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European Journal of Heart Failure 2006 8(5):539-546; doi:10.1016/j.ejheart.2006.01.015
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© 2006 European Society of Cardiology

Presence and development of atrial fibrillation in chronic heart failure

Experiences from the MERIT-HF Study

Dirk J. van Veldhuisena,*, Halfdan Aassb, Dia El Allafc, Peter H.J.M. Dunselmand, Lars Gullestadb, Matti Halinene, John Kjekshusb, Lis Ohlssonf, Hans Wedelg, John Wikstrandf,h,1 MERIT-HF Study Group

a Department of Cardiology, Thoraxcenter, University Medical Center Groningen PO Box 30 001, 9700 RB Groningen, The Netherlands
b Department of Cardiology, University of Oslo Rikshospitalet, Oslo, Norway
c Centre Hospitalier Hutois Huy, Belgium
d Amphia Hospital Breda and Department of Clinical Pharmacology, University of Groningen The Netherlands
e Kuopio University Hospital Kuopio, Finland
f Clinical Science AstraZeneca, Mölndal, Sweden
g Nordic School of Public Health Göteborg, Sweden
h Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital Göteborg, Sweden

* Corresponding author. Tel.: +31 50 3611327; fax: +31 50 3614391. E-mail address: d.j.van.veldhuisen{at}thorax.umcg.nl


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. ECG recording and...
 4. Statistical analysis
 5. Results
 6. Discussion
 Acknowledgments
 References
 
Background: Atrial fibrillation is common in heart failure, but data regarding beta-blockade in these patients and its ability to prevent new occurrence of atrial fibrillation are scarce.

Methods: Baseline ECGs in MERIT-HF were coded regarding baseline rhythm, and outcome was analyzed in relation to rhythm. Occurrence of atrial fibrillation during follow-up was also analyzed.

Results: At baseline atrial fibrillation was diagnosed in 556 patients (13.9%). Mean metoprolol CR/XL dose in patients in atrial fibrillation (154 mg) and sinus rhythm (158 mg) was similar, as well as decrease in heart rate (14.8 and 13.7 bpm, respectively). Only 61 (total of 362) deaths occurred in those in atrial fibrillation at baseline, 31 on placebo and 30 on metoprolol (RR 1.0; 95% CI 0.61–1.65). During follow-up, new atrial fibrillation was observed in 85 patients on placebo and 47 patients on metoprolol (RR 0.53; 95% CI 0.37–0.76; p=0.0005).

Conclusion: First, given the wide confidence interval, it was impossible to detect an interaction between metoprolol and mortality in patients with atrial fibrillation and heart failure. Second, in patients with sinus rhythm at baseline, metoprolol reduced the incidence of atrial fibrillation during follow-up. However, we must be extremely cautious in over-interpreting effects in these subgroups.

Key Words: Atrial fibrillation • Sinus rhythm • Chronic heart failure • Beta-blockade • Metoprolol CR/XL • Prognosis

Received July 28, 2005; Revised November 14, 2005; Accepted January 26, 2006


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. ECG recording and...
 4. Statistical analysis
 5. Results
 6. Discussion
 Acknowledgments
 References
 
Atrial fibrillation is the most common cardiac arrhythmia, it is associated with significant morbidity and mortality, and is present in many patients with chronic heart failure [1,2]. Atrial fibrillation increases with the severity of the disease and age, and has been reported to be present in about 10-40% of patients with heart failure [3-5].

Based on several large-scale clinical trials [6-11], the current treatment guidelines for heart failure due to left ventricular systolic dysfunction recommend beta-blockers as routine treatment for all patients who tolerate this medicine. In most of these large heart failure trials, however, the majority of patients were in sinus rhythm and the specific effect of beta-blockers in the subgroup of patients in atrial fibrillation has either not been reported, or was inconclusive [12,13]. Nevertheless, current treatment guidelines for heart failure state that beta-blockade should be considered in patients with atrial fibrillation, to control heart rate at rest and during exertion [14,15].

