Short-term and long-term effects of bisoprolol on chronic heart failure related to rheumatic heart disease and atrial fibrillation
Short-Term and Long-Term Effects of Bisoprolol on Chronic Heart Failure Related to Rheumatic Heart Disease and Atrial Fibrillation Maoqin Shu, MD, Ruixia Xi, PhD, Ping Zhang, MD, Guoxiang He, PhD, Zhiyuan Song, MD, Luxiang Chi, MD, and Guoqiang Zhuang, PhD ABSTRACT
treatment group showed improved NYHA class and exercise
Objective: We investigated whether a selective beta blocker,
capacity as well as a lower 24-hour average ventricular rate,
bisoprolol, improved chronic heart failure (HF) related to
lower systolic blood pressure; and a significantly decreased LA
rheumatic heart disease (RHD) and atrial fibrillation (AF).
diameter. However, no significant changes in the LVEF or LV
Methods: We randomly assigned 88 chronic HF patients
end-diastolic dimension were noted in the two groups during
with RHD, a cardiothoracic ratio below 65%, and AF with a
resting ventricular rate of 70 beats/minute or more for at least
Summar y: The data suggest that a selective beta blocker
three months to either a treatment group or a control group.
might improve NYHA class and exercise tolerance for patients
All patients received basic therapy: a diuretic, digoxin, an angio-
with chronic HF related to RHD and AF. Furthermore, the
tensin-conver ting enzyme (ACE)–inhibitor/angiotensin
advantage of these effects provided by this agent might be
receptor blocker (ARB), or nitrates, depending on their blood
mediated by a reduction in ventricular rate and LA volume.
pressure level and the presence of valvular lesions. All patientsalso received warfarin. Patients in the treatment group received
KEY WORDS: beta blocker, heart failure, rheumatic heart
bisoprolol. We then compared the short-term and long-term
clinical and hemodynamic variables between the two groups. Results: INTRODUCTION Basic Characteristics. Thirty-three treated patients
Traditionally, chronic heart failure (HF) has been attrib-
(75.0%) and 34 control patients (77.3%) completed the study.
uted to a reduced systolic left ventricular (LV) function, accom-
The follow-up period for both groups of patients was similar.
panied by an increase in LV filling pressures and volumes
There were no significant differences in age, sex, disease du-
(also called “systolic HF”). The important role of neuro-
ration, the use of diuretics and ACE-inhibitors or ARBs, left ven-
hormones in the pathophysiology of chronic HF is well rec-
tricular (LV) end-diastolic dimension, or left atrial (LA) diam-
ognized. Chronic HF is characterized by an increased activity
eter. The LV ejection fraction (LVEF) for all patients was found
of the neurohormonal system, such as the sympathetic ner-
to be higher than 40% in the two groups. Only three patients
vous system and the renin–angiotensin–aldosterone system
had an LVEF below 45%. The average maximum bisoprolol
dose was 6.52 ± 2.7 mg/day in the treatment group; 54.5% of
Beta-adrenergic blocking agents (beta blockers) and angio-
the patients tolerated at least 5 mg of bisoprolol once daily.
tensin-converting enzyme (ACE)–inhibitors or angiotensin II
Short-Term Results. The length of hospital stay was sig-
receptor blockers (ARBs) are well known as keystones in the
nificantly shorter for the treated patients. At hospital dis-
medical treatment of systolic HF because of their ability to sup-
charge, these patients had a slower 24-hour average ventricu-
press sympathetic drive and the RAAS.1,2 However, during the
lar rate and were able to walking farther over a period of six
past decade, it has become clear that about 50% of all patients
minutes, compared with the control group.
with chronic HF have preserved LV systolic function (also
Long-Term Results. During the follow-up period, the com-
called “diastolic HF”).3 Diastolic HF is suspected in patients
bined endpoint of chronic HF-related and thromboembolism-
with signs and symptoms of HF and a normal or mildly reduced
related death or hospitalization in the treated patients was
systolic LV ejection fraction (LVEF) greater than 40% and nor-
significantly lower than that in the control patients. After six
mal LV end-diastolic volumes.4,5 Diastolic HF may arise as a
to 12 months, only the control patients had a higher 24-hour
consequence of various underlying conditions that result in a
average ventricular rate, a worse New York Heart Association
modification of the physical properties of the myocardium.
