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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.
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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 Inclusion Criteria
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 Exclusion Criteria
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, Study Population
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
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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 Echocardiography
(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
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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
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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 DISCUSSION
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
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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 Function?
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
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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- Study Limitations
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 CONCLUSION
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 reduction in ventricular rate and LA volume.
Electrocardiol 2004;9(4):352–357.
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 19. Maack C, Elter T, Nickenig G, et al. Prospective crossover com- parison of carvedilol and metoprolol in patients with chronicheart failure. J Am Coll Cardiol 2001;38(4):939–946.
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