Development of atrial fibrillation in patients with heart failure is associated with clinical and hemodynamic deterioration and poor outcome [1-5,16,17]. Beta-blockade has been associated with a decreased incidence of atrial fibrillation in healthy subjects [18], and in patients with impaired left ventricular function after myocardial infarction [19]. In the Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF) as well as in the Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS) atrial fibrillation was reported as an adverse event more commonly in the placebo groups than on beta-blockade [9,11]. However no systematic analyses have been performed in these trials regarding the occurrence of atrial fibrillation during follow-up in patients with documented sinus rhythm at baseline.

The aims of the present analyses were to examine the clinical outcome in patients in atrial fibrillation at baseline in MERIT-HF, and also to analyze the effect of controlled release/extended release metoprolol succinate (CR/XL) on the occurrence of atrial fibrillation during follow-up in patients in sinus rhythm at baseline according to the baseline electrocardiogram (ECG).


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. ECG recording and...
 4. Statistical analysis
 5. Results
 6. Discussion
 Acknowledgments
 References
 
MERIT-HF was a prospective, double-blind, placebo-controlled trial that randomized 3991patients. The present post-hoc analyses focus on the subgroups of patients with different cardiac rhythm as defined from the ECG at baseline (see below).

The study design and main results have been published previously [8,9,20]. An optimal allocation procedure (minimization method) was used at randomization, taking into account baseline characteristics as described earlier [8,20]. The study was closed early after the 2nd interim analysis performed by the Independent Safety Committee, which showed a highly significant difference in total mortality favoring metoprolol CR/XL [8,20]. The mean follow-up time was 1 year.

Briefly, patients enrolled in MERIT-HF were men and women aged 40 to 80years in New York Heart Association (NYHA) classes II to IV with ejection fraction (EF) of <0.40, and who at the time of enrollment had a heart rate ≥68beats/min (bpm), and were receiving optimum standard therapy with diuretics and an angiotensin-converting enzyme (ACE) inhibitor.

After a single blind, placebo run-in phase of 2weeks, patients were randomized to metoprolol CR/XL or placebo, with recommended starting doses of 12.5 mg (NYHA classes III and IV) or 25 mg once daily (NYHA II). It was recommended that the dose be doubled every 2 weeks to a target dose of 200 mg once daily, or the highest tolerated dose.

The first primary endpoint was total mortality; the second primary endpoint was the combined endpoint of all-cause mortality and all-cause hospitalization (time to first event). The first secondary endpoint was the combined endpoint of all-cause mortality and hospitalization due to worsening heart failure (time to first event). Furthermore cause-specific mortality for cardiovascular causes, sudden death and death from worsening heart failure were predefined secondary endpoints, as were the total number of hospitalizations due to cardiovascular causes, and to worsening heart failure. Withdrawals of study drug for any cause, and for worsening heart failure were among the predefined tertiary endpoints.


   3. ECG recording and coding
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. ECG recording and...
4. Statistical analysis
 5. Results
 6. Discussion
 Acknowledgments
 References
 
The MERIT-HF Study protocol stipulated that an ECG should be recorded at randomization, and at the 1 year follow-up visit. When the decision to close the study early was taken, it was decided to record an ECG in connection with the closing visit for those patients who had not yet passed the 1-year visit (the last patient was randomized on April 14, 1998, and the study was closed on October 31, 1998). A group of doctors lead by one of the authors (HA Oslo group) coded all ECGs for cardiac rhythm, and this coding was performed in a blinded manner regarding study drug.

At baseline, atrial fibrillation was diagnosed on the ECG in 556patients (13.9%), and sinus rhythm in 3132patients. Ninety-five patients had pacemakers (49placebo, 46metoprolol CR/XL), and ECG was missing in 208 patients (107placebo, 101metoprolol CR/XL). These two latter subgroups (pacemakers+missing) constitute a subgroup defined as "other/unknown" (n=303). Of those patients with sinus rhythm at baseline, a follow-up ECG permitting evaluation of cardiac rhythm (atrial fibrillation or sinus rhythm) was available in 2465patients (see Results for further data). Of those patients with atrial fibrillation at baseline, a follow-up ECG permitting evaluation of cardiac rhythm (atrial fibrillation or sinus rhythm) was available in 403patients (see Results for further data).