(NYHA) class, and a lower exercise capacity. In contrast, the
These conditions (e.g., hypertension, ischemic heart disease,atrial fibrillation [AF], and valvular heart disease) can cause astructural impairment of the heart.6,7
Dr. Shu is Vice-Professor in the Department of Cardiology at South-
One study identified many patients with isolated AF or valvu-
west Hospital, The Third Military Medical University, in Chongqing,
lar heart disease, or both, who had dyspnea and normal or
China. Dr. He, Dr. Song, Dr. Chi, and Dr. Zhuang are Professors at
near-normal LV function.8 There is no doubt today that diastolic
Southwest Hospital. Dr. Xi is Vice-Professor in the Department of
HF is a pathophysiological clinical condition, distinct from or
Cardiology, The Third People’s Hospital, in Chongqing. Dr. Zhang
concomitant with systolic HF.9 However, many questions
is a physician in the Department of Ultrasound Diagnosis at South-
remain, not the least of which concerns methods of treatment,
because these two syndromes are not identical. 400 P&T® • July 2005 • Vol. 30 No. 7 Bisoprolol and Heart Failure
Previous studies have confirmed that the sympathetic ner-
puterized hospital information system. The study was
vous system is activated prior to the RAAS during the devel-
approved by the Ethics Committee of Southwest Hospital. We
opment of chronic HF, and plasma norepinephrine is one of the
carefully explained the nature and purpose of the investigation
most powerful predictors of mortality in early chronic HF.10
to the patients, who gave their written informed consent.
The Metoprolol CR/XL Randomized Intervention in Conges-tive Heart Failure (MERIT–HF) trial demonstrated consistent
and similar improvement in outcomes of patients receiving con-
Patients were included in the study if they had (1) a history
trolled-release or extended-release metoprolol when combined
of uncorrected rheumatic heart valvular disease or New York
with either a high or low dose of an ACE-inhibitor or digitalis
Heart Association (NYHA) functional class III or IV disease,
necessitating hospitalization; (2) a cardiothoracic ratio of less
Long-term beta-blocker treatment in chronic HF patients
than 65%; (3) AF with a resting ventricular rate of 70 beats/
who have already been treated with ACE-inhibitors showed
minute or more for at least three months, as depicted on the
plasma renin levels comparable to those without ACE-
electrocardiogram (ECG); and (4) an echocardiogram show-
inhibitors.12 Indeed, the suppression of angiotensin II by an
ing a significant mitral stenosis or aortic lesions and mitral
ACE-inhibitor is more effiective in patients who are also
receiving a beta blocker, and the escape (inhibitive effect) ofangiotensin II from ACE-inhibitors is attenuated in such
patients. Beta blockers have a renin-inhibiting effect and there-
Patients were excluded from the study if they had un-
fore hinder the sympathetic nervous system as well as the
corrected congenital heart disease, sustained ventricular
RAAS.13–16 These results suggest that beta blockers probably
tachycardia, severe liver and kidney dysfunction, chronic
have a more pronounced protective effect than ACE-inhibitors
obstructive pulmonary disease, bronchial asthma, obstruc-
against elevations in neurohormones.
tive or restrictive cardiomyopathy or myocarditis, myocardial
Rheumatic heart disease (RHD) often results in two main
infarction, or unstable angina within the previous three
pathophysiological changes: mitral valve stenosis and AF. AF
months. Patients were also ineligible for enrollment if they
is the most common cause of chronic HF resulting from a loss
required intensive care or concurrent intravenous therapy or
of atrial contraction and an associated rapid ventricular rate in
if they were using calcium-channel blockers, class I or III anti-
patients with RHD. Both mitral stenosis and AF result in a low
arrhythmic drugs, monoamine oxidase (MAO)–inhibitors or
cardiac output that activates the sympathetic nervous system.
Ozdemir et al. noted increased sympathetic activity in patients
On the basis of admission sequence, patients were ran-
with RHD, especially in patients whose disease was compli-
domly assigned to a treatment group or a control group. Con-
cated by AF.17 AF was an independent predictor of a higher risk
comitant therapy was kept as stable as possible throughout the
of diastolic HF in patients hospitalized with chronic HF.
study. All patients received warfarin for anticoagulation. At
Several studies have shown important differences in efficacy
the discretion of the treating physicians, all patients were
among different agents. Metoprolol succinate (e.g., Toprol®,
given concomitant therapy consisting of one of the following:
AstraZeneca) and bisoprolol (e.g., Concor®, Merck) are bothselective beta antagonists, whereas car vedilol (Coreg®,
• diuretics, as required, to control fluid retention
GlaxoSmithKline) is a nonselective beta blocker with addi-
• digoxin, extracted from Digitalis lanata
tional beta -blocking and antioxidant properties.18–20 A selec-
• ACE-inhibitors (or ARBs when ACE-inhibitors were not
tive beta blocker without a vasodilatory effect can decrease
tolerated) unless there were specific contraindications
the ventricular rate by suppressing sympathetic drive and
• nitrates, depending on the presence of valvular lesions and
without having a deteriorative effect on low cardiac output.14
Therefore, we thought that a selective beta blocker might be
more feasible for treating chronic HF related to RHD con-
Patients with predominant (pure or non-pure) mitral steno-
comitant with AF. However, the effects and mechanisms of this
sis or a systolic blood pressure below 100 mm Hg did not
agent in this subgroup of patients remain to be explored.
