) compared with Scandinavian studies (46% to
70%) is apparent. Although critics may correctly indicate that
JACC Vol. 26, No. 2
August 1995:547-52
KENNEDY AND ROSENSON
PHYSICIAN USE OF BETA-BLOCKERS
549
Table 1, Optional Use of Beta-Blocker Therapy
Study (tef. no.)
North America
Pagley et al. (63)
Lichstein et al. (61)
Cairns et al. (52)
The SOLVD Investigators (64)
The SOLVD Investigators (65)
Pfeffer et al. (66)
Kennedy et al. (62)
Pashos et al. (67)
Scandinavian countries
Emanuelsson et al. (68)
Herlitz et al. (69)
Swedberg et al. (70)
SSSS Group (71)
Other countries
Switzerland
Burkart et al. (53)
Germany, Canada, Switzerland
Willich et al. (72)
Italy
Santarelli et al. (73)
Ambrosioni et al. (74)
The Netherlands
Zijlstra et al. (75)
Mexico
Hermosillo et al. (76)
Duration
of Study
Study
Population
Diagnosis (clinical trial)
Beta-Blocker Usage
[% (no. of pts)]
1975-1990
1983-1986
1986-1988
1986-1989
1986-1990
1987-19911
1987-1991
1988-1992
5,480
1,084t
77
2,569
4,228
2,231
3,549
65,011
Acute M!
Acute M! (MDPIT)
Acute MI (CAMIAT)
NYHA 11-111CHF (SOLVD)
Asymptomatic CHF (SOLVD)
Acute MI (SAVE)
Post MI (CAST)
Acute MI
17-60'
12 (13~)
32 (25)
8 (197)
24 (1,015)
35 (789)
27 (718)
29-38~t
1986-1987
1986-1987
1990-1991
1988-1994
302
340
413
6,090
4,444
Post MI with CI-iF
Post MI no CHF
Acute MI
Acute MI (CONSENSUS 11)
Acute M! or Angina (SSSS)
46 (139)
71 {241)
68 (282)
67 (4,073)
57 (2,524)
1981-1987
340
Post MI (BASIS)
25 (78)
1982-1985
1,741
Acute MI (ISAM)
12 (206)
1987-1990
1991-1992
702
1,556
Acute MI (LAPIS)
Acute MI (SMILE)
18 (102)
20(311)
1990-1992
142
Acute MI
33 (47)
1991-1992
175
Acute MI
33 (58)
"1975, men 23%, women 17%; 1990, men 60%, women 48%. tPlacebo group of Multicenter Diltiazem PostInfarction Trial (MDPIT). :[:SMSAdministrative data base. BASIS = Basel Antiarrhythmic Study of Infarct Survival;
CAMIAT = Canadian Amiodarone Myocardial Infarction Arrhythmia Trial; CAST = Cardiac Arrhythmia Suppression
Trial; CHF = congestive heart failure; CONSENSUS = Cooperative North Scandinavian Enalapril Survival Study;
ISAM = Intravenous Streptokinase in Acute Myocardial Infarction Study; LAPIS = Late Potentials Italian Study; MI =
myocardial infarction; SAVE = Survival and Ventriculal Enlargement Trial; SOLVD = Studies of Left Ventricalar
Dysfunction; SMILE = Survival of Myocardial Infarction Long-Term Evaluation Study; SSSS = Scandinavian
Simvastatin Survival Study.
such data are confounded by diverse populations from varying
time trends and do not validate this perspective, nevertheless,
they present the best overall available perspective of individual
physician prescriptive attitudes regarding beta-blocker therapy. Others (77-79) have also called attention to the low
overall use of beta-blocker therapy in North America. What
differences in clinical training, continuing medical education,
exposure to commercial influences or selective biases have led
to such a low overall usage by North Americrn physicians?
Selective F a c t o r s Leading to N o n u s e o f
Beta-Blockers
Undoubtedly, one major reasoa for the nonprescription of
beta-blocker therapy for cardiovascular diseases in North
America is that internists and family practitioners have recently been shown (80) to be less aware or less certain than
cardiologists of cardiovascular medical advances established by
clinical trials. In a recent survey (80) of physician knowledge
and attitudes about therapy for acute myocardial infarction in
the states of New York and Texas, most striking was the finding
that only -50% of internists and fatally practitioners believed
that long-term use of beta-blockers definitely improved survival compared with 75% of cardiologist=. Whereas the investigators cited factors of 1) less knowledge of clinical trials
pertaining to cardiovascular disease among primary care physicians who treat a broader range of clinical problems; 2)
greater concern about therapeutic complications, such as congestive heart failure with beta-blocker therapy; and 3) greater
caution in accepting new data or changing established patterns
of treatment as perhaps accounting for these results, they also
recognized that younger physicians (<40 years of age) were
either more educated than older physicians with regard to data
from clinical trials or were more receptive to new standards of
practice (80,81). Because these latter data were derived from a
questionnaire and were not actual data taken from medical
550
KENNEDY
AND ROSENSON
PHYSICIAN USE OF BETA-BLGCKERS
]ACC Vol. 26, No. 2
August 1995:547-52
such medical concerns and chose another class of pharmaceurecords, the evidence of Table 1 suggests that many cardiolotical agents to avoid potential therapeutic complications. We
gists in North America "know the right answer" concerning
speculate that this "switch class" tactic has in part contributed
beta-blocker therapy but do not necessarily prescribe such
to the documented frequent use of calcium channel blocking
therapy (80).