   4. Statistical analysis
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. ECG recording and...
 4. Statistical analysis
5. Results
 6. Discussion
 Acknowledgments
 References
 
4.1. Data analysis plan for MERIT-HF
The MERIT-HF study had a predefined Data Analysis Plan, which in detail defined all pre-specified analyses to be performed. The analysis was by intention to treat (e.g. all patients randomized). The main analysis used the log-rank test for the comparison of the 2randomized groups and Cox proportional hazards model (unadjusted) to calculate relative risk and 95% confidence intervals. This Data Analysis Plan included one paragraph relating to subgroup analyses to be performed. The International Steering Committee decided to do such analyses only for safety reasons. The rationale for doing analyses as stated in this Data Analysis Plan was to explore any unfavorable outcome in 12pre-specified subgroups, and not to look for efficacy in subgroups because the study was only powered for pre-specified efficacy analysis in all patients randomized [8,9,20,21]. The pre-specified safety analyses in subgroups were to be performed only if a total of more than 180events in the two randomization groups combined were observed in the subgroup. One hundred eighty events would give a reasonable power to detect an unfavorable outcome. The results of these primary safety analyses have been published. The International Steering Committee of MERIT-HF also decided to provide data on complementary subgroups having less than 180events, for example giving data for females having less than 180deaths (64deaths), when giving data for males with more than 180deaths [22].

4.2. Analyses for the present paper
Student t-test for continuous variables and Fisher's exact test for categorical variables were used when analyzing differences in baseline characteristics between patients with atrial fibrillation and sinus rhythm, respectively. Cox proportional hazards model was used to calculate hazard ratios (HR), for convenience expressed as relative risks, and 95% confidence intervals (CI). Because of the post-hoc nature of the present analyses, analyses are presented both unadjusted and adjusted for the following baseline variables: age, sex, NYHA class, ejection fraction, ischemic etiology, history of MI, hypertension and diabetes, systolic blood pressure, heart rate and smoking status. Absolute risk has been expressed as number of events per patient-year of follow-up. Risk reduction was defined as (1–HR). A test of baseline rhythm (atrial fibrillation vs. sinus rhythm) by treatment interaction was performed, taking into account also the 12pre-specified subgroup analyses performed earlier [8,9,21].


   5. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. ECG recording and...
 4. Statistical analysis
 5. Results
6. Discussion
 Acknowledgments
 References
 
Of the 556patients with atrial fibrillation at baseline, 282 were randomized to placebo and 274 to metoprolol CR/XL; 3132 were in sinus rhythm, 1563 were randomized to placebo and 1569 to metoprolol CR/XL; the other/undefined group included 303patients, 156 were randomized to placebo and 147 to metoprolol CR/XL. The total survival experience for those in atrial fibrillation at baseline represented only 543patient-years of follow-up (267 on placebo and 276 on metoprolol CR/XL), to be compared with 3145patient-years for those in sinus rhythm (1553 on placebo and 1592 on metoprolol CR/XL). The total survival experience for all patients randomized was 1977 vs. 2004patient-years, respectively.

Baseline characteristics by randomization group for the three different subgroups are presented in Table 1. Compared to patients in sinus rhythm patients in atrial fibrillation were older, included fewer women, and had more severe heart failure as judged from symptoms and NYHA class. Patients in atrial fibrillation more often had non-ischemic etiology of heart failure, and less often a history of myocardial infarction. A higher proportion of patients in atrial fibrillation were treated with digitalis and oral anti-coagulants, and fewer with statins (Table 1).