receive an ACE-inhibitor or an ARB but often received nitrates
The aim of our study was to analyze the effects of bisopro-
unless nitrates were not well tolerated. The physicians fol-
lol therapy for six to 12 months on the clinical symptoms and
lowed the recommended titration schedule.21
prognosis in patients with chronic HF and normal or near-
All patients in the treatment group received bisoprolol at the
normal systolic function related to RHD and AF.
initial dose of 1.25 mg/day. The recommended maximal dosewas 10 mg/day. The dose schedule for titration of the selective
beta blocker was gradually increased over three to five days,
by two to three weeks, to as high as 10 mg/day, with adjust-
We identified 143 patients with HF related to RHD and AF
ments of diuretics and ACE-inhibitors, as clinically indicated.
from our hospital’s cardiology ward between August 2000 and
If the resting heart rate was lower than 50 beats/minute or
March 2002. Thirty-seven patients did not meet all of the
if patients had symptomatic postural hypotension (systolic
inclusion criteria for enrollment, and 18 patients had clinical
blood pressure below 90 mm Hg), the upward titrated dose of
or echocardiographic data that caused them to be ineligible.
bisoprolol was deferred, interrupted, or stepped down in the
Thus 88 patients were included in the study.
case of an increase in heart failure symptoms. The treatment
We obtained admission data by using case notes and a com-
Vol. 30 No. 7 • July 2005 • P&T® 401 Bisoprolol and Heart Failure Clinical Observations
LA diameters and LV end-systole and end-diastole dimen-
The diagnosis of HF was confirmed if two or three of these
sions were assessed by apical four-chamber views. The longest
criteria were met while patients were in the cardiology unit:22
RR intervals (pauses between heartbeats) were selected tomeasure the ejection fraction (EF) as the best function seen
• a documented history of heart failure necessitating hos-
for AF. The single-plane ellipse formula was used to calculate
the EF.24 LV function was categorized as definitely impaired if
• the presence of symptoms (orthopnea, dyspnea, asthenia,
or respiratory rate over 28 breaths/minute at rest)
Predominant mitral stenosis23 was defined as (1) being of at
• physical findings (S3 gallop, rales, raised jugular disten-
least moderate severity, with a mitral valve area smaller than
tion, hepatojugular reflux, ascites, or edema and heart
1.4 cm2; (2) a dilated left atrium and a hypertrophic right ven-
tricle (RV); (3) mild mitral valve regurgitation or mild aortic
lesions without a dilated left ventricle or mild mitral valveregurgitation without any other lesions.
Heart valve disease was classified as significant only if the
Six-Minute Walking Distance
At discharge and after six to 12 months of treatment, walk-
• aortic stenosis with a gradient greater than 20 mm Hg
ing distances over a period of six minutes were measured for
• mitral stenosis with a valve area of less than 1.5 cm2
all patients. Instruction on walking exercise was given two or
• mitral valve regurgitation lesions of at least moderate
three times before the formal walking distance was deter-
mined. After a rest of at least 30 minutes, the average six-minute walking distance, measured in meters, was obtained
RHD was defined as significant mitral stenosis with accom-
panying mitral valve regurgitation or aortic lesions or with noother lesions at all. Statistical Analysis
The decrease in NYHA class I or greater was regarded as
Measurement data are presented as mean ± standard devi-
an improvement in heart function. The discharge markers
ation (SD). To compare baseline values and changes at the end
included (1) NYHA class improvement, (2) a reduced number
of six to 12 months, we used the paired Student’s t test for
of chronic HF symptoms, and (3) increased signs of relief.
continuous variables within groups and the non-paired t test
The combined endpoint included chronic HF-associated
between groups. We used the x2 test to evaluate between-
and thromboembolism-associated hospitalization or death but
group differences in enumeration data assessment. A P value
not hospitalization or death unrelated to chronic HF and
of less than .05 was considered statistically significant. NYHA
classes I, II, III, and IV, respectively, were calculated as scores
An adverse drug event (ADE) was defined as (1) drug
intolerance, particularly weakness, fatigue or dizziness, dysp-nea, severe hypotension (below 90 mm Hg), and (2) a resting
ventricular rate below 50 beats/minute. Fundamental Characteristics
All patients underwent 24-hour ambulatory ECG studies at
Eleven treated patients (25%) and nine control patients
hospital discharge and after six to12 months of treatment.
