Ranking Rate Control and Rhythm Control Therapies for Heart Failure Patients With Atrial Fibrillation: A Network Meta-Analysis of Randomized Controlled Trials

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Cardiol Cardiovascmed 2018; 2 (2): 027-038 DOI: 10.26502/fccm.92920033
Cardiology and Cardiovascular Medicine - http://www.cardiolcardiovascmed.com/ - Vol. 2 No. 2 - Apr 2018. [ISSN 2572-9292] 27
Research Article
Ranking Rate Control and Rhythm Control Therapies for Heart
Failure Patients With Atrial Fibrillation: A Network Meta-Analysis
of Randomized Controlled Trials
Cong Zhang, Hongxing Luo, Yu Xu*, Juntao Wang, Yanan Shi, Pengfei Zhang
Department of Cardiology, Zhengzhou University People’s Hospital, Zhengzhou, Henan, China
*Corresponding Author: Yu Xu, Department of Cardiology, Zhengzhou University People’s Hospital,
Zhengzhou, Henan, China, Tel: +86 13653850619; E-mail: 2125089514@qq.com
Received: 08 March 2018; Accepted: 14 March 2018; Published: 18 March 2018
Abstract
Background: Rate control and rhythm control have demonstrated similar benefits for heart failure (HF) patients
with atrial fibrillation (AF), but no study has attempted to rank their benefits. We aim to conduct a network meta-
analysis of the efficacies of rate control and rhythm control therapies for HF patient with AF.
Methods: We searched PubMed, Embase, and Cochrane Library with various combinations of “rate control”,
“rhythm control”, “atrial fibrillation” and “heart failure”. The retrieved records were screened by “Patient-
Intervention-Control-Outcome” principle. The eligible randomized controlled trials were extracted for basic
characteristics, outcomes data, and synthesized with random-effects model.
Results: Eleven trials involving 2,086 patients and 8 rate control and rhythm control therapies were included. The
interventions for all-cause mortality reduction were ranked as follows: catheter ablation (mean rank [MR] 2.3,
surface under the cumulative ranking curves [SUCRA] 81.1%), atrioventricular node ablation and pacemaker (MR
3.1, SUCRA 70.0%), β-blocker (MR 3.9, SUCRA 58.8%), optimal medical treatment (MR 3.9, SUCRA 57.9%),
amiodarone (MR 4.3, SUCRA 52.9%), placebo (MR 4.5, SUCRA 50.3%), digoxin (MR 6.8, SUCRA 16.7%), β-
blocker and/or digoxin (MR 7.1, SUCRA 12.2%).
Conclusion: In HF patients with AF, catheter ablation may be the most effective therapy for rate control and rhythm
control, while digoxin is probably harmful.
Keywords: Atrial Fibrillation; Heart Failure; Rate Control; Rhythm Control; Network Meta-Analysis