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  		Table 1 Baseline characteristics separately given for the three subgroups atrial fibrillation, sinus rhythm and other/undefined, respectively (percent within brackets)

 
5.1. Dose of study medicine and heart rate during follow-up
Fig. 1 illustrates dose of metoprolol CR/XL vs. heart rate during the titration phase. At the 3-month follow-up visit the mean dose of metoprolol CR/XL was 150 mg in the atrial fibrillation group and 154 mg in the sinus rhythm group. The net reduction in heart rate (beta-blockade minus placebo) was 10.8 bpm in the atrial fibrillation group and 12.6 bpm in the sinus rhythm group. The mean dose of metoprolol CR/XL at the last follow-up visit was 154 mg in patients in atrial fibrillation at baseline, 158 mg in those in sinus rhythm, and 154 mg in those with rhythm undefined; corresponding placebo doses were 173, 176, and 166 mg, respectively. In the metoprolol CR/XL group heart rate was reduced by 14.8 bpm in those in atrial fibrillation at baseline (10.7 bpm net vs. placebo); and by 13.7 bpm for those in sinus rhythm (net 11.3 bpm), and by 8.0 bpm in the other/undefined subgroup (net 5.9 bpm).


Figure 1
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  		Fig. 1 Illustration of dose of metoprolol CR/XL vs. heart rate during the titration phase. Net reduction in heart rate refers to beta-blockade minus placebo.

 
5.2. Total and cause-specific mortality
In patients in atrial fibrillation at baseline randomized to placebo, 31deaths occurred during follow-up (11.2% per patient-year of follow-up); corresponding figures in the metoprolol CR/XL group were 30deaths (10.8%); relative risk 1.00 (95% CI 0.61 to 1.65; p>0.2; Fig. 2; Cox adjusted 1.06; 95% CI 0.64 to 1.77; p>0.2). In patients in sinus rhythm at baseline randomized to placebo 160 deaths occurred during follow-up (10.3% per patient-year of follow-up); corresponding figures in the metoprolol CR/XL group were 102 deaths (6.4%); relative risk 0.62 (95% CI 0.48 to 0.80; p<0.0001; Cox adjusted 0.61; 95% CI 0.47 to 0.78; p<0.0001). Test of baseline rhythm (atrial fibrillation vs. sinus rhythm) by treatment interaction was non-significant. In the other/undefined group 26deaths occurred in the placebo group (17.7% per patient-year of follow-up); corresponding figures in the metoprolol CR/XL group was 13deaths (9.0%); relative risk 0.50 (95% CI 0.26 to 0.98; p=0.039; Cox adjusted 0.61; 95% CI 0.30 to 1.21; p=0.16). Corresponding figures for all patients randomized were 217deaths (11.0%) vs. 145 deaths (7.2%); relative risk 0.66 (95% CI 0.53 to 0.81; p<0.0001; Cox adjusted 0.65; 95% CI 0.53 to 0.81; p<0.0001). Fig. 2 also illustrates point estimates for relative risk and 95% confidence intervals for cause-specific mortality separately given for the three subgroups (atrial fibrillation, sinus rhythm and other/undefined), and for all patients randomized. If patients with atrial fibrillation in the placebo group (n=282) were compared to patients in sinus rhythm on placebo (n=1563), there were no significant differences in outcome, when using Cox regression analyses (for total mortality the hazard ratios were 1.089unadjusted and 1.016adjusted for atrial fibrillation vs. sinus rhythm).


Figure 2
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  		Fig. 2 Point estimates for hazard ratios and 95% confidence intervals for all-cause mortality, for cardiovascular mortality, sudden death, and death from worsening heart failure separately given for the three subgroups (atrial fibrillation, sinus rhythm and other/undefined), and for all patients randomized. Number of deaths by randomization group is also given for all groups illustrated. The percent figures given for risk reduction refer to all patients randomized.