(20.5%) did not complete the study. Among the treated
During the day of the test, patients were instructed to conduct
patients, five (11.3%) withdrew because of suspected ADEs
their activities as usual. The 24-hour average ventricular rates
from bisoprolol: weakness, dizziness, and dyspnea. No severe
were calculated according to the ambulatory ECG.
hypotension occurred in either group. Fourteen patients were
We obtained follow-up information by conducting telephone
excluded from the evaluation at follow-up. Seven patients had
interviews with the patients or with follow-up visits by two phy-
echocardiographic or 24-hour ECG data of insufficient quality,
sicians (one physician for the controls and another physician
and seven patients withdrew because of telephone-connection
for the treated group). Topics included survivorship, the NYHA
difficulties. Their withdrawal from this study did not affect our
classification, chronic HF symptoms or signs, hospitalization,
conclusions because these patients were equally distributed in
and the use of medications. The interviewer was not informed
of the immediate outcome, the presence of valvular lesions,
Among all patients, 67 (76.1%) fulfilled complete clinical,
echocardiographic data, or the 24-hour ECG at discharge.
ECG, and echocardiographic data and six to 12 months offollow-up data. The follow-up period was similar for the controls
(263 ± 56 days, or 207–319 days) and for the treated patients
Echocardiographic studies were performed with the HDI
(247 ± 74 days, or 173–321 days). There were no significant
5000 ultrasound system (Philips, The Netherlands). Both
differences in age, sex, NYHA class, disease duration, or the
groups of patients received Doppler echocardiographic exam-
use of diuretics and nitrates (Table 1).
inations at hospital discharge and after six to 12 months with
The severity of mitral or aortic lesions did not differ in either
an acceptable two-dimensional registration. All images were
group: (1) two treated patients (6.1%) and one control patient
recorded and weresubsequently analyzed by experienced
(2.9%) had mitral valve regurgitation of at least moderate sever-
ultrasound physicians who did not know the patients’ classifi-
ity and/or mild stenosis; (2) six treated patients (18.2%) and
eight control patients (23.5%) had combined mitral stenosis of
402 P&T® • July 2005 • Vol. 30 No. 7 Bisoprolol and Heart Failure
Table 1 Fundamental Characteristics of Patients with Heart Failure (Mean ± SD) Control Patients Treated Patients Parameter P Value
Resting ventricular rate at admission (beats/minute)
24-hour average ventricular rate at hospital
Left ventricular end-diastolic dimension (mm)
* P < .05 compared with the control group of patients. mm = millimeters; Hg = mercury; NYHA = New York Heart Association; SD = standard deviation.
Table 2 Clinical Characteristics for the Follow-up Period in Patients with Heart Failure (Mean ± SD) Control Patients Treated Patients Parameter P Value
24-hour average ventricular rate (beats/minute)
*P < .05 compared with the control group of patients. mm = millimeters; Hg = mercury; NYHA = New York Heart Association; SD = standard deviation.
at least moderate severity and mitral valve regurgitation; and
treatment group showed a significantly lower 24-hour average
(3) 21 treated patients (63.6%) and 22 control patients (64.7%)
ventricular rate at discharge (80 ± 14 beats/minute, 95 ± 14
had combined mitral and aortic valve disease.
beats/minute; P < .001). The length of hospital stay for the
Sixteen treated patients (48.5%) and 17 control patients
treated patients (6.8 ± 3.4 days) was significantly shorter than
(50.0%) had significant mitral stenosis. In both groups, approx-
that for the control patients (9.5 ± 4.3 days, P = 0.046). Further,
imately 50% of patients had pure and non-pure (predominant)
the treated patients had better exercise capacity at discharge
mitral stenosis. The LVEF was higher than 40% in all patients
(391 ± 32 meters, 309 ± 28 meters; P < .001) (see Table 1).
in the two groups and was below 45% in three patients (two
At discharge, although the treated group had a mild higher
patients in the treatment group and one in the control group).
systolic blood pressure than the controls, the LV end-diastolic
All patients had combined mitral and aortic valve disease.
dimension and the average LA diameter did not dif fer
During follow-up, the use of ACE-inhibitors/ARBs and
between the two groups (see Table 1).
digoxin was similar for all patients. Thirteen treated patients(39.4%) and 16 controls (47.1%) received ACE-inhibitors/ARBs,
Long-Term Clinical Effects
and 30 treated patients (90.9%) and 32 controls (94.1%)
During follow-up, the combined endpoint accounted for 11
received digoxin. The average maximum bisoprolol dose was
cases of HF in the controls (32.4%) and four cases in the
6.52 ± 2.7 mg/day in the treatment group; 54.5% of the patients
treated patients (12.1%, P = .048) (Table 2). Ten controls and
tolerated at least 5 mg of bisoprolol once daily. Nineteen treated
three treated patients were hospitalized for complaints
patients (55.9%) and 20 controls (60.6%) received nitrates.
associated with chronic HF; one treated patient and one con-trol were admitted with these complaints. Short-Term Clinical Effects
Also at follow-up, NYHA class in the treated patients re-
At hospital admission, the resting ventricular rate was sim-
mained stable. The condition of only two patients deteriorated
ilar in both treated and control patients. Both groups had a
to NYHA class IV, and 75.8% of patients were in class I or II.
