Download Rate vs rhythm control in patients with atrial fibrillation

European Journal of Internal Medicine 22 (2011) 448–455
Contents lists available at ScienceDirect
European Journal of Internal Medicine
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m
Review article
Rate vs rhythm control in patients with atrial fibrillation and heart failure:
A systematic review and meta-analysis of randomised controlled trials
Daniel Caldeira a, Cláudio David a, b,⁎, Cristina Sampaio a, c
a
b
c
Clinical Pharmacology and Therapeutics Laboratory, Faculty of Medicine, Lisbon, Portugal
Department of Cardiology, Santa Maria University Hospital, Lisbon, Portugal
Institute of Molecular Medicine, Lisbon, Portugal
a r t i c l e
i n f o
Article history:
Received 9 January 2011
Received in revised form 27 April 2011
Accepted 2 May 2011
Available online 30 June 2011
Keywords:
Rate
Rhythm
Atrial fibrillation
Heart failure
Hospitalisation
Mortality
a b s t r a c t
Background: Atrial fibrillation (AF) is a common arrhythmia that can promote or worsen heart failure (HF).
Our purpose was to compare the effects of rate and rhythm control in patients with atrial fibrillation and heart
failure.
Methods: We developed a systematic search in August 2010 through CENTRAL and MEDLINE databases to
identify randomised controlled trials (RCTs) comparing rate control with rhythm control in patients with both
AF and HF.
We analysed mortality, hospitalisations, stroke/thromboembolic events, quality of life, and drugs adverse
events. Relative risks (RR) and 95% confidence intervals (95% CI) were calculated for mortality and
hospitalisations. The remaining outcomes were analysed qualitatively.
Results: Four RCTs with a total of 2486 patients with atrial fibrillation and heart failure were identified.
Mortality and stroke/thromboembolic events were not significantly different in rate and rhythm control arms
[RR 1.03; 95% CI: 0.90–1.17] and [RR 1.09; 95% CI: 0.61–1.96], respectively. Hospitalisations were less frequent
with rate control than with rhythm control [RR 0.92; 95% CI: 0.86–0.98; p = 0.008], in 3 studies involving 2425
patients. Number needed to treat to prevent one hospitalisation was 19 patients.
Conclusions: In patients with AF and HF, rate control compared with rhythm control showed inferior risk of
hospitalisation.
© 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction
Atrial fibrillation (AF) and heart failure (HF) are important cardiac
disorders and the prevalence of both is increasing [1–3]. Atrial
fibrillation can worsen HF or lead to this condition through
tachycardia-mediated cardiomyopathy [4–7], and patients with HF
have increased risk for atrial fibrillation [8]. Forty-one percent of
patients with HF will experience AF during their lifetime and 42% of
patients with AF will have congestive heart failure (CHF) [9]. Whether
AF is a risk factor of death in HF patients is still unclear [9–13] and its
prognostic significance in the presence of left ventricular systolic
dysfunction is controversial [14–16].
The treatment of AF patients follows one of two possible
strategies:
(1) Rate control: control ventricular rate with beta-blockers, nondihydropyridine calcium-channel blocker and/or digitalis.
⁎ Corresponding author at: Laboratório de Farmacologia Clínica e Terapêutica.
Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Lisboa, 1649028, Portugal.
E-mail address: [email protected] (C. David).
(2) Rhythm control: restore and maintain sinus rhythm with
electrical cardioversion and/or antiarrhythmic agents.
It is known that rate and rhythm control strategies have similar
results in patients with atrial fibrillation [17]. AF–CHF (Atrial
Fibrillation and Congestive Heart Failure) randomised controlled
trial assessed the effects of referred strategies in patients with both
atrial fibrillation and heart failure. This study showed similarity in the
efficacy of rate and rhythm control [18]. Nevertheless some other
studies also evaluated rate vs rhythm control approaches in patients
with atrial fibrillation and heart failure.
The aim of this review was to systematically review randomised
controlled trials to compare rate control with rhythm control in
patients with atrial fibrillation and heart failure, regarding relevant
clinical outcomes.
2. Methods
2.1. Searching
A searching strategy was developed in August 2010 using
CENTRAL (Cochrane Library issue April 2010) and MEDLINE databases
0953-6205/$ – see front matter © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.ejim.2011.05.001
D. Caldeira et al. / European Journal of Internal Medicine 22 (2011) 448–455
for identification of relevant studies. There were no language
restrictions. References of original studies were comprehensively
searched. Subgroup and post-hocanalyses of some studies were
also retrieved. The electronic search was taken using the following
keywords: “rate”, “beta-blocker”, “acebutolol”, “atenolol”, “bisoprolol”, “carvedilol”, “esmolol”, “metoprolol”, “nadolol”, “pindolol”,
“propranolol”, “timolol”, “calcium-channel blocker”, “verapamil”,
“diltiazem”, “digitalis”, “digoxin”, “rhythm”, “amiodarone”, “propafenone”, “disopyramide”, “dofetilide”, “flecainide”, “ibutilide”, “sotalol”,
“dronedarone” and “azimilide”, “atrial fibrillation”, “heart failure” and
“ventricular dysfunction”. Boolean operators AND and OR were used
to combine the terms.
