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European Journal of Heart Failure 2002 4(4):489-494; doi:10.1016/S1388-9842(02)00031-4
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© 2002 European Society of Cardiology

Is beta-blockade useful in heart failure patients with atrial fibrillation? An analysis of data from two previously completed prospective trials

Jeffrey W.H. Fung, Skiva K.W. Chan, Leata Y.C. Yeung and John E. Sanderson*

Division of Cardiology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong Prince of Wales Hospital Shatin, NT, Hong Kong SAR, PR China

* Corresponding author. Tel: +852-2632-2064; fax: +852-2637-3852. E-mail address: jesanderson{at}cuhk.edu.hk


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Background: Beta-adrenergic blockade is of proven value in chronic heart failure. It is uncertain, however, if beta-blockade provides a similar degree of clinical benefit for heart failure patients with atrial fibrillation (AF) as those in sinus rhythm (SR).

Aims: To compare the effectiveness of beta blockade in patients with heart failure and AF.

Methods: Patients with chronic heart failure were randomized to treatment (double blind) with metoprolol 50 mg twice daily or carvedilol 25 mg twice daily in addition to standard therapy. Response was assessed after 12 weeks by a quality of life questionnaire, New York Heart Association class, exercise capacity (6-min walk test), radionucleotide ventriculography for LVEF, 2-D echocardiography measurement of left ventricular (LV) dimensions and diastolic filling and 24-h electrocardiograph monitoring to assess heart rate changes.

Results: Both beta-blockers produced significant improvements in LVEF in both the SR group: (+6±10% at 12-week, P<0.001) and the AF group: (+11±9% at 12-week, P<0.05). However, significant improvement in symptoms (P<0.001) and exercise capacity (P<0.001) were observed only in the SR group but not in the AF group despite a significant improvement in LVEF.

Conclusion: Beta-blockers were effective in improving LV ejection fraction in chronic heart failure patients in either SR or AF but had less effect on symptoms and exercise capacity in those with AF.

Key Words: Atrial fibrillation • Beta-blockers • Heart failure

Received May 29, 2001; Revised November 26, 2001; Accepted January 12, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
It is well proven that beta-adrenergic blockade is useful for patients with chronic heart failure [1,2]. The MERIT-HF study and several other studies have provided strong evidence supporting favourable effects of β-blockade on left ventricular (LV) ejection fraction and the combined risk of death and hospitalization for heart failure [3,4]. Metoprolol and carvedilol were the beta-blockers studied in these trials [1–4]. The effects of metoprolol and carvedilol in the treatment of chronic heart failure are comparable, as we have previously reported [5]. It is estimated that atrial fibrillation (AF) was present in 15–30% of patients with dilated cardiomyopathy and moderate to advanced heart failure [6–8]. Beta-blockers have been shown to reduce arrhythmic events and have a significant impact on AF [9–11]. However, there is limited data about the clinical benefit, if any, of using beta-blockers in heart failure patients with AF. Therefore, we have analyzed two previous prospective trials [5,12] to compare the clinical benefits of beta-blockers, either metoprolol or carvedilol, in the treatment of chronic heart failure patients with either sinus rhythm (SR) or AF. Response was assessed by symptoms, exercise capacity, LV systolic and diastolic function and heart rate changes over a 3-month period.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Trial design
Both trials were prospective, parallel group, double blind-controlled trials with similar design [5,12]. Inclusion criteria of the two studies were identical. Patients with typical symptoms of heart failure and reduced LV ejection fraction (<0.45) were recruited into the studies. The first study compared metoprolol to celiprolol in patients with chronic heart failure [12] and the second study compared metoprolol to carvedilol [5]. Patients were divided into SR and AF groups. Only patients who received either metoprolol or carvedilol were recruited for analysis because the beneficial effects of these two beta-blockers have been well proven in other heart failure trials [1–4]. There was a 4-week titration period, increasing the dose of carvedilol from 3.125 to 25 mg twice daily and metoprolol from 6.25 to 50 mg twice daily. Doses were increased at weekly intervals. Maintenance of doses was continued for 8 weeks (total of 12 weeks of treatment). At the end of 12 weeks, baseline measurements were repeated. Clinical assessment was carried out at 1, 2, 4 and 8 weeks. Compliance was checked by counting the remaining capsules at each visit.