similar NYHA class from admission to discharge. However, the
However, NYHA class in the controls worsened to some
Vol. 30 No. 7 • July 2005 • P&T® 403 Bisoprolol and Heart Failure
degree; the health of nine patients deteriorated to class IV, and
mg/day. In the treatment group, 54.5% of patients tolerated at
50% were in class III. NYHA class scores of the treated patients
least 5 mg of bisoprolol once daily during the maintenance
were significantly lower than those of the controls (2.2 ± 0.7
phase. Five patients (11.3%) withdrew from the study because
score, 3.2 ± 0.8 score; P < .001). In addition, compared with the
of suspected ADEs from bisoprolol. No severe hypotension or
controls, the treated patients receiving the study regimen had
bradycardia occurred. Bisoprolol decreased the length of hos-
lower 24-hour average heart ventricular rates, decreased sys-
pital stay, reduced the incidence of cardiac events, and
tolic blood pressure readings (P < .001), and longer six-minute
improved exercise capacity over six to 12 months of treatment.
Our results were similar to the findings of the Cardiac
Compared with the findings at discharge, the LV end-
Insufficiency Bisoprolol Study II (CIBIS–II),14 the Carvedilol
diastolic dimension in both groups did not differ significantly
Prospective Randomized Cumulative Survival Study (COPER-
at follow-up. For all patients in the two groups, the LVEF was
NICUS),15 and the MERIT–HF trial.16 In our study, the average
higher than 40%. The LVEF was below 45% in four patients (one
maximum bisoprolol dose was lower, but the tolerance of at
treated patient and three controls). Thus, no significant
least 5 mg of bisoprolol once daily was not significantly dif-
changes in EF or LV end-diastolic dimension were found in
ferent from that of the CIBI–II trial (54.5% versus 67%), prob-
either group during the follow-up evaluation. However, the
ably because the cause of chronic HF in our study differed
treated patients did show a significantly decreased LA diam-
eter compared with the control group at follow-up.
Chronic HF caused by RHD is associated with a lower car-
diac output, which can bring about deterioration in the
increased sympathetic nervous system. However, our results
Do Selective Beta Blockers Affect Chronic Heart Failure
and those of other studies showed that the benefits derived
Related to Rheumatic Fever?
from bisoprolol, when used to treat patients with chronic HF,
The evidence supports a profound protective effect of beta
clearly outweighed the risk of ADEs.
blockers in their ability to inhibit activation of the neuro-
In clinical practice, these patients cannot usually tolerate
endocrine system in regard to chronic HF: (1) the early
optimum doses of both an ACE-inhibitor and a beta blocker.
activation of the sympathetic nervous system in chronic HF;10
This lack of tolerance is especially common among the elderly.
(2) the beneficial effect of beta blockers on sudden death,
The CIBIS–III findings indicated that chronic HF therapy
especially important in early stages of chronic HF; and (3) the
should be not started with both an ACE-inhibitor and a beta
dual inhibitory effect of beta blockers on renin and the sym-
blocker simultaneously, especially in elderly patients or in
those with special circumstances.26 Therefore, we concluded
ACE-inhibitors have been shown to decrease mortality by
that a selective beta blocker might be a reasonable choice of
approximately 25% in patients with chronic HF. Some large out-
therapy for chronic HF patients with RHD.
come studies and several meta-analyses have documented areduction in mortality of approximately 35% with the addition
Do Selective Beta Blockers Affect Chronic Heart
of a beta blocker.15,16 The escape of angiotensin II from ACE-
Failure Related to Atrial Fibrillation?
inhibitors is attenuated in the patients who take beta blockers.
In patients with RHD, AF is the most common sustained
RHD is still an important cause of chronic HF in developing
arrhythmia and it is the most common cause of chronic HF
countries, including China. The predominant pathological
resulting from a loss of atrial contraction and an associated
change associated with RHD is rheumatic mitral stenosis.
rapid ventricular rate. One study showed that decreased sym-
Numerous studies have reported increased sympathetic activ-
pathetic activity after balloon mitral valvuloplasty occurred
ity in patients with mitral stenosis, because low cardiac output
only in patients with mitral stenosis and sinus rhythm but not
mediated by mitral stenosis activates the sympathetic nervous
in patients with AF.17 The results indicated that patients with
mitral stenosis and AF experienced a more adverse neuro-
As shown by Razzolini et al., sympathetic activity decreased
hormonal change. However, the effects of selective beta block-
after mitral balloon valvuloplasty was significantly correlated
ers on chronic HF accompanying AF remain to be explored.
with the increase in the cardiac index.25 ACE-inhibitors or
In patients without HF, beta blockers improved ventricular
nonselective beta blockers with alpha-adrenergic activity have
rate control in AF when they were added to digoxin or when
an obvious vasodilatory effect, which can worsen a low cardiac
they were used alone. Among patients with AF and HF, only a
output, whereas a selective beta adrenoceptor antagonist (e.g.,
few trials have suggested that beta blockers reduce ventricu-
bisoprolol with a half-life of 10 to 12 hours) does not have any
lar rate, improve ventricular function, and are well tolerated.27,28
partial agonist or vasodilatory effect.16–18 On the basis of these
However, these studies used agents with high intrinsic sym-
assumptions, the selective beta blocker bisoprolol was used
pathomimetic activity, and these agents are now generally
to treat chronic HF patients with RHD in this study.21
thought to be contraindicated for patients with HF.
