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The extent of heart rate reduction during hospitalization using beta-blockers, not the achieved heart rate itself at discharge, predicts the clinical outcome in patients with acute heart failure syndromes
Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita 565-8565, Osaka, JapanResearch and Development Initiative Center, National Cerebral and Cardiovascular Center, Suita 565-8565, Osaka, Japan
Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita 565-8565, Osaka, JapanResearch and Development Initiative Center, National Cerebral and Cardiovascular Center, Suita 565-8565, Osaka, Japan
It has been uncertain whether patients with acute heart failure syndromes (AHFSs) benefit from a lower heart rate (HR) itself or from treatment for heart failure (HF) that reduces sympathetic tone with consequent HR reduction (HRR). The present study investigated the influence of HRR during hospitalization on the prognosis of AHFS patients.
Methods and results
In 421 AHFS patients, we analyzed the relationship between HRR during hospitalization and the prognosis after discharge. During a mean follow-up period of 1.9 years, 76 and 55 patients died or were re-hospitalized for HF, respectively. Although HR at discharge did not influence cardiac events (hazard ratio [HR]: 1.00 [95% CI; 0.99–1.02], p = 0.22), the extent of HRR was a predictor of cardiac events (HR: 0.89 [0.84–0.96], p < 0.001). Kaplan–Meier analysis revealed that the cardiac event rate of the HRR-positive group (≥27 bpm reduction of HR from 114 ± 24 at admission to 65 ± 11 bpm at discharge) was significantly lower than that of the HRR-negative group (≤26 bpm (=median value) reduction of HR from 74 ± 14 to 71 ± 14 bpm). In the HRR-positive group, the cardiac event rate was significantly lower in patients receiving beta-blockers. Furthermore, the extent of HR change was an important predictor of cardiac events among other markers, compared with the change in systolic blood pressure or B-type natriuretic peptide.
Conclusion
The HR itself at discharge was not associated with the prognosis, but the extent of HRR achieved by treatment of HF with beta-blockers was a strong predictor for the clinical outcome in AHFS patients.
]. The resting heart rate (HR) has been reported to be a strong predictor of cardiovascular mortality and morbidity in patients with chronic HF, hinting at the beneficial effects of lowering the HR [
]. It was recently reported that ivabradine, which slows HR by selective If current inhibition independently of the effect of beta-adrenergic receptor blockade, improved the outcome of HF patients in the Systolic Heart Failure treatment with the If inhibitor ivabradine Trial (SHIFT) [
SHIFT Investigators. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomizd placebo-controlled trial.
]. Thus beta-blockers are used widely in the treatment of HR to reduce cardiovascular sympathetic tone, which leads to secondary heart rate reduction [
CIBIS III Investigators Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite sequence: results of the randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III.
]. However, it has been unclear whether the benefit for patients with HF is related to lower HR itself or to the inhibition of sympathetic tone with HR reduction (HRR) as a secondary effect.
Against this background, we investigated whether the HR itself at discharge or the extent of HRR was related to long-term mortality in patients with acute heart failure syndromes (AHFSs). We also investigated the differing effects of HRR on long-term mortality in AHFS patients with or without beta-blocker therapy. In addition, although previous reports have focused on the influence of HR in patients with chronic HF, we investigated the clinical significance of HRR from acute to chronic phase of AHFS.
Methods
Study design
From July 2006 to June 2009, 545 consecutive AHFS patients who met the Framingham criteria [
] were prospectively enrolled to National CardiovAScular Center Acute DEcompensated Heart Failure (nCASCADE) database, which is a single-center registry for patients with AHFS that excludes patients with acute coronary syndromes (ACSs). On admission, the information related to HF was obtained, such as a history of hypertension, dyslipidemia, diabetes, implantable pacemaker, dialysis, or chronic respiratory disease. Physical examination was performed at admission to assess the following: New York Heart Association (NYHA) functional class, absence or presence of congestion (assessed by orthopnea, rales, jugular venous dilation, abdominal jugular reflux, hepatomegaly, and edema), adequacy of perfusion [assessed by the proportional pulse pressure (low < 25%)], cold extremities, and systolic and diastolic blood pressures (BPs), and HR, and the presence of alternans. HR at admission was measured by electrocardiogram (ECG). HR at discharge was measured at rest by a nurse on the day of discharge. Echocardiography was also done at admission and before discharge. Biochemistry tests were performed at admission and before discharge, including measurement of blood urea nitrogen, serum creatinine, hemoglobin, C-reactive protein, total bilirubin, and plasma B-type natriuretic peptide (BNP). Patients’ identifying information was not used in the collection of data. This study was approved by the institutional review board, and was conducted in accordance with the ethical principles of the Declaration of Helsinki.