Cardiol Cardiovascmed 2018; 2 (2): 027-038 DOI: 10.26502/fccm.92920033
Cardiology and Cardiovascular Medicine - http://www.cardiolcardiovascmed.com/ - Vol. 2 No. 2 - Apr 2018. [ISSN 2572-9292] 28
1. Introduction
Atrial fibrillation (AF) and heart failure (HF) are global cardiovascular epidemics with increasing incidence and
socioeconomic burdens [1]. The prevalence of AF in HF patients is high: 53%, 60% and 65% in HF with preserved,
midrange and reduced ejection fraction, respectively [2]. AF increases the all-cause mortality, rehospitalization, and
cerebrovascular attacks in HF patients of any ejection fraction group [3]. Both diseases share similar
pathophysiological changes (e.g, structural cardiac remodeling and activation of neurohormonal mechanisms) and
risk factors (e.g, aging, hypertension and obesity) [4].
Rate control and rhythm control are two major goals of AF treatment. Heart rate can be controlled by medications
such as β-blocker, calcium channel blockers and digoxin, and non-medication strategies such as atrioventricular
node ablation and pacemaker (AVNP). Heart rhythm can be controlled by antiarrhythmic drugs (class I, class III and
multichannel blockers), catheter ablation (CA) and direct current cardioversion (DCC). A previous trial of AF and
congestive HF has demonstrated no significant differences between rate control (β-blocker, digoxin, and AVNP;
n=694) and rhythm control (amiodarone, sotalol, dofetilide, DCC, and permanent pacemaker; n=682) for all-cause
mortality [5]. The meta-analysis about rate control vs. rhythm control (β-blocker, calcium channel blockers and
digoxin vs. antiarrhythmic agents and DCC) in AF and HF patients has shown no significant differences in mortality
[6]. However, no study has been conducted to rank the efficacy of rate control and rhythm control therapies in
mortality reduction.
This study aims to use network meta-analysis of randomized controlled trials (RCTs) to compare the efficacies of
rate control and rhythm control therapies for patients with AF and HF.
2. Methods
2.1 Database searches
On July 31, 2017, we searched for records in PubMed, Embase, and Cochrane Library using the various
combinations of “rate control”, “rhythm control”, “atrial fibrillation”, and “heart failure” (Supplement 1). We
restricted the publication language for English, but the publication date was not restricted.
2.2 Study selection
After removal of duplicates, article type was firstly screened to include the original articles. Secondly, we screened
the remaining records by PICO (Patient-Intervention-Control-Outcome) principle, using the following criteria: 1)
AF and HF patients; 2) rate control or rhythm control therapies; 3) the outcomes included all-cause mortality.
Thirdly, the reference lists of the eligible articles were checked to find potentially relevant studies. Fourthly, we
eliminated the non- randomized controlled trial and created a network evidence, including all rate control and
rhythm control therapies from the remaining RCTs, then the RCTs with isolated therapies were removed because
they could not connect with the others.

Cardiol Cardiovascmed 2018; 2 (2): 027-038 DOI: 10.26502/fccm.92920033
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2.3 Data extraction
For each record, baseline characteristics and outcome data were extracted (Supplements 2, 3). Some articles showed
the data only available in the figures, and they were extracted by a proven reliable tool WebPlotDigitizer [7].
2.4 Statistical analysis
The dichotomous outcome variables were compared with odd ratios (OR) with 95% credible intervals (CrIs) by
means of network meta-analysis with random-effects model. Effect sizes (ES) were calculated to compare the
differences of the means of continuous variables between two groups. Tau presented the between-trial variance and
was as a measure of the heterogeneity between trials in the network for outcome and comparison. A tau estimates of
0.04 may be interpreted as a low, 0.14 as a moderate and 0.40 as a high degree of heterogeneity between trials. The
direct comparisons with each trial, the comparisons of all available treatments across trials, and the comparison of
one intervention against the others were performed by the network meta-analysis with consistency model. Placebo
was used as the common comparator in the network model. The contribution plot was used to present the influence
of each direct comparison to the estimation of the overall network effects, of which weighted squares and the
respective percentages represented the contribution of each direct comparison. Rank graphs, surface under the
cumulative ranking curves (SUCRA) and mean ranks (MR) were estimated to rank the intervention hierarchy in the
network meta-analysis. The comparison-adjusted funnel plot was used to analyze publication bias and small study
effects.
For this study, the outcome was all-cause mortality. The several metrics for each intervention were calculated to
estimate treatment effects. An intervention with a mean rank of 0 had the most favorable effect. Treatments in
networks were also ranked using probabilities, with high probabilities representing favorable treatments. SUCRA is
an indicator of the efficacy of a treatment. A value of 100 percent represented the most effective treatment, whereas
0 represented the least effective treatment. All statistical analyses were performed in Stata version 14.0.
3. Results
We primarily obtained 2193 records, including 930, 349, and 914 records from PubMed, Cochrane Library, and
Embase databases, respectively. After removal of duplicates, 1175 records were screened based on article type and
PICO strategies, and 16 studies were included. Then we checked the reference lists of the 16 studies and identified 5
relevant studies. Finally, we eliminated 5 non-RCTs and created the evidence network, including all rate and rhythm
control therapies from the remaining 16 RCTs, so 5 RCTs with isolated therapies were removed. Therefore, 11
RCTs investigating 8 different rate control or rhythm control therapies were included in this network meta-analysis
(Figure 1) [8-18]. The 11 RCTs involving 2,084 patients were conducted during 2001-2016, of which 6 in UK, 3 in
US, 1 in France, and 1 in Turkey. The mean age of participants was 66.2 years and the mean follow-up time was 14
months (Supplement 2). The quality of the included studies was assessed by the Cochrane Collaboration’s risk of
bias assessment tool (Supplement 4) [19].