We assessed 67 patients: 16 treated patients (48.5%) and 17
In our study, all patients in the treated group received biso-
control patients (50.0%) had significant mitral stenosis. Thus,
prolol. Thirty patients (90.9%) in the treated group and 32
approximately 50% of patients with RHD had pure and non-pure
patients (94.1%) in the control group used digoxin. Compared
mitral stenosis; for these patients, the use of vasodilators might
with the control patients, the treated patients showed a shorter
be not appropriate. In our study, only 13 treated patients (39.4%)
length of hospital stay (–2.4 ± 3.8 days) and better exercise tol-
and 16 controls (47.1%) used an ACE-inhibitor/ARB.
The average maximum bisoprolol dose was 6.52 ± 2.7
During six to 12 months of follow-up, the combined endpoint
404 P&T® • July 2005 • Vol. 30 No. 7 Bisoprolol and Heart Failure
of chronic HF-related and thromboembolism-associated hospi-
increased left-sided heart preload or afterload. Eventually,
talization or death decreased significantly, from 32.4% in the
patients with either condition exhibit an elevated pulmonary
controls to 12.1% in the treated patients. The 24-hour average
ventricular rate did not change significantly in the control group,
Various factors may lead to diastolic dysfunction by complex
but the rate did decrease in the treated patients (see Table 1).
interactions because of a hemodynamic coupling of RV and LV
The difference in the absolute change between the two groups
functions.35 Patients with a cardiothoracic ratio below 65% and
was statistically significant (P < .001).
without severe hepatic or renal dysfunction were included in
We found that bisoprolol benefited patients with chronic
our study. There was no significant age difference between the
HF related to RHD and AF. A study by Fung et al. supported
controls and the treated patients (see Table 1). For all patients
the idea that the benefits of the beta blocker in patients with
at discharge, the LVEF was higher than 40%. Only three patients
HF extend to patients with HF complicated by AF.29 The beta
had an LVEF below 45% (two treated patients and one control).
blocker had an incremental benefit when added to digoxin for
At the end of the study, we observed a significant change in
the management of AF in patients with HF.30
LVEF: it measured below 45% in four patients (in one treatedpatient and in three control patients). All of the patients with
Are Selective Beta Blockers More Useful in Chronic Heart
an LVEF below 45% had combined mitral and aortic valve dis-
Failure Accompanying Normal or Near-Normal Systolic
ease. Our findings supported the phenomenon that chronic HF
related to AF and valvular heart disease without an advanced
LV diastolic dysfunction usually precedes systolic dysfunc-
course had a normal or near-normal LV function.
tion, but it can also be present for a longer period of time, even
How to best treat diastolic HF remains to be determined.
years. Impairment of diastolic function appears to be age-
The IMPROVEMENT–HF study6 and the IN-CHF registry34
related. Although fewer than 10% of patients with heart failure
showed that beta blocker use was higher in patients with
younger than 50 years of age tend to have diastolic dysfunction,
diastolic HF, and patients with diastolic HF tolerated beta
the number rises to 70% in patients older than 80 years of
blockers well. Beta blockers were associated with decreased
age.4–6 However, the prognosis of chronic HF patients with pre-
resting and peak exercise heart rates and blood pressure and
served systolic function (or diastolic HF) is similar to that for
an increased early and late (atrial) phase (E/A ratio).36 Many
patients with impaired RV function or pulmonary hypertension
Although there is currently no worldwide accepted defini-
have also benefited from beta blockers.37,38
tion of diastolic HF, the American College of Cardiology/Amer-
Some studies showed that a six-month course of carvedilol
ican Heart Association Guidelines5 have proposed that if
therapy did not reduce the LV diameter at end-diastole and at
patients have symptoms of HF but normal systolic function,
end-systole, but it did restore physiological early diastolic fill-
they should be classified as having HF with preserved systolic
ing by complex interactions between relaxation and chamber
function; thus, it is no longer mandatory for diastolic function
stiffness.33 Our study also indicated the same phenomenon; the
to be assessed objectively in these patients.
beneficial effect of bisoprolol was not significantly related to
Diastolic HF may originate because of conditions that alter
the changes in LV volume and systolic function.