Exclusion criteria
In the present study, we excluded patients with pacemakers and patients who died during hospitalization. We also excluded patients with sustained ventricular tachycardia or fibrillation at the measurement of HR.
Clinical outcomes
During the follow-up period, we investigated deaths from any cause and re-hospitalization for HF by telephone and letters. Cardiac events were defined as all-cause death and re-hospitalization for HF.
Criteria for HRR
Previous studies reported that the mean HRR from admission to discharge was 11–29 bpm, although there has been some variation [
Effects of carperitide on the long-term prognosis of patients with acute decompensated chronic heart failure – the PROTECT multicenter randomized controlled study.
OPTIMIZE-HF investigators and coordinators. Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure.
]. In the present study, the HRR was defined as showing a decrease of HR ≥ 27 bpm at discharge compared with that at admission according to a median value of HRR (26 bpm).
Statistical analysis
Results are presented as the mean ± standard deviation (SD). Multivariate analysis was performed with the Cox proportional hazards model to identify the factors significantly related to cardiac events after adjustment for other variables. For the multivariate model, we included general variables (age, gender, and NYHA functional class) and systolic BP, HR, the presence of sinus rhythm, log plasma BNP, and left ventricular diastolic diameter (LVDd). For investigation of survival and hospitalization for HF, Kaplan–Meier analysis and the log-rank test were used. Probability (p) values < 0.05 were considered statistically significant. As previously reported [
], time-dependent ROC curve analysis was applied to changing variables (HR, systolic BP, and BNP) with adjustment for age. This method defined the sensitivity and the specificity at each event time as components of the receiver operating characteristic (ROC) curve. The area under the curve (AUC) indicates the predictive power of each variable. Summary measurements of AUC curves over time were determined by the integrated summary C index. All statistical analyses were performed using SPSS software, Version 11 (SPSS Japan, Tokyo, Japan) and SAS version 9.1 (SAS Institute Inc., Cary, NC, USA).
Results
Characteristics of the patients
According to the exclusion criteria, we excluded 124 patients (71 patients with pacemakers, 20 who died during hospitalization, and 33 whom we could not follow up because of missing laboratory or any other physical data at the point of discharge) from the present study. We excluded patients with sustained ventricular tachycardia or fibrillation at the measurement of HR. Therefore we analyzed 421 patients in the present study and their characteristics are shown in Table 1. There were 281 men and 140 women. Among the total study population, 241 patients (57%) were in NYHA functional class 3 and 169 (40%) were in NYHA class 4. The causes of HF were due to ischemic heart disease (32%), cardiomyopathy (19%), hypertensive heart disease (14%) and valvular heart disease (31%) (Table 1). The characteristics of these patients at admission and discharge are shown in Table 2. During follow-up for 705 ± 400 days, 76 patients died of any cause and 55 patients were re-hospitalized for worsening of HF.
Table 1Characteristics of the patients.
n
421
Age (y.o.)
72 ± 13
Gender (male %)
281 (67%)
NYHA III
241 (57%)
NYHA IV
169 (40%)
Etiology
Ischemic heart disease
32%
Cardiomyopathy
19%
Hypertensive heart disease
14%
Valvular heart disease
31%
n, number of patients; NYHA, New York Heart Association functional class; y.o., years old.
Table 3 shows the results of univariate and multivariate analyses. NYHA functional class and log plasma BNP level were recognized as independent predictors of cardiac events in our patients with HF. However, the HR at discharge was not related to the occurrence of cardiac events (hazard ratio [HR]: 1.00 [95% CI; 0.99–1.02], p = 0.22). Survival analysis revealed that there was no significant difference in the cardiac event rate between two equal groups divided according to a median value of HR (=66 bpm) at discharge, which were a lower HR group (≤65 bpm) and a higher HR group (≥66 bpm) (Fig. 1A ).