2.2. Selection
Inclusion criteria featured randomised controlled trials (RCT)
comparing pharmacological approaches of rate control and rhythm
control (including non-invasive procedures of electrical cardioversion) in patients with atrial fibrillation and heart failure. Heart failure
was defined as the presence of NYHA ≥ class II symptoms or systolic
dysfunction (left ventricular ejection fraction b 50%). Studies in postoperative and post-percutaneous AF were excluded. Trials that
evaluated invasive catheter ablation techniques as first intervention
were not considered for analysis.
449
Studies were required to have intention-to-treat analysis or
provide data that allows this type of calculation. Clinically relevant
studies' outcomes were retrieved and pooled analysis was made when
possible.
2.3. Validity assessment
The quality of data reporting of the retrieved trials was assessed
by PEDro score [19]. This score is based on the presence/absence of
11 items: eligibility criteria, random allocation, allocation concealment, similar baseline characteristics, blinding of all subjects, blinding
of therapists, blinding of outcome assessors, crossover rate b 15%,
intention-to treat analysis, statistical comparisons between groups
and measures of variability.
2.4. Data abstraction
Studies from searching strategy that met the criteria outlined
above were assessed by one review author and checked by another.
Data entry into software was also double checked. All disagreements
were solved by consensus.
2.5. Quantitative data synthesis
The statistical analyses were performed using the RevMan version
5.0.23, provided by Cochrane Collaboration. Dichotomous outcomes
were analysed by Mantel–Haenszel method and relative risk (RR) was
calculated. Uncertainty in results was expressed using 95% confidence
intervals (CI). The results estimates were based on fixed effects model
or random effects model according with heterogeneity. Statistical
heterogeneity was assessed using the I² test. It was assumed if I² N 50%.
Clinical heterogeneity was assessed by authors based on the interventions and studied populations.
Numbers needed to treat (NNT) were calculated in the outcomes
with statistically significant results.
3. Results
Fig. 1. Flowchart of studies selection.
By screening of records obtained Medline and CENTRAL we found
198 citations. One-hundred fifty eight records were not relevant and/
or did not have the required design (RCT). Remaining 40 studies were
selected for full-text assessment and some were excluded for the
following reasons: seventeen did not compare rate vs rhythm control
(Fig. 1), six were post-operative and ten studies did not report data
for a heart failure/systolic dysfunction subgroup; Major trials such as
HOT-CAFÉ (How to Treat Chronic Atrial Fibrillation), STAF (Strategies
of Treatment of Atrial Fibrillation), PIAF (Pharmacological Intervention in Atrial Fibrillation) and J-RHYTHM (Japanese Rhythm Management Trial for Atrial Fibrillation) were not included due to this latter
reason [20–23]. One study was excluded due to the lack of data
necessary to analyse on an intention-to-treat basis. For quantitative
analysis we used data of four RCTs from 6 studies [18,24–26]. AF–CHF
and CAFE-II enrolled exclusively patients with both AF and HF [18,26];
RACE (Rate Control vs Electrical Cardioversion for Persistent Atrial
Fibrillation Study) and AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) studies were general atrial fibrillation
RCTs with post-hoc reports of HF subgroup's data [24,25,27,28].
Analysed populations included a total of 2486 patients with
paroxysmal or persistent atrial fibrillation and heart failure. Table 1
shows the main characteristics of each study.
PEDro scores of the selected trials ranged between 6 and 7 (scale
maximum of 11). All trials had unblinded interventions.
In the quantitative analysis, we used random effects' method due
to the existence of clinical heterogeneity, particularly different sequences or combinations of drugs and differences between the studies
populations.
450
D. Caldeira et al. / European Journal of Internal Medicine 22 (2011) 448–455
Fig. 2. Forest plot comparing rate and rhythm control for total mortality in patients with AF and HF.
Table 2 shows the pooled results of the following outcomes.
3.1. Mortality
Individual studies comparing rate and rhythm control did not
find significant differences in mortality despite a trend favouring
rhythm control in RACE patients with atrial fibrillation and heart
failure [27]. In our meta-analysis the difference also did not achieve
significance with a risk ratio of 1.03 (CI 0.90–1.17) (Fig. 2).
3.2. Hospitalisations
Hospitalisation data were retrieved from 3 trials with 2425
patients. None of the studies individually showed statistically significant differences but AF–CHF showed benefit of rate control in the
first year after enrolment (p = 0.001) and a tendency favouring rate
control (p = 0.06) when the study was analysed in full length. AF–CHF
was the study that provided more information about hospitalisation causes. This non-significant disproportion in hospitalisations
was due to atrial fibrillation (9% rate control vs 14% rhythm control,
p = 0.001) and bradyarrhythmias (3% rate control vs 6% rhythm
control, p = 0.02). Rhythm control patients were more commonly
treated with electrical cardioversion (59% vs 9% of rate control,
p b 0.001) [18].
Pooled analysis of hospitalisations showed a RR of 0.92 (CI 0.86–
0.98, p = 0.008) favouring rate control (Fig. 3). Number needed to
treat (NNT) with rate control (vs. rhythm control) to prevent one
hospitalisation was 19.
rhythm control. Fourteen of the nineteen patients who experienced
thromboembolic events had inadequate anticoagulant therapy with
INR (international normalised ratio) below the desired level [24].