2.2. Study objectives
To compare the clinical benefits of beta-blockers in heart failure patients with either SR or AF, by assessment of symptoms (using the Minnesota Quality of Life Heart Failure Questionnaire), exercise capacity (6-min walk test), LV ejection fraction (measured by radionucleotide ventriculography and echocardiography) and heart rate changes (24-h ambulatory electrocardiograph (ECG) monitoring). The primary end points were symptom score, exercise time and LV ejection fraction. The study had a 90% power to detect a 55% reduction in symptoms score, a 20% increase in the 6-min walk time and a 12% increase in LV ejection fraction from baseline for each group, all of which would be considered clinically significant.

2.3. Study patients
Patients with a clinical diagnosis of chronic heart failure who were on standard therapy with diuretics, digoxin- and angiotensin-converting enzyme inhibitors and with a LV ejection fraction of <0.45 (by radionucleotide ventriculography) were recruited. Patients were excluded if they had significant valvular heart disease as the etiology of LV dysfunction, active myocarditis, unstable angina, a documented history of sustained ventricular tachycardia or symptomatic nonsustained ventricular tachycardia or second- or third-degree atrioventricular block. Patients with chronic obstructive lung diseases, asthma, long-term alcohol or drug abuse or chronic renal failure (serum creatine >200 µmol/l), hepatic, hematological, neurological or collagen vascular disease were excluded. All subjects gave written informed consent, and the study was approved by the Ethics Committee of the Faculty of Medicine, the Chinese University of Hong Kong.

2.4. Study measurements
Baseline measurements included assessment of symptoms using the Minnesota Heart Failure Symptom Questionnaire, New York Heart Association (NYHA) class and routine clinical examination (pulse, heart rate, sitting and standing blood pressure, examination of jugular venous pressure, position of the apex beat and presence or absence of a heart murmur or lung rales). A 6-min corridor walk test was carried out. Two baseline walk tests were carried out and the results averaged. Routine 2-D Doppler echocardiography was performed with measurement of LV dimensions. Pulse-wave Doppler echocardiography was performed to assess mitral inflow velocities. The usual variables were measured: peak early mitral filling velocity (E wave), peak atrial filling velocity (A wave), ratio of the peak early and atrial filling velocities (E/A), deceleration time of the E wave (DT) and isovolumic relaxation time, as previously described [13]. Radionucleotide ventriculography was used to assess LV ejection fraction in the usual way. A 24-h ambulatory ECG monitoring was undertaken using the Marquette (Milwaukee, Wisconsin) MARS 8000 analyzer. Maximum, average and minimum heart rate analyses were undertaken. Routine blood laboratory tests were performed at baseline, and at 4 and 8 weeks.

2.5. Statistical analysis
Differences between the AF and SR groups were carried out by repeated-measures analysis of variance for continuous variables (ANOVA) with Barlets test with homogeneity test if P<0.05, Friedman's test for non-parametric data and Fisher exact test for differences between proportions. Differences between baseline and week 12 within groups were tested by paired t-tests, and Wilcoxon matched pairs signed ranks test for non-parametric data. The results are expressed as mean±S.E.M. Differences were considered significant if P<0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
3.1. Subjects
Sixty-three patients with a mean LV ejection fraction of 26±10% were in SR while 12 patients with a mean LV ejection fraction of 26±7% were in AF. In the SR group, 42 patients were taking metoprolol and the rest were taking carvedilol. In the AF group, 5 were taking metoprolol and 7 were taking carvedilol. There were no significant differences in age, gender or other baseline characteristics except that the AF group had lower exercise capacity than the SR group (Table 1). The majority of patients had idiopathic dilated cardiomyopathy (44%) with ischemic cardiomyopathy as the etiology in 25% and hypertensive heart disease in 30%. All but one patient were taking an angiotensin-converting enzyme inhibitor or an angiotensin II receptor antagonist. The average daily dose of frusemide was similar in both groups.


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  		Table 1 Baseline clinical characteristics of study patients

 
3.2. Withdrawals
In the SR group, 7 patients did not complete the study. The reason for withdrawal was mainly worsening of symptoms, in particular, weakness, dizziness and dyspnoea. One patient developed angioneurotic edema. In the AF group, 3 patients did not complete the study and the reasons for withdrawal were similar to that of the SR group. There was no difference between the SR and AF groups.