 
5.3. Hospitalizations
Ninety-nine of the patients in atrial fibrillation at baseline randomized to placebo were hospitalized (all-cause) during follow-up (44.5% per patient-year of follow-up); corresponding figures in the metoprolol CR/XL group were 91patients (43.4%; ns; Fig. 3, upper panel). Five hundred and eight of the patients in sinus rhythm at baseline randomized to placebo were hospitalized (all-cause) during follow-up (40.3% per patient-year of follow-up); corresponding figures in the metoprolol CR/XL group were 442patients (33.3%; p=0.0084). In the other/undefined group corresponding figures were 61patients (52.7%) and 48patients (41.4%), respectively (ns). Fig. 3 (lower panel) illustrates data for hospitalizations for worsening heart failure separately given for the three subgroups (atrial fibrillation, sinus rhythm and other/undefined), and for all patients randomized.


Figure 3
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  		Fig. 3 Bar diagrams illustrating number of patients hospitalized (all-cause, upper panel) by randomization group separately given for the three subgroups (atrial fibrillation, sinus rhythm and other/undefined), and for all patients randomized. The lower panel gives similar data for hospitalization for worsening heart failure.

 
5.4. Combined endpoints
Relative risk for patients on metoprolol vs. those on placebo, for the combined endpoint of all-cause mortality and all-cause hospitalization (time to first event) in the three subgroups and in all patients randomized was 0.96 (atrial fibrillation); 0.79 (sinus rhythm); 0.80 (other/undefined); and 0.82 (all patients randomized; Cox adjusted 1.04, 0.77, 0.87, and 0.81, respectively). Corresponding data for the combined endpoint of all-cause mortality and hospitalization for worsening heart failure (time to first event) was 1.02, 0.62, 0.86, and 0.69 (Cox adjusted 1.09, 0.60, 0.96, and 0.68, respectively).

5.5. Tolerability
Of those in atrial fibrillation at baseline 44patients in each randomization group discontinued study drug during follow-up (all-cause); this was due to worsening heart failure in 10 (placebo) vs. 9patients (metoprolol CR/XL). Corresponding data for those in sinus rhythm were 229 and 200patients for all causes, respectively (and 64 and 47patients specifically for worsening heart failure, on placebo and metoprolol CR/XL, resp.). For patients not in sinus rhythm or atrial fibrillation ("other/undefined") the number of patients was 37 and 35 for all causes, respectively, and 11 vs. 8patients for worsening heart failure, respectively.

5.6. Conversion back to sinus rhythm from atrial fibrillation
At follow-up, ECGs were available in 403 of the 556patients with atrial fibrillation at baseline (200patients on placebo and 203patients on metoprolol). In the placebo group, 23 of the 200patients (11.5%) had converted back to sinus rhythm, as compared to 19 of the 203patients (9.4%) on metoprolol (p>0.5 between groups).

5.7. Newly diagnosed atrial fibrillation during follow-up
Newly diagnosed atrial fibrillation (for those in sinus rhythm at baseline n=3132) was reported as an adverse event for 42patients on placebo and for 19patients on metoprolol CR/XL; corresponding data from the follow-up ECG (available for 2465patients in sinus rhythm at baseline) was 45 vs. 32patients. When these two sources were combined (if a patient had newly diagnosed atrial fibrillation reported as an adverse event, and it was also found on follow-up ECG, it was only counted once), there were 85 vs. 47patients on placebo and metoprolol resp.; relative risk 0.53 (95% CI 0.37 to 0.76; p=0.0005; Fig. 4; Cox adjusted 0.52; 95% CI 0.37 to 0.75; p=0.0004). When baseline characteristics of patients who had newly diagnosed atrial fibrillation during the study (n=132) were compared to those who did not (n=3000), those with new atrial fibrillation were older (66±9 vs. 63±10 years) and more often male (81 vs. 76%). In addition, those with new atrial fibrillation generally had more advanced disease (64 vs. 57% NYHA functional class III/IV) and more often a history of hypertension (54 vs. 44%) and diabetes (32 vs. 25%), although their EF was not significantly different. Baseline heart rate and body mass index were also similar.


Figure 4
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  		Fig. 4 Kaplan-Meyer estimates of newly diagnosed atrial fibrillation during follow-up in patients in sinus rhythm at baseline. Baseline rhythm defined from baseline ECG. Atrial fibrillation during follow-up was reported as an adverse event and/or defined from the follow-up ECG (time to first event, see text for comments). Atrial fibrillation is only counted once in each patient.