Cardiol Cardiovascmed 2018; 2 (2): 027-038 DOI: 10.26502/fccm.92920033
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Figure 1: PRISMA flowchart of study selection
PICO=Patient-Intervention-Control-Outcome
Eight different interventions were collected from the 11 eligible RCTs: 1) placebo (n=693), 2) amiodarone (n=211),
3) atrioventricular node ablation and pacemaker (AVNP, n=40), 4) β-blocker (n=733), 5) β-blocker and/or digoxin
(BD, n=124), 6) catheter ablation (CA, n=217), 7) digoxin (n=23), 8) optimal medical treatment (OMT, n=43).

Cardiol Cardiovascmed 2018; 2 (2): 027-038 DOI: 10.26502/fccm.92920033
Cardiology and Cardiovascular Medicine - http://www.cardiolcardiovascmed.com/ - Vol. 2 No. 2 - Apr 2018. [ISSN 2572-9292] 31
Eleven RCTs involving 2084 patients assessed all-cause mortality across 8 different interventions in this network
meta-analysis. We drew a network map to show which treatments were directly compared against other treatments
(Figure 2). The between-trial variance was evaluated with a tau estimate of 0 interpreted as a low degree of
heterogeneity, and there was no significant inconsistency in this network meta-analysis (P=0.0847 > 0.05,
Supplement 5). A consistency model could be fitted to perform network meta-analysis in our study. The contribution
plot showed the most informative direct evidence was CA vs amiodarone with an overall contribution of 20.9% to
the network estimates (Supplement 6). The forest plots of direct and indirect comparison were presented in Figure 3.
The rank graphs of all rate control and rhythm control therapies were shown in Figure 4. The comparisons of all-
cause mortality between all rate control and rhythm control therapies were shown in Supplement 7.
Figure 2: Network of eligible comparisons included in the analyses for outcomes
The size of every circle is proportional to the number of assigned patients and indicates the sample size. The lines
link direct compared intervention, the width of which corresponds to the number of studies that assessed the
comparison. RCT=randomized controlled trial. AVNP=atrioventricular node ablation and pacemaker. BD=β-blocker
and/or digoxin. CA=catheter ablation. OMT= optimal medical treatment.

Cardiol Cardiovascmed 2018; 2 (2): 027-038 DOI: 10.26502/fccm.92920033
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Figure 3: Estimates of the treatment effects on all-cause mortality of different rate control and rhythm control
therapies.
AVNP=atrioventricular node ablation and pacemaker. BD=β-blocker and/or digoxin. CA=catheter ablation. OMT=
optimal medical treatment.