Table 3Results of univariate and multivariate analyses of risk factors for cardiac events.
Variable
Univariate analysis
Multivariate analysis
HR
(95% CI)
p value
HR
(95% CI)
p value
Age
1.04
(1.02–1.06)
<0.01
1.02
(0.99–1.04)
0.16
Gender
1.10
(0.77–1.56)
0.61
1.09
(0.68–1.73)
0.72
NYHA
1.33
(1.15–1.54)
<0.01
1.36
(1.13–1.63)
<0.01
SBP
1.00
(0.98–1.01)
0.99
1.00
(0.98–1.01)
0.68
HR
1.00
(0.99–1.02)
0.22
0.90
(0.98–1.02)
0.9
Log BNP
2.62
(1.71–4.03)
<0.01
2.36
(1.35–4.14)
<0.01
Creatinine
1.12
(1.00–1.28)
0.04
1.10
(0.86–1.42)
0.44
Atrial fibrillation
1.11
(0.78–1.57)
0.57
1.02
(0.65–1.61)
0.92
LVDd
1.00
(0.98–1.01)
0.84
1.00
(0.97–1.02)
0.74
%FS
0.90
(0.98–1.01)
0.90
1.00
(0.98–1.04)
0.43
NYHA, New York Heart Association functional class; SBP, systolic blood pressure; HR, heart rate; BNP, B-type natriuretic peptide; LVDd, left ventricular end-diastolic diameter; %FS, % fractional shortening.
Fig. 1Kaplan–Meier analysis of patients with acute heart failure syndromes stratified according to HR. Kaplan–Meier analysis according to the HR at discharge (A) or the change of HR during hospitalization (ΔHR; the difference between HR at admission and discharge) (B). (A) The lower HR group (HR at discharge; ≤65 bpm: average HR 58 ± 5 bpm, n = 209) and higher HR group (HR at discharge ≥66 bpm: average HR 76 ± 11 bpm, n = 212) are shown as blue line and red line, respectively. (B) The HRR-positive group (blue line) showed a reduction of HR by ≥21 bpm at discharge compared with that at admission (n = 213). Average HR at admission and that at discharge were 119 ± 23 and 65 ± 11 bpm, respectively. The HRR-negative group (red line) showed a reduction of HR by ≤20 bpm at discharge compared with that at admission (n = 208). Average HR at admission and that at discharge were 77 ± 16 and 70 ± 13 bpm, respectively. HR, heart rate; HRR, heart rate reduction. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
The average HR decreased from 98 ± 29 bpm at admission to 68 ± 12 bpm at discharge (Table 2). According to the HRR criterion, patients were divided into the HRR-positive group with ≥27 bpm reduction (from 119 ± 23 bpm at admission to 65 ± 11 bpm at discharge) and the HRR-negative group with ≤26 bpm reduction (from 77 ± 16 bpm to 70 ± 13 bpm). Table 4 compares the characteristics of the HRR-negative and -positive groups. Compared with the HRR-negative group, systolic BP was higher (148 ± 40 vs. 139 ± 33 mmHg), LVDs was larger (45 ± 12 vs. 41 ± 13 mm), and %fractional shortening was lower (19 ± 10% vs. 25 ± 13%) at admission in the HRR-positive group. Log BNP was not significantly different between these two groups at admission and discharge. The ratio of patients receiving beta-blockers at admission was significantly lower in the HRR-positive group than the HRR-negative group. In contrast, there was no significant difference between the two groups at discharge in the respect of the ratio receiving beta-blockers (Table 4). At discharge, the ratios of patients receiving angiotensin receptor blockers and calcium channel blockers were significantly lower and higher in the HRR-positive group than the HRR-negative group, respectively (Table 4). Kaplan–Meier analysis revealed that cardiac event rate was significantly lower in the HRR-positive group than the HRR-negative group (p = 0.01) (Fig. 1B). This tendency was observed in patients with both sinus rhythm and atrial fibrillation (Fig. 2A and B ). Fig. 3A shows the comparison of the cardiac events between HRR-positive and -negative groups. ROC curve showed that the extent of HRR was linearly related to the cardiac events’ AUC (0.607) (Fig. 3B).
Table 4Comparison of characteristics of the patients between HRR-positive and negative group.
HRR-negative group
HRR-positive group
p value
n
208
213
Age (y.o.)