agents and relative nonuse of beta-blockers in patients with
A major factor affecting physician use of beta-blocker
ischemic heart disease in North America (63,79,89,90). Furtherapy is a well entrenched, exaggerated concern held by
thermore, beta-blockers have generally been regarded by the
many physicians for the therapeutic complications resulting
pharmaceutical industry (from a business perspective) as relafrom beta-blocker adverse effects. Such is the case for the
tively low cost agents and, as such, historically have not enjoyed
widespread belief that beta-blocker therapy is detrimental to
widespread promotional efforts of the pharmaceutical industry
patients with left ventricular dysfunction, whereas in reality
in the form of sponsored national continuing medical educabeta-blocker therapy has proved particularly advantageous in
tional symposia or multinational megatrials. However, these
decreasing mortality, cardiovascular events and new or worslatter factors appear to be changing in the present climate of
ened congestive heart failure in this subset of patients
clinical guidelines and cost-consciousness with outcome mea(27,43,45,60-62). Another often maligned adverse effect of
surements (90).
beta-blocker therapy both among physicians and visa vis lay
This evolving perspective, however, must also be tempered
people is its presumed negative quality of life, resulting from
by our recognition of the valid anecdotal experiences of many
increased fatigue, depression or decreased libido. Critical
capable clinicians who initially used nonselective beta-blockers
analysis of the data relating to the adverse aspects of beta(frequently in doses now regarded as too high) and encounblocker therapy discloses that such beliefs are often exaggertered adverse effects that seeded their personal negative
ated and cannot be substantiated for the vast majority of
attitudes. These negative attitudes, unfortunately, all too often
beta-blocker agents, particularly for those that are betatwere ingrained by the forces described and persisted despite
selective with a long plasma half-life (82-84).
Although well designed studies using randomized clinical
the emergence of clinical trial data to the contrary (67).
trials do not currently exist to critically define these issues, the
available data overall do not support a major rejection of the
Present Physician Attitudes and Trends
use of beta-blocker agents on the basis of such adverse effects
(82-84). Other areas of clinical concern that may have been
It is encouraging that physician attitudes appear to be
exaggerated in the thinking of some practicing clinicians is the
changing. The CAST results showed that a significant increase
relative contraindication of beta-blocker therapy in patients
in the use of beta-blocker therapy occurred from CAST I (1987
with diabetes mellitus or peripheral vascular disease (85-87).
to 1989, 27%) to CAST II (1989 to 1991, 34%) (62). Another
The overall data suggest that for the majority of diabetic
recently reported retrospective cohort study (67) of 65,011
patients or those with peripheral vascular disease, who often
patients treated in 88 hospitals for acute myocardial infarction
have clinical or covert coronary artery disease, the relative
from 1988 to 1992 showed an increase in beta-blocker therapy
risk-benefit value of beta-blocker therapy is advantageous
from 29% to 38%. Still another retrospective community(85-87). Although caution should be exercised in patients with
based multihospital study (63) of 16 hospitals in Worcester,
severe forms of diabetes or vascular disease, the use of low or
Massachusetts examined time trends of prescribed therapy for
intermediate doses of betarspecific beta-blockers confers a
acute myocardial infarction from 1975 to 1990 and found a
clinical benefit that more than outweighs any real or theoretic
twofold to threefold increase in the use of beta-blocker therapy
adverse effect that may coexist (83,84).
for both genders (men 23% to 60%; women 17% to 48%).
Finally, it must be realized that commercial influence in the
Therefore, in North America, physician usage of beta-blocker
lucrative pharmaceutical competitive marketplace of the North
therapy is increasing.
American continent has also contributed to negative attitudes
As suggested by Ayanian et al. (80), a number of factors
of physicians regarding beta-blocker therapy. Pharmaceutical
could be anticipated to improve the knowledge and practice
industry competitiveness with tactics of "seeding trials," false
patterns of physicians. These efforts include a multifaceted
and misleading claims and "switch campaigns" to gain market
approach to increasing physician knowledge of clinical trial
share for a "me too" or "better" product have been reported
results through continuing-education programs, broader dis(88). Less substantiated is what we choose to descr:.be as the
semination of practice guidelines, more rigorous recertification
"exaggerated adverse effects" or "switch class" campaign. It is
procedures, provision of feedback concerning clinical practices
our experience that frequently in the past, all beta-blockers
and participation in community-based clinical trials (80,89were "lumped" by pharmaceutical competitors into a pharma92). The success of such efforts specifically for the appropriate
cologic category associated with "harmful lipid effects," "deutilization of beta-blocker therapy in post-myocardial infarccreased sexual function," "increased heart failure" or "detion patients has been preliminarily documented (90), but it
creased exercise performance." In reality, such claims were
also seems appropriate for each physician to reflect on his or
often exaggerated, unsubstantiated or untrue and rarely apher knowledge of beta-blocker therapy, be aware of the
plied to the majority of beta-blocking agents (83-87). Neverinfluences that have affected his or her attitudes and gain
theless, it appears that many physicians were susceptible to
insight from this evolving experience. In today's health care
JACC Vol. 26, No. 2
August 1995:547-52
marketplace, which is currently undergoing many clinical and
economic reforms, competitive commercial influences will
surely contitlue, but the advantages of low cost beta-blocker
therapy should clearly be recognized.
KENNEDY AND ROSENSON
?HYSICIAN USE OF BETA-BLOCKERS
551
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