AF–CHF only provided hazard ratio for stroke (0.74; 95% CI 0.40–
135). For quantitative analysis we have assumed the proportional
hazards ratio model and used this risk estimate as risk ratio. According
with AF–CHF abstract stroke incidence was 4% for rate control and 3%
for rhythm control groups. Inputted events used to approximate risk
ratio to hazards ratio also correspond, respectively, to 4%
(25/694 = 3.6%) and 3% (18/682 = 2.6%) of stroke incidence in rate
and rhythm control arms [18].
Meta-analysis did not show statistically significant result with RR
of 1.09 and 95% confidence interval between 0.61 and 1.96 (Fig. 4).
3.4. Quality of life
Only two RCTs, RACE and CAFÉ-II, reported the quality of life effects
of rate and rhythm control, but obtained results were heterogeneous
[26,27].
Scales used to assess this outcome were different amongst trials
producing different conclusions. In RACE study Short-form 36 instrument showed that rate control improved physical role limitations,
social functioning and mental health subscales, whereas rhythm
control only improved this last subscale [27]. In CAFÉ-II, rhythm
control was superior to rate control in the global score of Short-form
36 version II as well as mental and physical functioning subgroup,
but in the same study when Minnesota Living With Heart Failure
(MLWHF) questionnaire was applied no difference was found between interventions [26].
3.3. Stroke/Thromboembolic complications
3.5. Used drugs and adverse events
Only two trials provided data on this outcome with both studies
showing similarities in rate and rhythm control interventions
regarding thromboembolic events.
In RACE study thromboembolic events were seen in 8 of the 130
patients assigned to rate control and in 11 of 131 patients treated
with rhythm control strategy. No statistical significance was found
(p = 0.49). In rate control group 85% of patients were on continuous
anticoagulation during all trial compared with 66% of patients under
AF–CHF and AFFIRM had data about used drugs and RACE reported
data on adverse events.
In AF–CHF beta-blockers were preferentially used for rate control (88% of the patients). Digoxin was used in 75% of patients and
calcium-channel blockers in 3%. Preferred drug for rhythm control
was amiodarone which was used by 82% of the patients. About 80% of
patients assigned to rhythm control also used beta-blockers. Sotalol
Fig. 3. Forest plot comparing rate and rhythm control for hospitalisations in patients with AF and HF.
D. Caldeira et al. / European Journal of Internal Medicine 22 (2011) 448–455
451
Fig. 4. Forest plot comparing rate and rhythm control for stroke/thromboembolic events in patients with AF and HF.
and dofetilide were used in 2% and less than 1% of rhythm control
group, respectively. More than 90% of patients in both groups used
angiotensin-converting enzyme inhibitors or angiotensin-receptor
blockers.
In AFFIRM, rhythm control patients were mainly treated with
amiodarone or sotalol. Dofetilide was used in 0.6% of these patients [25].
Data of antiarrhythmics used in patients with both atrial fibrillation and
heart failure was not available. In this trial beta-blockers were the
preferred drugs for rate control in patients with AF and HF [28].
In RACE analysis of patients with AF and HF, drug adverse events
were less frequent in rate control than rhythm control. Digoxin
intoxication induced ventricular tachycardia in one patient on rate
control treatment, whilst amiodarone and flecainide induced other
brady- and tachyarrhythmias in 8 patients on rhythm control strategy
[27].
4. Discussion
This review evaluated important outcomes in patients with atrial
fibrillation and heart failure. AF–CHF was the larger analysed trial
designed to detect differences in cardiovascular mortality between
interventions. The inclusion of CAFÉ-II trial and subgroup analysis of
RACE and AFFIRM studies contributed with additional information to
the review and increased meta-analysis power resulting in significant
differences in hospitalisation outcome.
Here we discuss the analysed outcomes according with existing
evidence:
4.1. Mortality
Mortality was similar in rate and rhythm control in the four
individual RCTs and in the meta-analysis. This was concordant to what
was already known for AF not restricted to HF patients [18,24–29].
Our study strengthens actual evidence showing that the choice of one
specific pharmacological strategy (rate or rhythm control) for patients
with AF and HF does not affect survival.
Rate control beta-blockers are keystones of heart failure therapy
because they showed to reduced mortality in placebo-controlled
trials, but CIBIS-II post-hoc analysis in HF patients with AF suggested
that carvedilol was not useful [30–32].
Table 1
Trials' main characteristics.
Trials
RACE [20,23]
AFFIRM [21,24]
AF–CHF [18]
CAFE-II [22]
AF population
Recurrent persistent AF or flutter
for less than 1 year
Paroxysmal or persistent AF less
than 1 year
Persistent AF
Heart failure
NYHA II–III
Likely to be recurrent AF in pts older
than 65 years old with risk factors for
stroke or death
LVEF less than 50%
NYHA II–III
No. pts
Age
Male
Anticoagulation
261
69 (mean)
65%
Acenocoumarol or fenprocoumon
4 weeks before and after electrical
cardioversion. Rate arm
anticoagulated if more than
65 year-old or cardiac disease.
Digitalis, non-dihydropyridine
calcium-channel blocker and
beta-blocker
Electrical cardioversion and sotalol,
flecainide, propafenone or
amiodarone
2.3 ± 0.6
Composite of cardiovascular death,
heart failure, embolism, bleeding,
pacemaker implantation, severe
adverse effects of drugs
In patients with mild to moderate
CHF, rate control is not inferior to
rhythm control. However, if sinus
rhythm can be maintained, outcome
may be improved.