73 ± 12
71 ± 4
0.330
Gender (male %)
59%
69%
0.526
At admission
NYHA
3.2 ± 0.6
3.4 ± 0.6
0.022
SBP
139 ± 33
148 ± 40
<0.001
HR
77 ± 16
119 ± 23
<0.001
% Sinus rhythm
63%
55%
0.102
Log BNP
2.8 ± 0.4
2.8 ± 0.4
0.645
Creatinine
1.3 ± 1.1
1.4 ± 1.4
0.801
Hb
11.3 ± 2.2
12.5 ± 2.3
<0.001
T-Bil
0.8 ± 0.6
1.0 ± 0.8
0.104
LVDd
54 ± 11
55 ± 10
0.034
LVDs
41 ± 13
45 ± 12
<0.001
%FS
25 ± 13
19 ± 10
<0.001
Beta-blockers
43%
36%
<0.001
At discharge
NYHA
2.0 ± 0.8
2.0 ± 0.9
0.942
SBP
117 ± 16
115 ± 14
0.075
HR
70 ± 13
65 ± 11
<0.001
% Sinus rhythm
63%
67%
0.370
Log BNP
2.4 ± 0.5
2.3 ± 0.4
0.065
Creatinie
1.4 ± 1
1.4 ± 1.2
0.328
LVDd
55 ± 11
56 ± 11
0.401
LVDs
41 ± 13
43 ± 12
0.104
%FS
27 ± 12
24 ± 11
0.009
Beta-blockers
57%
63%
0.183
ACE inhbitors
37%
40%
0.483
ARBs
31%
22%
0.035
Digoxin
20%
30%
0.345
Ca channel blockers
29%
34%
0.018
HRR, heart rate reduction; NYHA, New York Heart Association functional class; SBP, systolic blood pressure; HR, heart rate; BNP, B-type natriuretic peptide; LVDd, left ventricular end-diastolic diameter; LVDs, left ventricular end-systolic diameter; %FS, % fractional shortening; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.
Fig. 2Kaplan–Meier analysis of patients with sinus rhythm or atrial fibrillation with acute heart failure syndromes stratified according to HR. Kaplan–Meier analysis according to the ΔHR in patients with sinus rhythm at admission (A) or with atrial fibrillation (B). HRR-positive group and -negative group are shown as blue line and red line, respectively. HR, heart rate; HRR, heart rate reduction; Pts, patients. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
Fig. 3(A) Comparison between cardiac events in the HRR-positive and -negative group. Blue line shows the risk of the cardiac events. (B) Receiver operating characteristic curve between the extent of HRR and cardiac events. Area under the curve for change of the extent of HRR (ΔHR = HR at admission − HR at discharge) is shown. HR, heart rate; HRR, heart rate reduction. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
Table 5 shows the results of univariate analysis for several variables. The changes in both HR and plasma BNP levels were predictive factors for cardiac events, while systolic BP was not. These findings were obtained from patients receiving beta-blockers (Table 6A), but not in patients without beta-blockers at discharge (Table 6B). The extent of HRR was significantly greater in patients receiving beta-blockers (99 ± 30 bpm to 66 ± 12 bpm) compared with those without beta-blockers (95 ± 28 bpm to 70 ± 13 bpm). In contrast, in the patients without beta-blockers, the HR at discharge was significantly decreased compared with that at admission, but the extent of HRR was not significantly related to the clinical outcome by univariate analysis (Table 6B).
Table 5Univariate analysis of the influence of changes of variables during hospitalization.
When time-dependent ROC was applied to patients with beta-blockers, the ROC at 1 year showed that the change in HR had a larger AUC (0.675) than the change in systolic BP (0.635) or the percent reduction of the plasma BNP level (0.624) (Fig. 2). In patients without beta-blockers, the change in HR had a smaller ROC (0.578) than in those with beta-blockers. To determine the predictive power of the change in HR from admission, we equally divided the patients with beta-blockers based on the HR at admission (42–95 bpm and 96–200 bpm) and found that the integrated AUC indices were 0.68 and 0.60 for the higher and lower HR groups at admission, respectively, as shown in Fig. 3.