Cardiol Cardiovascmed 2018; 2 (2): 027-038 DOI: 10.26502/fccm.92920033
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Figure 4: Cumulative ranking plot of the rate control and rhythm control therapies compared by all-cause mortality
1=placebo, 2=amiodarone, 3=AVNP, 4=β-blocker, 5=BD, 6=CA, 7=digoxin, 8=OMT. AVNP=atrioventricular node
ablation and pacemaker. BD=β-blocker and/or digoxin. CA=catheter ablation. OMT= optimal medical treatment.
The rank of intervention for reducing all-cause mortality was as follows (Table 1): CA (MR 2.3, SUCRA 81.4%);
AVNP (MR 3.1, SUCRA 70.6%); β-blocker (MR 3.8, SUCRA 59.8%); OMT (MR 3.9, SUCRA 58.7%);

Cardiol Cardiovascmed 2018; 2 (2): 027-038 DOI: 10.26502/fccm.92920033
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amiodarone (MR 4.3, SUCRA 53.4%); placebo (MR 4.4, SUCRA 51.4%); digoxin (MR 7.0, SUCRA 13.9%); BD
(MR 7.2, SUCRA 10.8%). Comparison-adjusted funnel plots showed no significant evidence of publication bias or
small-study effects (Supplement 8).
All-cause mortality
Treatment SUCRA (%) MR
placebo 51.4 4.4
amiodarone 53.4 4.3
AVNP 70.6 3.1
β-blocker 59.8 3.8
BD 10.8 7.2
CA 81.4 2.3
digoxin 13.9 7.0
OMT 58.7 3.9
Table 1: Rank chart of efficacy outcomes
SUCRA= the surface under the cumulative ranking line. MR= mean rank. AVNP=atrioventricular node ablation and
pacemaker. BD=β-blocker and/or digoxin. CA=catheter ablation. OMT= optimal medical treatment.
4. Discussion
To the best knowledge, this is the first study ranking the efficacies of rate control and rhythm control therapies in HF
patients with AF. Our principal findings are: 1) CA, AVNP, β-blocker, OMT, and amiodarone were associated with
significantly lower all-cause mortality than placebo; 2) CA may be the most effective therapy for reducing all-cause
mortality; 3) digoxin may not be effective for reducing all-cause mortality.
Rate control and rhythm control are often required for HF patients with AF. Rate control is determined by the
conduction of atrioventricular node and the balance of sympathetic and parasympathetic activities. Rate control
drugs are divided into three groups: β-blocker (blocking sympathetic activities of the atrioventricular node), non-
dihydropyridine calcium channel blocker (blocking calcium channels to increase the refractory period of
atrioventricular node), and cardiac glycoside (increasing parasympathetic activity and slowing atrioventricular node
conduction). They may be used alone or in combination. AVNP can effectively control ventricular rate when
conventional therapies fail or serious drug-related adverse effects occur. Rhythm control aims to restore and
maintain sinus rhythm and includes DCC, class I antiarrhythmic drugs, class III antiarrhythmic drugs, and
multichannel blockers [4]. CA is used for refractory symptomatic AF patients who are irresponsive to at least one
class I or class III antiarrhythmic drugs and who are intolerant to other therapies [4].
Rhythm control therapies are effective when sinus rhythm is restored and maintained for at least 1 year [13].
Recurrence rate at 1 year recorded in the published studies is 17% in the Atrial Fibrillation Follow-up Investigation