7
LVEF equal or less than 35% and
NYHA II–IV
1376
67 (mean)
82%
Recommended for all pts: ACC/
AHA/ESC 2006 AF guidelines
Rate intervention
Rhythm intervention
Years follow-up
Primary outcome
Conclusions in HF subset
PEDro score
788
71% N65 years
75%
Both arms anticoagulated, if after
4–12 weeks with antiarrhythmic
agents sinus rhythm is restored,
anticoagulation could be stopped
Beta-blocker, non-dihydropiridine
calcium-channel blocker and digoxin.
Many antiarrhythmic agents and/or
electrical cardioversion
3.5 (mean)
All-cause mortality
There was no significant improvement
in mortality, hospitalisation, and NYHA
class with the strategy of rhythm
control in mild, moderate or severe
ejection left ventricular dysfunction.
6
Beta-blocker and digoxin. AV
nodal ablation and pacemaker
(if refractory)
Electrical cardioversion and
amiodarone (or sotalol or
dofetilide)
3.1 ± 1.6
Cardiovascular death
Primary outcome was not
different in both interventions.
Hospitalizations were more
frequent in rhythm control.
6
61
72 ± 7
84%
Recommendeda for all pts:
warfarin (INR 2–3)
Digoxin and beta-blocker
Amiodarone and electrical
cardioversion
1.2 (median)
QoL SF-36vII at 1 year
Rhythm control improved the
primary outcome, LV function
and NT-proBNP. NYHA and
6MWT were similar in both
interventions.
7
6MWT = 6-minutes walk test; ACC = American College of Cardiology; AF = atrial fibrillation; AFFIRM = Atrial Fibrillation Follow-up Investigation of Rhythm Management;
AF–CHF = Atrial Fibrillation and Congestive Heart Failure; AHA = American Heart Association; AV = atrioventricular; CAFÉ-II = Controlled study of rate vs rhythm control in
patients with chronic atrial fibrillation and heart failure; CHF = congestive heart failure; ESC = European Society of Cardiology; LV = left ventricular; LVEF = Left Ventricular
Ejection Fraction; NYHA = New York Heart Association Class; QoL SF-36vII = Quality of Life Short Form-36 version II; RACE = Rate Control vs Electrical Cardioversion for Persistent
Atrial Fibrillation Study.
452
D. Caldeira et al. / European Journal of Internal Medicine 22 (2011) 448–455
Table 2
Summary of results.
Outcome
Trials
Patients
Rate/Rhythm patients
RR
[95%CI]
p value for RR
NNT
Mortality
4
2486
1235/1251
0.69
-
Hospitalisations
3
2425
1204/1221
0.008
19
Stroke/Thromboembolic events
2
1637
824/813
1.03
[0.90–1.17]
0.92
[0.86–0.98]
1.09
[0.61–1.96]
0.77
-
Digitalis did not show to reduce mortality in HF patients [33]. A
cohort of patients with AF and HF treated with digoxin alone had
death rates similar to patients without rate control treatment and had
higher mortality compared with patients treated with beta-blockers
alone or beta-blockers in association with digoxin [34].
Amiodarone, a commonly used antiarrhythmic drug, showed
heterogeneous mortality results in patients with HF [35–38], whilst
class I antiarrhythmic agents can increase death rate [13]. Dronedarone, an antiarrhythmic agent with similarities to amiodarone but
without iodine-related adverse reactions showed to be harmful in
patients with severe HF [39]. In patients with atrial fibrillation,
dronedarone reduced cardiovascular mortality [40,41] and appeared
to be safe in patients with AF and stable HF [40,42,43].
4.2. Hospitalisations
Individually none of the trials showed clear benefit regarding
hospitalisations, but the larger trials showed tendency towards lower
incidence with rate control. Our meta-analysis showed statisticallysignificant superiority of rate control in this outcome.
Digitalis and beta-blockers have proved to reduce hospitalisation
risk in heart failure [30,32,33], but no data are available for patients
with both atrial fibrillation and heart failure. Antiarrhythmic agent
dofetilide reduced the incidence of this outcome in patients with AF
and left ventricular dysfunction [44,45]. All trials considered betablockers for heart rate control, but despite the possible benefit, data of
AFFIRM and AF–CHF studies reported that dofetilide was only used in
less than 1% of rhythm control patients.
Hospitalisations were mainly due to bradiarrhythmias or hemodynamic deterioration [18]. AF–CHF trial showed that rhythm control group had a higher incidence of both. The need for repeated
cardioversion as inpatients after baseline strategy implementation
may have contributed to higher frequency of hospitalisations with
rhythm control. Initiation of antiarrhythmic drugs as inpatient or
possible negative inotropic effects of these agents could have also
contributed to hospitalisations in this latter strategy.
In patients with chronic HF taking angiotensin-converting enzyme
inhibitors and diuretics, digoxin improved mortality and hospitalisation as a composite outcome [46]. Dronedarone reduced mortality and
hospitalisation composite outcome in patients with AF, including in
the heart failure subgroup [40]. This opens new perspectives for
rhythm control strategy in selected patients with AF and HF.