Discussion
In the present study, we found that (1) the achieved HR itself at the point of discharge does not influence cardiac events, but (2) the extent of the decrease in HR from the admission to discharge is a strong predictor of cardiac events in patients with AHFS with both sinus rhythm and atrial fibrillation, obviously in patients receiving beta-blockers, (3) the extent of HR change was an important predictor of cardiac events among other markers, compared with the change in systolic BP or BNP during hospitalization for heart failure (Fig. 4, Fig. 5).
Fig. 4Time dependent receiver operating characteristic (ROC) curves for changes of variables at 1 year in patients with or without beta-blockers. Time-dependent ROC curves at 1 year for changes in HR, systolic BP, and %reduction of plasma BNP in patients receiving beta-blockers and change in HR in patients without beta-blockers during hospitalization. They are shown by solid line (upper), dotted line (middle-upper) and coarse dotted line (lower-upper), fine dotted line (lower), respectively. BB, beta-blockers; BNP, B-type natriuretic peptide; BP, blood pressure; HR, heart rate; Pts, patients.
Fig. 5AUC of the time-dependent ROC for HR for admission HR. AUC of time-dependent ROC for change of HR is shown. The upper and lower curves are for patients with a higher HR at admission (96–200 bpm) and those without a higher HR (42–95 bpm), respectively. AUC, area under the curve; HR, heart rate; ROC, receiver operating characteristic.
Previous studies have shown a relation between HR and the clinical outcome of HF, and suggested that reduction in HR is beneficial for patients with chronic HF. Several physiological reasons for this observation can be considered. First, Braunwald reported that reduction in HR decreases myocardial oxygen consumption [
], which may be cardioprotective. Second, the increase in diastolic filling period with reduction of HR increases coronary flow and thus prevents subendocardial ischemia in an animal model [
]. Third, beta-blockers are widely used to treat HF, and one of their effects is reducing the HR in addition to decreasing oxidative stress and suppression of sympathetic activity in the myocardium [
Pathophysiological mechanisms underlying the effects of beta-adrenergic agonists and antagonists on functional capacity and survival in chronic heart failure.
Recently, the SHIFT study revealed a better clinical outcome in patients with chronic HF receiving ivabradine, which is a selective If current inhibitor that lowers HR independently of any effect of blocking of beta-adrenergic receptors [
SHIFT Investigators. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomizd placebo-controlled trial.
]. However, it has been uncertain whether patients with AHFS benefit from a lower HR itself or from treatment of HF that reduces sympathetic tone with consequent HRR. In addition, it also remained unknown the significance of HRR from acute phase during hospitalization for HF and comparison with other surrogate markers and systolic BP. In the present study, we addressed these issues as described.
Novel findings of the present study
In the present study, the extent of the decrease in HR from the admission to discharge, not the achieved HR at the point of discharge, was a strong predictor of cardiac events in patients with AHFS compared to other markers during hospitalization, in patients receiving beta-blockers. To the best of our knowledge, this was the first comparison of HR changes with other markers from acute phase during hospitalization in patients with AHFS. The extent of HR change was found to be an important predictor of cardiac events among other markers, while that of systolic BP was not a significant predictor in the present study. It has been unclear whether the extent of change in various parameters during hospitalization for HF was a predictor of future cardiac events. For example, the plasma level of BNP has been confirmed as a diagnostic and prognostic marker for HF patients [
Val-HeFT Investigators. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT).
]. In addition, previous studies have focused on the influence of HR in patients with chronic HF, so the significance of HRR from acute phase in patients with AHFS has been unclear. We found the change in HR from admission to discharge was an important predictor of future cardiac events rather than the absolute HR at discharge.
Possible mechanisms
In the normal myocardium, isometric contraction can be increased by stimulation up to 150–180 bpm [
]. It was also reported that reduction in HR decreases myocardial oxygen demand and increases the diastolic perfusion time that is a major determinant of subendocardial blood flow [
SHIFT Investigators. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomizd placebo-controlled trial.
]. Consistent with previous studies performed in patients with chronic HF, we found that HRR from the acute phase to discharge was a strong predictor for patients with AHFS, while the achieved HR at discharge was not related to the clinical outcome. However, this relation was weaker in patients without beta-blockers in the present study. These findings suggested that sympathetic inhibition might be also essential when treating patients with AHFS, synergistic to HRR per se.