the myocardial structure (i.e., AF and valvular heart dis-
It is known that baseline heart rates and changes in heart
ease).6–8 A certain pattern of LV diastolic filling always results
rates are related to the prognosis in patients with chronic
from a complex interaction of various factors such as heart rate
HF.30–32 Perhaps resting heart rate, as a simple clinical surro-
and rhythm, preload, aortic or mitral valve disease, right ven-
gate for sympathetic nervous system activity, might prove to be
tricular (RV) competence, ventricle–septum interaction, active
a simple and clinically useful predictor of benefit from beta-
LV relaxation, LV elasticity properties, and LA contraction.33
blocker therapy.21 A short diastolic period is always detrimental
Aging, disease progression, and changes in loading condi-
if myocardial function is compromised. Beta blockers prolong
tions may lead to diastolic dysfunction. It is known that atrial
the diastolic period more than they prolong the systolic period,
contraction is very important for the filling of the heart, espe-
which promotes diastolic filling, improves myocardial per-
cially in elderly patients. Thus, abbreviated filling, in terms of
fusion and metabolism, and might offer direct protective action
sudden onset of AF, may exacerbate diastolic dysfunction and
on the myocytes against catecholamine excess.39
may even cause dramatic symptoms and signs (pulmonary
Bergstrom et al.40 noted that patients with higher heart rates
congestion). We found the incidence of AF to be higher in sub-
benefited more from carvedilol than patients with lower heart
jects with diastolic HF, that is, in a quarter to a third of patients.
rates. Patients with a heart rate above 71 beats/minute who
In the Italian Network on Congestive Hear t Failure
took carvedilol showed an improved E:A ratio and E-wave ve-
(IN–CHF) registry,34 16% of patients with a low LVEF had AF,
locity, whereas there was less effect on the A-wave velocity,
compared with 25% of patients with an LVEF above 45%.
In a multivariate analysis, AF was an independent predictor
These findings indicate that patients with diastolic dys-
of a higher risk of diastolic HF in patients hospitalized with
function and higher heart rates experience improved diastolic
chronic HF. According to pathophysiological changes, patients
filling through a shift of diastolic volumes from late to early
with RHD may be classified into two groups: (1) those with
diastole. It appears that this redistribution of filling volumes
predominant mitral stenosis and (2) those with predominant
toward a more normal pattern is brought about by an improve-
mitral valve regurgitation and/or aortic lesions. Predominant
ment in early filling in particular, thereby inducing a more nor-
mitral stenosis may result in dilation of the LA and a hyper-
trophic right ventricle. The latter condition may cause an
However, it is difficult to differentiate the effects on heart rate
Vol. 30 No. 7 • July 2005 • P&T® 405 Bisoprolol and Heart Failure
systematic overview of data from individual patients. ACE-Inhib-
per se from other beta-blocker effects. There is evidence that the
itor Myocardial Infarction Collaborative Group. Lancet 2000;
mode of action of beta blockade is not solely through the
reduction of the hear t rate. Other dr ugs with hear t
3. Hogg K, Swedberg K, McMurray J. Heart Failure with preserved
rate–reducing effects (e.g., calcium-channel blockers and dig-
left ventricular systolic function: Epidemiology, clinical charac-teristics, and prognosis. J Am Coll Cardiol 2004;43(3):317–327.
italis) do not share the positive effects of beta blockers in HF
4. European Study Group on Diastolic Heart Failure. How to diag-
treatment.42 The exact mechanism of their effect is not entirely
nose diastolic heart failure. Eur Heart J l998;19(7):990–1003.
clear, but the data suggest that the primary mechanism of
5. ACC/AHA [American College of Cardiology/American Heart
action of beta blockers in chronic HF is to prevent and reverse
Association] Guidelines for the Evaluation and Management of
adrenergically mediated intrinsic myocardial dysfunction and
Chronic Heart Failure in the Adult: Executive Summary. J HeartLung Transplant 2002;21(2):189–203.
6. Cleland JGF, Cohen-Solal A, Aguilar JC, et al. Management of
Our study included patients with a resting ventricular rate
heart failure in primary care (the IMPROVEMENT of Heart Fail-
of at least 70 beats/minute. The 24-hour average ventricular
ure Programme): An international survey. Lancet 2002;360(9346):
rate decreased significantly in the treatment group, in contrast
7. Vasan RS, Benjamin EJ. Diastolic heart failure: No time to relax.
to the control patients. The significantly decreased LA diam-
N Engl J Med 2001;344(1):56–69.
eter and reduced systolic blood pressure were observed only
8. Davies MK, Hobbs FDR, Davis RC, et al. Prevalence of left-
in the treated patients. This difference in ventricular rates
ventricular systolic dysfunction and heart failure in the Echo-
might be attributable to the fact that a selective beta blocker
cardiographic Heart of England Screening study: A population-
can allow longer diastolic filling by decreasing resting and
based study. Lancet 2001;358(9280):439–444.