Although hospitalisations were reported to be an independent
predictor of death, our quantitative analysis found that rate control
may decrease hospitalisations without reducing mortality. Since
hospitalisations are a major contributor to the cost of AF and HF our
study suggests that the choice of rate control strategy may decrease
the economic burden of patients with AF and HF [47–51].
4.3. Stroke/Thromboembolic complications
Rate and rhythm control were not different regarding stroke/
thromboembolic outcome. In RACE trial, these events were mostly
associated with inadequate anticoagulation. Low INR is a powerful
predictor of stroke in patients with AF [52]. Heart failure alone leads to
a small increase in stroke risk, but patients with AF and HF need
anticoagulation because thromboembolic events are much more
frequent [53,54].
Obtained data should be interpreted carefully because thromboembolic rates in these studies may underestimate real world risk due
to the current underuse and inadequate control of anticoagulants
[55,56].
4.4. Quality of life
Patients with atrial fibrillation or heart failure have worse quality
of life (QoL) than healthy controls [57,58]. Life quality is related to
exercise performance in patients with AF and is a predictor of
rehospitalisation and mortality in patients with HF [59–62].
QoL data of analysed interventions in patients with AF and HF are
still very sparse and heterogeneous, and other studies that evaluated
this question in general AF population did not find differences between rate and rhythm control [21,57,63–65].
Better life quality is more likely to be achieved if patients with AF
under rate control treatment have maximal heart rate and average
resting heart rate below 110 and 80 bpm, respectively [66]. Calciumchannel blockers use is associated with better QoL compared to betablocker in patients with AF taking digitalis [67].
Patients with AF that remain on sinus rhythm have better quality
of life and rhythm control drugs have shown to improve this QoL
outcome from baseline status [59,68].
Heart failure data have demonstrated that beta-blockers were
associated with life quality improvements [69].
4.5. Drugs adverse events
Drug adverse events were reported in RACE and were uncommon,
occurring more frequently in rhythm control and were related with
other arrhythmias.
In patients with HF, beta-blockers are effective and safe, especially
if drug uptitration is done with caution [70].
Non-dihydropyridinic calcium-channel blockers have few safety
data but due to negative inotropic effects, these drugs are not recommended for patients with HF, particularly those with left ventricular
dysfunction.
Digoxin alone has raised some safety problems. Against placebo it has
prevented hospitalisations, but compared with other drugs/combinations
it was associated with higher mortality and worse control of ventricular
rate [34,71].
Safety of rhythm control drugs in patients with heart failure has
always been a concern [38]. Amiodarone appears to be the drug more
effective in converting to and maintaining sinus rhythm but its use is
associated to important adverse effects [35]. Actual evidence suggests
that dofetilide may be the antiarrhythmic drugs with the best safety
profile in HF patients [45]. Dronedarone may have a role in patients
with mild or moderate heart failure and atrial fibrillation [40].
D. Caldeira et al. / European Journal of Internal Medicine 22 (2011) 448–455
4.6. Other interventions
Data of AF–CHF showed that most of patients were treated with a
renin–angiotensin–aldosterone system (RAAS) blocker. Its use was
balanced in both rate and rhythm arms, but it may influence some
outcomes as discussed ahead.
RAAS is hyperactivated in heart failure. Angiotensin II levels are
elevated and can contribute to atrial fibrillation through cardiac
remodelling, fibrosis and direct pro-arrhythmic effects [72,73].
Blockade of RAAS in heart failure has proven to be useful to improve
symptoms and survival. In atrial fibrillation, despite positive results of
small trials with angiotensin-converting enzyme inhibitors or
angiotensin receptor blockers (ARBs), the studies CAPRAF and GISSIAF showed that ARBs were not effective in the prevention of AF in
patients in sinus rhythm with recent history of AF [74–76]. ACTIVE-I
study enrolled more than 9000 patients with AF, and preliminary
reports showed that irbesartan did not reduce the primary outcome of
major cardiovascular events, but HF hospitalisations were significantly lower compared with placebo [77]. Definite results and further
analysis of this trial will bring more strong and possibly more precise
evidence on this topic.
Our purpose was to analyse non-invasive procedures such as drug
therapy and electrical cardioversion but the importance of electrophysiological invasive techniques has been increasing. Electrophysiological procedures have been used in an increasing number of
patients, particularly in those with drugs-refractory AF. In the subset
of patients with AF and HF, atrioventricular node ablation with
biventricular pacemaker was exceeded by pulmonary-vein isolation
procedure that leads to better left ventricular ejection fraction,
functional capacity and quality of life [78]. However long-term
follow-up studies are still missing and the efficacy of this intervention
in clinical outcomes, such as mortality and hospitalisations, in patients
with persistent atrial fibrillation and heart failure is unclear. Future
CASTLE-AF results could help to clarify the role of pulmonary-vein
isolation in these patients [79].
453
AFFIRM substudy analysed only left ventricular dysfunction
patients. RACE trial only supplied cardiovascular mortality and heart
failure hospitalisations.
Even using random effects method, pooling such data results limits
the strength of conclusions.
Including results from post-hoc analysis of randomised controlled
trials AFFIRM and RACE cannot exclude selection bias.