To explain the beneficial effects of beta-blockers in the setting of HF, several pathophysiologic mechanisms have been considered. These include reduced adrenergic drive, a decrease in catecholamine-induced myocyte apoptosis and ventricular wall stress, and prevention of beta-receptor downregulation [
CIBIS III Investigators Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite sequence: results of the randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III.
], not only HRR. The findings of the present study and accumulating evidence suggest that only HRR per se might not be sufficiently beneficial for patients with acute HF, in the setting of highly activated systemic sympathetic tone, even if the HR is slowed by non-beta-blockers such as ivabradine. To resolve this issue, further investigation and a large-scale randomized clinical trial such as the comparison between beta-blockers and ivabradine, would be necessary for patients with AHFS.
Clinical implications
The present study yielded two important findings with clinical application. First, the extent of decrease in HR was related to the clinical outcome, in patients with HF who were on beta-blockers. In other words, the benefit of the HRR was provided to patients with beta-blockers. Beta-blockers have currently become a standard therapy for patients with HF. Carvedilol was reported to achieve dose-related improvement in patients with chronic HF [
MUCHA Investigators. Low-dose carvedilol improves left ventricular function and reduces cardiovascular hospitalization in Japanese patients with chronic heart failure: the multicenter carvedilol heart failure dose assessment (MUCHA) trial.
]. In the clinical setting, we usually employ vital signs and surrogate markers to decide on up-tiltration of beta-blockers in patients with HF. Although markers such as BNP, BP, and HR have been reported as useful for adjusting the dose of beta-blockers, it has not been clarified which markers are important for up-titration of beta-blocker therapy in patients with HF. In the present study, the change in HR was a stronger predictor of cardiac events in patients with HF compared with other markers.
In addition, both HR and systolic BP at admission in the HRR-positive group were significantly higher than those in the HRR-negative group (119 ± 23 vs. 77 ± 16 bpm, 148 ± 40 vs. 139 ± 33 mmHg, respectively), indicating that the patients with higher HR at admission, whose HR could be decreased using beta-blockers during the hospitalization for HF, had better clinical outcome than the patients in the HRR-negative group. This result indicates that our findings would be mainly applicable to the patients with higher HR or BP at admission, or in other words, with highly activated systemic sympathetic tone at admission in AHFS patients.
Study limitation
There are several limitations in this study. First, it was a single-center registry with a moderate number of enrolled patients. It was also an observational study, so it was not designed to compare the effects of beta-blockers and other treatment slowing HR in patients with AHFS. Future randomized large-scale clinical trials such as the comparison between beta-blockers and ivabradine would be necessary to confirm our findings.
Second, there was also a marked difference between HR and plasma BNP values, so change in BNP value was analyzed as percent reduction. Third, we could not completely exclude the influence of ventricular premature conduction. We could not follow the change in treatment after discharge in all patients. There is a tendency that patients without beta-blockers were complicated with valvular regurgitation or bronchical asthma or other complications, although baseline conditions were similar between the two groups as shown in Table 4. Since the present study was an observational study, we could not set the criteria for beta-blocker administration. In addition, we could not evaluate the thyroid function in all patients at acute phase and completely exclude the presence of hypo- or hyperthyroidism patients.
Conclusion
The HR at discharge did not predict the risk of future cardiac events in the present study. In contrast, the change in HR during hospitalization was a stronger predictor of the risk of future cardiac events in patients with AHFS compared with other markers, in patients receiving beta-blockers.
Acknowledgment
This work was supported by grants from the Japan Heart Foundation, and grants from the Japan Cardiovascular Research Foundation. There are no relationships with industry.
SHIFT Investigators. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomizd placebo-controlled trial.
Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite sequence: results of the randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III.
Effects of carperitide on the long-term prognosis of patients with acute decompensated chronic heart failure – the PROTECT multicenter randomized controlled study.
OPTIMIZE-HF investigators and coordinators. Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure.
Pathophysiological mechanisms underlying the effects of beta-adrenergic agonists and antagonists on functional capacity and survival in chronic heart failure.
Val-HeFT Investigators. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT).
MUCHA Investigators. Low-dose carvedilol improves left ventricular function and reduces cardiovascular hospitalization in Japanese patients with chronic heart failure: the multicenter carvedilol heart failure dose assessment (MUCHA) trial.
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