3.3. Symptoms
The results of the symptom (quality of life) questionnaire score and assessment of NYHA functional class are shown in Table 2. A highly significant reduction in symptom questionnaire score was observed in SR group (P<0.001) but not in AF group. Neither the SR nor AF groups had any reduction of NYHA class though a trend (P=0.07) of reduction was observed in the SR group after 12-weeks of beta-blocker therapy. However, there were no significant differences between SR and AF in terms of NYHA class (P=0.104) and quality of life questionnaire score (P=0.61) at the end of the study.


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  		Table 2 Effects of beta-blockers on symptoms, exercise capacity, blood pressure and heart rate (Mean±SEM)

 
3.4. Blood pressure and heart rate (Table 2)
At 12 weeks, beta-blockers produced a highly significantly reduction in systolic and diastolic blood pressures compared with baseline in SR group. In AF group, a reduction in systolic and diastolic blood pressures was also observed. At the end of the study, blood pressures were significantly lower in the AF group when compared to the SR group (P=0.012). A significant reduction of maximum, average and minimum heart rate was observed in both the SR and AF groups at 12 weeks when compared to baseline. There was no difference in average heart rate in both groups at 12 weeks (64.6±1.4 beats/min in SR and 63.4±2.6 beats/min in AF).

3.5. Exercise capacity (Table 2)
With similar degree of LV ejection fraction, the AF group had worse exercise capacity than the SR group at baseline (Table 1). At 12 weeks, a significant improvement in exercise capacity as measured by 6-min walk test was observed in the SR group only. Moreover, exercise capacity at 12 weeks in the SR group was better than that in the AF group (1323±31 feet vs 984±90 feet, respectively, P<0.001).

3.6. LV systolic and diastolic functions (Table 3)


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  		Table 3 Effects of beta-blockers on systolic and diastolic LV function

 
Both groups showed significant improvement in LV ejection fraction with beta-blocker therapy. There was no difference in LV ejection fraction between the two groups at 12 weeks (32±1.6% in SR and 37±5.1 in AF). At 12 weeks, the SR group, but not the AF group, showed a significant reduction in LV end-diastolic dimension. Beta-blockers produced no change in peak mitral E wave velocity but prolonged the deceleration time of the mitral E value towards normal in both groups.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
In this 3-month study comparing the clinical efficacy of beta-blocker therapy in chronic heart failure patients with either SR or AF, we have demonstrated that beta-adrenergic blockade significantly improves LV ejection fraction in both groups. However, the benefit of beta-blocker therapy in improving exercise capacity and quality of life as reflected by the symptom questionnaire score could only be demonstrated in the SR group. Beta-blocker therapy lowered blood pressures in both groups. Both groups showed a marked reduction in heart rates with beta-blocker therapy. With regard to LV diastolic function, significant prolongation of mitral E deceleration time was observed in both groups.

In our study, 16% of patients with chronic heart failure were in AF. Such a proportion is consistent with other studies which range from 15 to 30% [6–8]. The proportion of heart failure patients with AF in V-HeFT I [14] was 16% and in V-HeFT II [15] was 13%. Thus, our study cohort is quite similar to other heart failure studies. However, the small number of patients in AF when compared with those in SR makes statistical analysis difficult [6].