In the outcomes other than mortality and hospitalisations we
could not be more conclusive because information was very sparse
and heterogeneous.
5. Conclusion
Comparing with rhythm control in patients with HF and AF, rate
control significantly reduces hospitalisations. Mortality was similar
with both interventions. There was no clear quality of life benefit of
any of these interventions.
Funding
None.
Competing interests
None to declare.
Learning points
• Atrial fibrillation and heart failure are diseases with increasing
prevalence.
• Rate and rhythm control strategies provide similar survival in
patients with AF and HF.
• Hospitalisations are important contributors to financial burden of AF
and HF.
• Rate control strategy significantly reduced hospitalisations in
patients with AF and HF.
4.7. Implications to practise
Patients with AF and HF should be primarily treated with rate
control drugs in order to reduce hospitalisations. NNT data shows that
to prevent one hospitalisation, a mean of 19 patients would have to be
treated with rate control strategy instead of rhythm control.
Recent cohort data suggests caution in the use of digoxin not
associated with a beta-blocker in rate control [34].
Conflict of interest statement
Daniel Caldeira has no relationships with other people or organisations that could inappropriately influence the work.
Cláudio David has no relationships with other people or organisations that could inappropriately influence the work.
Cristina Sampaio has no relationships with other people or organisations that could inappropriately influence the work.
4.8. Implications to research
References
Further RCT are needed to provide more precise estimates in
outcomes like stroke and to define whether one of these strategies is
more likely to improve life quality. Antiarrhythmic agents such as
dofetilide in a greater number of patients and/or dronedarone should
be tested against rate control agents.
4.9. Limitations
The trials included in this review had unblinded methods for
patients and medical staff involved in the treatment strategies.
This could be explained by the physical nature of electrical cardioversion that is very distinct of rate control procedures. Use of fake
electrical cardioversion for patient blinding would raise ethical issues
and would interfere with hospitalisations and with quality of life
outcomes. Nevertheless, adjudicators of events were not aware of
allocated treatment on outcomes assessment in AF–CHF, AFFIRM and
RACE studies.
[1] Curtis LH, Whellan DJ, Hammill BG, Hernandez AF, Anstrom KJ, Shea AM, et al.
Incidence and prevalence of heart failure in elderly persons, 1994–2003. Arch
Intern Med 2008;168:418–24.
[2] Roger VL, Weston SA, Redfield MM, Hellermann-Homan JP, Killian J, Yawn BP, et al.
Trends in heart failure incidence and survival in a community-based population.
JAMA 2004;292:344–50.
[3] Naccarelli GV, Varker H, Lin J, Schulman KL. Increasing prevalence of atrial
fibrillation and flutter in the United States. Am J Cardiol 2009;104:1534–9.
[4] Packer DL, Bardy GH, Worley SJ, Smith MS, Cobb FR, Coleman RE, et al. Tachycardiainduced cardiomyopathy: a reversible form of left ventricular dysfunction. Am J
Cardiol 1986;57:563–70.
[5] Opasich C, Febo O, Riccardi PG, Traversi E, Forni G, Pinna G, et al. Concomitant
factors of decompensation in chronic heart failure. Am J Cardiol 1996;78:354–7.
[6] De Ferrari GM, Klersy C, Ferrero P, Fantoni C, Salerno-Uriarte D, Manca L, et al.
Atrial fibrillation in heart failure patients: prevalence in daily practice and effect
on the severity of symptoms. Data from the ALPHA study registry. Eur J Heart Fail
2007;9:502–9.
[7] Maisel WH, Stevenson LW. Atrial fibrillation in heart failure: epidemiology,
pathophysiology, and rationale for therapy. Am J Cardiol 2003;91:2D–8D.
[8] Kannel WB, Wolf PA, Benjamin EJ, Levy D. Prevalence, incidence, prognosis, and
predisposing conditions for atrial fibrillation: population-based estimates. Am J
Cardiol 1998;82:2N–9N.
454
D. Caldeira et al. / European Journal of Internal Medicine 22 (2011) 448–455
[9] Wang TJ, Larson MG, Levy D, Vasan RS, Leip EP, Wolf PA, et al. Temporal relations of
atrial fibrillation and congestive heart failure and their joint influence on
mortality: the Framingham Heart Study. Circulation 2003;107:2920–5.
[10] Wyse DG, Love JC, Yao Q, Carlson MD, Cassidy P, Greene LH, et al. Atrial fibrillation:
a risk factor for increased mortality—an AVID registry analysis. J Interv Card
Electrophysiol 2001;5:267–73.
[11] Middlekauff HR, Stevenson WG, Stevenson LW. Prognostic significance of atrial
fibrillation in advanced heart failure. A study of 390 patients. Circulation 1991;84:40–8.
[12] Carson PE, Johnson GR, Dunkman WB, Fletcher RD, Farrell L, Cohn JN. The influence of
atrial fibrillation on prognosis in mild to moderate heart failure. The V-HeFT Studies.
The V-HeFT VA Cooperative Studies Group. Circulation 1993;87 VI102-10.
[13] Stevenson WG, Stevenson LW, Middlekauff HR, Fonarow GC, Hamilton MA, Woo
MA, et al. Improving survival for patients with atrial fibrillation and advanced
heart failure. J Am Coll Cardiol 1996;28:1458–63.