 

   6. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. ECG recording and...
 4. Statistical analysis
 5. Results
 6. Discussion
Acknowledgments
 References
 
Beta-blockers are now part of the mainstay of therapy in patients with heart failure, but data on their effect on outcome in patients with atrial fibrillation is sparse. The present report describes a post-hoc analysis of the MERIT-HF study. Data showed that test of baseline rhythm (atrial fibrillation vs. sinus rhythm) by treatment interaction on total mortality was non-significant. Nevertheless, given the point estimate of 1.0 with a wide 95% confidence interval, regarding the effect of metoprolol CR/XL in patients with atrial fibrillation and heart failure, we could not detect an effect on mortality in the subgroup of patients with atrial fibrillation. However, a positive finding was that for patients in sinus rhythm at baseline the risk of developing atrial fibrillation during follow-up was lower in those randomized to metoprolol CR/XL.

As discussed above, somewhat surprisingly, there are only few other data regarding the value of beta-blockade in patients with heart failure and atrial fibrillation. In the only prospectively designed, double-blind, placebo-controlled study by Khand et al. [23] in 47patients with heart failure and atrial fibrillation, the combination of carvedilol and digoxin was clinically superior to digoxin alone. This included improvement of ejection fraction and symptom score, but also lowering of ventricular rate during 24h ambulatory monitoring and submaximal exercise, after 4 months treatment. Meng et al. [24], in a retrospective analysis, examined the effects of metoprolol or carvedilol in 24heart failure patients with atrial fibrillation, and observed favorable effects on left ventricular dimensions after 4 and 16-48weeks, that were similar to those observed in patients with sinus rhythm.

In addition to these 2studies, there are 3post-hoc analyses in patients with atrial fibrillation, from large heart failure trials [12,13,17]. In a subanalysis of the CIBIS-II study, 521patients with atrial fibrillation were analyzed, results showed that bisoprolol had no effect on mortality in this subgroup [13]. In CIBIS II, bisoprolol was found to have a less pronounced effect on heart rate in patients with atrial fibrillation (–8.8 bpm) than in those with sinus rhythm (–10.6 bpm, p=0.02). In the US Carvedilol Program, 136patients with atrial fibrillation were included, but only 84 of them were treated with beta-blockade [12]. In a post-hoc analysis, a trend towards a reduction in heart rate (–13 bpm for carvedilol vs. – 7bpm for placebo) was observed, as well as a trend in the combined end-point of death and heart failure hospitalization, but clearly, the number of patients was small. Unfortunately, data on atrial fibrillation from COPERNICUS are not available. In a recent substudy of COMET, 600patients with heart failure and atrial fibrillation were examined, as well as the new onset of atrial fibrillation over the course of the study [17]. Patients were treated with carvedilol or metoprolol, but there was no (placebo-) control for comparison.

Whether beta-blockade reduces the new development of atrial fibrillation in patients with heart failure has also not yet been resolved. In the large heart failure survival trials, this was not a pre-specified endpoint. In the COPERNICUS study, 29 of 1156patients on carvedilol were hospitalized for atrial tachyarrhythmia vs. 52 of 1133patients on placebo [11]. In an earlier report from MERIT-HF, the onset of atrial fibrillation "leading to withdrawal of study drug" was observed in 17patients on placebo, compared to 2patients on metoprolol CR/XL [9], but the present data show that most patients who developed this arrhythmia did not discontinue study drug. Data from the CIBIS-II and US Carvedilol Program are not available regarding this issue. Recently retrospective data from the CAPRICORN study, in patients with left ventricular dysfunction after myocardial infarction have been published [19]. In this study, carvedilol reduced the new development of atrial fibrillation from 5.4% in the placebo group to 2.3%, after a mean of 1.3years follow-up, but the analysis was based on reports of adverse events only, with no systematically analyzed ECG data, which makes it less reliable. Nevertheless, given the fact, that development of atrial fibrillation after myocardial infarction is generally associated with a worse prognosis [25,26], this finding may be relevant. The present study is the first to systematically analyze (i.e. by using also ECGs) the effect of beta-blockade on the development of atrial fibrillation in patients with heart failure.