9. Cleland JGF, Swedberg K, Follath F, et al. The Euro Heart Fail-
exercise ventricular rates and may produce a higher cardiac
ure Survey Programme: A survey on the quality of care among
output, thereby leading to a decreased atrial diameter.
patients with heart failure in Europe. Part 1: Patient characteris-
Thus, we concluded that a selective beta blocker might be
tics and diagnosis. Eur Heart J 2003;24(5):442–463.
feasible for chronic HF accompanying normal or near-normal
10. Benedict CR, Shelton B, Johnstone DE, et al., for the SOLVD
[Studies of Left Ventricular Dysfunction Prevention] Investigators.
systolic function; we were less concerned about the negative
Prognostic significance of plasma norepinephrine in patients with
inotropic effect of the beta blocker in patients with diastolic HF
asymptomatic left ventricular dysfunction. Circulation 1996;
than we were about systolic HF. In our study, patients were
somewhat younger, had higher basic ventricular rates, and did
11. Ghali JK, Dunselman P, Waagstein F, et al. Consistency of the ben-
not have end-stage disease. This was also an important reason
eficial effect of metoprolol succinate extended release across awide range dose of angiotensin-converting enzyme inhibitors
why bisoprolol exerted beneficial effects in this subgroup.
and digitalis. J Cardiac Fail 2004;10(6):452–459.
12. Teisman ACH, Veldhuisen DJV, Boomsma F, et al. Chronic beta-
blocker treatment in patients with advanced heart failure: Effects
We focused on patients with RHD and AF who had no com-
on neurohormones. Int J Cardiol 2000;73(1):7–12.
13. Domanski MJ, Krause-Steinrauf H, Massie BM, et al., for the
plications associated with chronic HF, such as myocardial dys-
BEST Investigators. A comparative analysis of the results from
function and liver or renal dysfunction. It was necessary to
four trials of beta-blocker therapy for hear t failure: BEST,
include this highly selective population as a first step to iden-
CIBIS–II, MERIT–HF, and COPERNICUS. J Cardiac Fail 2003;
tifying the feasibility and effectiveness of bisoprolol without
confounding variables. Further studies are needed to address
14. CIBIS-I Investigators and Committees, for the Cardiac Insuffi-
ciency Bisoprolol Study II (CIBIS–II): A randomised trial. Lancet
the effect of bisoprolol in patients with advanced RHD.
Another element of potential bias was the use of an
15. Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on
unblinded treatment, which might affect hospital patient dis-
the morbidity of patients with severe chronic heart failure: Results
of the Carvedilol Prospective Randomized Cumulative SurvivalStudy (COPERNICUS). Circulation 2002;106(12):2194–2199.
16. Wikstrand J, Hjalmarson A, Waagstein F, et al., for the MERIT–HF
Study Group. Dose of metoprolol CR/XL and clinical outcomes
We suggest that a selective beta blocker, such as bisopro-
in patients with heart failure: Analysis of the experience in Meto-
lol, can improve NYHA class and exercise tolerance for patients
prolol CR/XL Randomized Intervention Trial in Chronic Heart
with chronic HF related to RHD and AF. The advantage of
Failure (MERIT–HF). J Am Coll Cardiol 2002;40(3):491–498.
17. Ozdemir O, Alyan O, Soylu M, et al. Sympathetic overactivity in
these effects provided by this agent might be mediated by a
patients with rheumatic mitral stenosis. Ann Noninvasive
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18. Packer M, Antonopoulos GV, Berlin JA, et al. Comparative effects
Acknowledgments: Dr. Shu was supported by a fellowship
of carvedilol and metoprolol on left ventricular ejection fractionin heart failure: Results of a meta-analysis. Am Heart J 2001;
from the Departments of Cardiology and Ultrasound Diagno-
sis in Southwest Hospital. We thank Dr. Chen-Ping for his
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DIGESTIVE HEALTH CONSULTANTS SIDE EFFECTS OF INTERFERON, PEGYLATED INTERFERON, CONSENSUS INTERFERON AND RIBAVIRIN THERAPY General and miscellaneous: Fever, chills, flu-like symptoms, headache, dizziness, hearing loss, insomnia, fatigue, inflammation and pain in the joints, muscle aches, muscle contractions/cramps, numbness and tingling, nerve damage, thinning of hair, weight
A “Yang-invigorating” Chinese herbal suppository preparation relieves symptoms in patients with Parkinson’s disease K.M. Ko1*, K. Chan2, L. Shek3, J. Yeung2 and S.H. Chui2 1Department of Biochemistry, Hong Kong University of Science &Technology, 2Research and Development Department, School of Chinese Medicine, Hong Kong Baptist University, 3Medical Clinic, Suit 613 Melbourne Pl