[14] Pai RG, Varadarajan P. Prognostic significance of atrial fibrillation is a function of
left ventricular ejection fraction. Clin Cardiol 2007;30:349–54.
[15] Vasan RS, Larson MG, Benjamin EJ, Evans JC, Reiss CK, Levy D. Congestive heart
failure in subjects with normal versus reduced left ventricular ejection fraction:
prevalence and mortality in a population-based cohort. J Am Coll Cardiol 1999;33:
1948–55.
[16] Parkash R, Maisel WH, Toca FM, Stevenson WG. Atrial fibrillation in heart failure: high
mortality risk even if ventricular function is preserved. Am Heart J 2005;150:701–6.
[17] de Denus S, Sanoski CA, Carlsson J, Opolski G, Spinler SA. Rate vs rhythm control in
patients with atrial fibrillation: a meta-analysis. Arch Intern Med 2005;165:258–62.
[18] Roy D, Talajic M, Nattel S, Wyse DG, Dorian P, Lee KL, et al. Rhythm control versus
rate control for atrial fibrillation and heart failure. N Engl J Med 2008;358:
2667–77.
[19] Maher CG, Sherrington C, Herbert RD, Moseley AM, Elkins M. Reliability of the PEDro
scale for rating quality of randomized controlled trials. Phys Ther 2003;83:713–21.
[20] Opolski G, Torbicki A, Kosior DA, Szulc M, Wozakowska-Kaplon B, Kolodziej P,
et al. Rate control vs rhythm control in patients with nonvalvular persistent atrial
fibrillation: the results of the Polish How to Treat Chronic Atrial Fibrillation (HOT
CAFE) Study. Chest 2004;126:476–86.
[21] Carlsson J, Miketic S, Windeler J, Cuneo A, Haun S, Micus S, et al. Randomized trial of
rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of
Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol 2003;41:1690–6.
[22] Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial fibrillation—
Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial.
Lancet 2000;356:1789–94.
[23] Ogawa S, Yamashita T, Yamazaki T, Aizawa Y, Atarashi H, Inoue H, et al. Optimal
treatment strategy for patients with paroxysmal atrial fibrillation: J-RHYTHM
Study. Circ J 2009;73:242–8.
[24] Van Gelder IC, Hagens VE, Bosker HA, Kingma JH, Kamp O, Kingma T, et al. A
comparison of rate control and rhythm control in patients with recurrent
persistent atrial fibrillation. N Engl J Med 2002;347:1834–40.
[25] Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, et al. A
comparison of rate control and rhythm control in patients with atrial fibrillation. N
Engl J Med 2002;347:1825–33.
[26] Shelton RJ, Clark AL, Goode K, Rigby AS, Houghton T, Kaye GC, et al. A randomised,
controlled study of rate versus rhythm control in patients with chronic atrial
fibrillation and heart failure: (CAFE-II Study). Heart 2009;95:924–30.
[27] Hagens VE, Crijns HJ, Van Veldhuisen DJ, Van Den Berg MP, Rienstra M, Ranchor AV,
et al. RAte Control versus Electrical cardioversion for persistent atrial fibrillation
study group. Rate control versus rhythm control for patients with persistent atrial
fibrillation with mild to moderate heart failure: results from the RAte Control versus
Electrical cardioversion (RACE) study. Am Heart J 2005;149:1106–11.
[28] Freudenberger RS, Wilson AC. AFFIRM investigators and committees. Comparison
of rate versus rhythm control for atrial fibrillation in patients with left ventricular
dysfunction (from the AFFIRM Study). Am J Cardiol 2007;100:247–52.
[29] Kong MH, Shaw LK, O'Connor C, Califf RM, Blazing MA, Al-Khatib SM. Is rhythmcontrol superior to rate-control in patients with atrial fibrillation and diastolic
heart failure? Ann Noninvasive Electrocardiol 2010;15:209–17.
[30] The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet
1999;353:9–13.
[31] Lechat P, Hulot JS, Escolano S, Mallet A, Leizorovicz A, Werhlen-Grandjean M, et al.
Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic
heart failure in CIBIS II Trial. Circulation 2001;103:1428–33.
[32] Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised
Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001–7.
[33] The effect of digoxin on mortality and morbidity in patients with heart failure. The
Digitalis Investigation Group. N Engl J Med 1997;336:525–33.
[34] Fauchier L, Grimard C, Pierre B, Nonin E, Gorin L, Rauzy B, et al. Comparison of beta
blocker and digoxin alone and in combination for management of patients with
atrial fibrillation and heart failure. Am J Cardiol 2009;103:248–54.
[35] Torp-Pedersen C, Metra M, Spark P, Lukas MA, Moullet C, Scherhag A, et al. The
safety of amiodarone in patients with heart failure. J Card Fail 2007;13:340–5.
[36] Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, et al. Amiodarone or an
implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med
2005;352:225–37.
[37] Doval HC, Nul DR, Grancelli HO, Perrone SV, Bortman GR, Curiel R. Randomised
trial of low-dose amiodarone in severe congestive heart failure. Grupo de Estudio
de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA). Lancet
1994;344:493–8.
[38] Flaker GC, Blackshear JL, McBride R, Kronmal RA, Halperin JL, Hart RG. Antiarrhythmic
drug therapy and cardiac mortality in atrial fibrillation. The stroke prevention in atrial
fibrillation investigators. J Am Coll Cardiol 1992;20:527–32.