The annual incidence of atrial fibrillation in patients with heart failure ranges from 2-5%, depending on the severity of the condition [27]. Traditionally, the treatment goal for these patients was often aimed at restoration of sinus rhythm, but this may be difficult to achieve, and even if initially successful, many patients will relapse early [28,29]. Therefore, in patients with atrial fibrillation in the setting of heart failure, treatment for rate control rather than rhythm control should be considered [29]. To support this, a recent subanalysis of the RACE study in patients with atrial fibrillation and mild to moderate heart failure showed that rate control was not inferior to rhythm control in the prevention of a combined end point of morbidity and mortality during 2.3years of follow-up [30]. However, it was also found, that if sinus rhythm could be maintained, the outcome was considerably better [30], which was also observed by Swedberg et al. [17]. A definitive answer regarding this issue will hopefully be given by the currently ongoing AF-CHF trial [31]. Until results from this study become available, present evidence supports the general use of beta-blockers in patients with heart failure, to improve outcome and to prevent new onset atrial fibrillation, as well as for rate control in those with pre-existing atrial fibrillation [23].

6.1. Limitations
We must always be extremely cautious in over-interpreting effects in subgroups, both in those predefined and also in those that are post-hoc [21]. The present subgroup analysis was performed post-hoc and the total survival experience (and the number of years of follow-up) of patients with atrial fibrillation as compared to the total population was limited. Also, since only two ECGs were recorded during 1 year follow-up, even frequent paroxysms may have been unnoticed. In addition, a significant proportion of patients with sinus rhythm at baseline did not have a follow-up ECG, and some of them might also have developed atrial fibrillation. Both factors imply that the number of patients with newly diagnosed atrial fibrillation may in fact have been higher than 85+47=132 patients now reported.

While heart rate was also clearly reduced in atrial fibrillation patients, it remained higher than in those with sinus rhythm, and may also not have been properly blocked during exercise. Additional prospective studies focusing on patients with atrial fibrillation will therefore be of value [31].


   Acknowledgments
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. ECG recording and...
 4. Statistical analysis
 5. Results
 6. Discussion
 Acknowledgments
References
 
With regard to Data Management and Biostatistics, we are indebted to Peter Johansson, from AstraZeneca, Mölndal, Sweden. Dr. Van Veldhuisen is an Established Investigator of the Netherlands Heart Foundation (Grant 97.017).


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. ECG recording and...
 4. Statistical analysis
 5. Results
 6. Discussion
 Acknowledgments
 References
 
1 Members of the MERIT-HF Study Group are given in Ref. [8]. Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. ECG recording and...
 4. Statistical analysis
 5. Results
 6. Discussion
 Acknowledgments
 References
 

  1. Wang T.J., Larson M.G., Levy D., et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham heart study. Circulation (2003) 107:2920–2925.[Abstract/Free Full Text]
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  6. Packer M., Bristow M.R., Cohn J.N., et alfor the US Carvedilol Study Group. Effect of carvedilol on morbidity and mortality in chronic heart failure. N Engl J Med (1996) 334:1349–1355.[Abstract/Free Full Text]
  7. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet (1999) 353:9–13.[CrossRef][Web of Science][Medline]
  8. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet (1999) 353:2001–2007.[CrossRef][Web of Science][Medline]
  9. Hjalmarson Å., Goldstein S., Fagerberg B., et alfor the MERIT-HF Study Group. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure. The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). JAMA (2000) 283:1295–1302.[Abstract/Free Full Text]
  10. Packer M., Coats A.J.S., Fowler M.B., et alfor the Carvedilol Prospective Randomized Cumulative Survival Study Group (COPERNICUS). Effect of Carvedilol on survival in severe chronic heart failure. N Engl J Med (2001) 344:1651–1658.[Abstract/Free Full Text]
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