In this study, beta-blocker therapy was shown to be equally effective in improving LV systolic function in heart failure patients with either AF or SR. In a retrospective analysis of the US Carvedilol Heart Failure Trials Program [16], a similar degree of improvement in LV ejection fraction in patients with AF by carvedilol when compared to placebo was also observed. There was a non-significant trend of reduction in combined endpoints of death or heart failure hospitalization in the carvedilol group. However, different results were observed in the CIBIS II trial [17] using bisoprolol. The survival benefit and reduction in heart failure hospitalization by bisoprolol was not observed in those patients in AF. This suggests that different beta-blockers may not have the same benefits to heart failure patients with AF. It is interesting to note that, although the LV ejection fraction was similar in both groups at baseline and end of week 12 in the present study, patients in AF had a worse exercise capacity and were more symptomatic than patients in SR. Moreover, significant improvement in exercise capacity and symptoms by beta-blockers was only observed in the SR group. It has also been shown that baseline heart rate and heart rate changes are significantly related to prognosis in patients with heart failure [17]. In the present study, however, rate control differences after beta-blocker therapy cannot explain the difference as the maximum, average and minimum heart rates were similar in both groups after 12 weeks of therapy. There are two possible explanations why patients in AF were more symptomatic and had worse exercise capacity. First, statistical error might be responsible, as the sample size of patients in AF was small. The second explanation is that it might be related to the physiological impact of ventricular rate irregularity. In a meta-analysis, Wood et al. reported that ablation and pacing therapy in chronic refractory AF can significantly improve quality of life [18]. Controlled regular ventricular rate provided by pacing might contribute to this improvement. Clark et al. [19] reported an acute pacing study in patients after atrioventricular nodal (AVN) ablation. Pacing with a regular rate in the VVI mode at the average rate of AF resulted in higher cardiac output than pacing at the same rate and rhythm in the VVT mode triggered to the RR intervals present in AF. Daoud et al. [20] reported that cardiac output was higher with regular vs irregular right ventricular apical pacing at two paced sites in patients after AVN ablation. Irregular ventricular rate in AF may influence preload, afterload, or inotropic state in turn affecting ventricular performance. The marked beat-to-beat variability in the intensity of pulse and blood pressures is due to changes in LV contractility, according to Frank–Starling mechanism [21]. Postextrasystolic potentiation occurs following a short–long RR sequence [22]. In heart failure patients, this beat-to-beat variability in LV contractility may have deleterious effects by further exacerbating increases in sympathetic tone and salt and water retention present as compensatory responses. These physiological changes may explain why heart failure patients in AF have more symptoms and worse exercise capacity. However, there are conflicting results in terms of any difference in exercise tolerance between the AF and SR groups. In the V-HeFT I [14] study using vasodilator therapy, peak oxygen capacity was similar in both the AF and SR groups. In the V-HeFT II study [15], there was no difference in change in peak oxygen consumption during the first 2 years but patients with AF showed a decline at 2.5 years. Data on beta-blocker therapy in patients with AF or SR in terms of exercise capacity is limited. Our study may contribute to this information.

In patients with dilated cardiomyopathy, restrictive filling pattern with short mitral E deceleration time was associated with worse prognosis [23–25]. Prolongation of mitral E deceleration time in both groups by beta-blocker reflected an improvement in diastolic function and possibly might have an impact on survival improvement.

There is controversy about the choice and doses of beta-blocker in patients with heart failure. Gilbert et al. [26] reported that carvedilol may be associated with greater improvement in NYHA functional class. In our previous double blind-randomized study [5], both metoprolol and carvedilol were equally effective in improving LV ejection fraction, quality of life and exercise capacity. The observed difference between SR and AF groups in this study is probably independent of the choice of beta-blocker. The dose (50 mg/d) of carvedilol in the current study was comparable to the mean dose (44–49 mg/d) of this drug used in the multicentre trials [1,2,27] showing a reduction in morbidity and mortality in patients with heart failure. The dose (100 mg/d) of metoprolol in this study was slightly lower than that in Metoprolol in Dilated Cardiomyopathy Trial (108 mg/d) [28]. In the MERIT-HF study [3,4], slow-release form of metoprolol succinate was used and the adjusted equivalent dose of metoprolol tartrate was 119 mg/d.

4.1. Study limitations
This study had a relatively small number of patients, especially in the AF group, and there is a possibility of a type II error. It was not powered to detect any differences in mortality and was designed to determine if there were any obvious or major differences in clinical efficacy, especially in terms of symptoms, quality of life and exercise capacity between the SR and AF groups. To this end, we used a wide range of well-validated techniques including the Minnesota Heart Failure Symptom Questionnaire and the 6-min walk test. Several studies have now demonstrated a clear independent inverse relation between the 6-min walk test and both mortality and morbidity [29].


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
In this study, we have confirmed the beneficial effects of the beta-blockers metoprolol and carvedilol, in improving LV ejection fraction in chronic heart failure patients, in either SR or AF. However, the improvement in exercise capacity and quality of life by beta-blocker therapy, could only be observed in patients in SR.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

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