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of Rhythm Management study, 43% in the Strategies of Treatment of Atrial Fibrillation study and 44% in the
Pharmacological Intervention in Atrial Fibrillation study, respectively [20-22]. Moreover, HF is usually
accompanied by dilated atria and structural heart diseases which give rise to a high recurrence rate [23]. Low dosage
(≤200 mg/d) is more effective and safer than sotalol or propafenone for maintaining sinus rhythm for 1 year [24].
The adverse effects of amiodarone are related to the dosage and duration of therapy. The dosage of amiodarone to
maintain sinus rhythm should be less than 200 mg/d in the included RCTs [11, 13, 18]. However, amiodarone may
not be safe enough for HF patients with AF in long term [25]. Pulmonary toxicity, hepatic toxicity, thyroid toxicity,
and severe arrhythmia have been reported in the long-term use of amiodarone. The follow-up time of most patients
(181/211) treated with amiodarone was more than 1 year in our study [11, 18]. Beta-blocker has been shown to be
ineffective in reducing the all-cause mortality of HF patients with AF in a recent meta-analysis [26]. The main site
of β-blocker to reduce heart rate in patients AF is atrioventricular node, but sinus node is the main target for heart
failure patients with sinus rhythm. Therefore, β-blocker is less effective in those with sinus rhythm than AF. To
achieve the same degree of rate control, the dosage of β-blocker may be higher in patients with AF than those with
sinus rhythm. However, the higher dosage of β-blocker also weakens the myocardial contractility and reduces
cardiac output. Digoxin significantly increased all-cause mortality in AF patients with HF as shown by a recent
meta-analysis [27]. The therapeutic window of digoxin is narrow. However, only one trial [10] monitored the serum
digoxin concentration (SDC) in our 4 included trials of digoxin. The mean SDC was more than 1.2 ng/ml both in the
baseline and endpoint. The SDC 0.5-0.9 ng/ml is associated with all-cause mortality reduction, but digoxin increases
all-cause mortality when SDC is >1.2 ng/ml in HF patients [28]. A high SDC relates to cardiotoxicity, and leads to
life-threatening tachyarrhythmias or bradyarrhythmias. The unusual activation of platelets and endothelial cells may
also lead to unfavorable effects in the patients taking digoxin [29].
CA and AVNP are interventional therapies with potential interventional complications and direct injuries to heart
structures. The complication rate of CA for AF patients in a large prospective study was 5.2% [30], which is 9.2% in
this study [12, 14, 16-18]. The complication rate of AVNP for the AF patients with HF in our study was 17.5% [12].
AVNP is safe in AF patients but its effects in HF patients with AF remain unknown [31]. The salutary effect of
AVNP on left ventricular systolic function, diastolic function, and cardiac output is significantly related to the strict
control of heart rate without negative inotropic effects [32]. It also enhances diastolic filling time and reverses
tachycardia-induced cardiomyopathy [33]. The previous meta-analysis has suggested that CA improved cardiac
function and quality of life in HF patients with AF as compared with rate control therapy [34]. CA provides the
opportunity to achieve and maintain sinus rhythm with a relatively low risk of complications and side effects. The
continually increasing toxicity risks with amiodarone should be seriously considered for patients requiring long-term
treatments. CA may be an alternative to amiodarone. There are no evidence comparing CA and rate control drugs
for all-cause mortality reduction for HF patients with AF. As a result, mortality data may be insufficient. In the
future, the studies about the mortality of HF patients with AF who receive different rate control and rhythm control
therapies are needed.
Firstly, we have included a relatively small number of studies about rate control and rhythm control in HF patients
with AF. Secondly, although we have referenced numerous documents to optimize our study protocol and search

Cardiol Cardiovascmed 2018; 2 (2): 027-038 DOI: 10.26502/fccm.92920033
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strategies, our meta-analysis may not have covered all studies related to rate control and rhythm control. Thirdly, as
a network meta-analysis, our results have been inevitably influenced by the quality of the included studies.
5. Conclusion
In HF patients with AF, catheter ablation may be the most effective therapy for rate control and rhythm control,
while digoxin is probably harmful. Our study results should be tested by more clinical studies in the future.
Acknowledgement
None.
Conflicts of interest
None.
Supplementary File
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http://www.cardiolcardiovascmed.com/10.26502/fccm.92920033.pdf
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This article is an open access article distributed under the terms and conditions of the
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Citation: Cong Zhang, Hongxing Luo, Yu Xu, Juntao Wang, Yanan Shi, Pengfei Zhang. Ranking Rate
Control and Rhythm Control Therapies for Heart Failure Patients With Atrial Fibrillation: A Network Meta-
Analysis of Randomized Controlled Trials. Cardiology and Cardiovascular Medicine 2 (2018): 027-038.