[39] Køber L, Torp-Pedersen C, McMurray JJ, Gøtzsche O, Lévy S, Crijns H, et al.
Increased mortality after dronedarone therapy for severe heart failure. N Engl J
Med 2008;358:2678–87.
[40] Hohnloser SH, Crijns HJ, van Eickels M, Gaudin C, Page RL, Torp-Pedersen C, et al.
Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med
2009;360:668–78.
[41] Hohnloser SH, Crijns HJ, van Eickels M, Gaudin C, Page RL, Torp-Pedersen C, et al.
Dronedarone in patients with congestive heart failure: insights from ATHENA. Eur
Heart J 2010;31:1717–21.
[42] Le Heuzey JY, De Ferrari GM, Radzik D, Santini M, Zhu J, Davy JM. A short-term,
randomized, double-blind, parallel-group study to evaluate the efficacy and
safety of dronedarone versus amiodarone in patients with persistent atrial
fibrillation: the DIONYSOS study. J Cardiovasc Electrophysiol 2010;21:
597–605.
[43] Singh BN, Connolly SJ, Crijns HJ, Roy D, Kowey PR, Capucci A, et al. Dronedarone for
maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med
2007;357:987–99.
[44] Torp-Pedersen C, Møller M, Bloch-Thomsen PE, Køber L, Sandøe E, Egstrup K, et al.
Dofetilide in patients with congestive heart failure and left ventricular dysfunction.
Danish investigations of arrhythmia and mortality on Dofetilide Study Group. N Engl J
Med 1999;341:857–65.
[45] Pedersen OD, Bagger H, Keller N, Marchant B, Køber L, Torp-Pedersen C. Efficacy of
dofetilide in the treatment of atrial fibrillation–flutter in patients with reduced left
ventricular function: a Danish investigations of arrhythmia and mortality on
dofetilide (diamond) substudy. Circulation 2001;104:292–6.
[46] Digitalis Investigation GroupAhmed A, Waagstein F, Pitt B, White M, Zannad F,
et al. Effectiveness of digoxin in reducing one-year mortality in chronic heart
failure in the Digitalis Investigation Group trial. Am J Cardiol 2009;103:82–7.
[47] Kim MH, Lin J, Hussein M, Kreilick C, Battleman D. Cost of atrial fibrillation in
United States managed care organizations. Cost of atrial fibrillation in United
States managed care organizations. Adv Ther 2009;26:847–57.
[48] Sanoski CA. Clinical, economic, and quality of life impact of atrial fibrillation.
J Manag Care Pharm 2009;15:S4–9.
[49] Liu L. Changes in cardiovascular hospitalization and comorbidity of heart failure in
the United States: findings from the national hospital discharge surveys 1980–
2006. Int J Cardiol 2010.
[50] Setoguchi S, Stevenson LW, Schneeweiss S. Repeated hospitalizations predict
mortality in the community population with heart failure. Am Heart J
2007;154:260–6.
[51] Otero-Raviña F, Grigorian-Shamagian L, Fransi-Galiana L, Názara-Otero C,
Fernández-Villaverde JM, del Alamo-Alonso A, et al. Morbidity and mortality
among heart failure patients in Galicia, N.W. Spain: the GALICAP Study. Int J
Cardiol 2009;136:56–63.
[52] Hylek EM, Go AS, Chang Y, Jensvold NG, Henault LE, Selby JV, et al. Effect of
intensity of oral anticoagulation on stroke severity and mortality in atrial
fibrillation. N Engl J Med 2003;349:1019–26.
[53] Dunkman WB, Johnson GR, Carson PE, Bhat G, Farrell L, Cohn JN. Incidence of
thromboembolic events in congestive heart failure. The V-HeFT VA Cooperative
Studies Group. Circulation 1993;87:VI94–VI101.
[54] Rietbrock S, Heeley E, Plumb J, van Staa T. Chronic atrial fibrillation: incidence,
prevalence, and prediction of stroke using the Congestive heart failure, Hypertension,
Age N 75, Diabetes mellitus, and prior Stroke or transient ischemic attack (CHADS2)
risk stratification scheme. Am Heart J 2008;156:57–64.
[55] Ogilvie IM, Newton N, Welner SA, Cowell W, Lip GY. Underuse of oral anticoagulants
in atrial fibrillation: a systematic review. Am J Med 2010;123:638–45.
[56] Sarawate C, Sikirica MV, Willey VJ, Bullano MF, Hauch O. Monitoring anticoagulation in atrial fibrillation. J Thromb Thrombolysis 2006;21:191–8.
[57] Hagens VE, Ranchor AV, Van Sonderen E, Bosker HA, Kamp O, Tijssen JG, et al.
Effect of rate or rhythm control on quality of life in persistent atrial fibrillation.
Results from the Rate Control Versus Electrical Cardioversion (RACE) Study. J Am
Coll Cardiol 2004;43:241–7.
[58] Ekman I, Fagerberg B, Lundman B. Health-related quality of life and sense of
coherence among elderly patients with severe chronic heart failure in comparison
with healthy controls. Heart Lung 2002;31:94–101.
[59] Singh SN, Tang XC, Singh BN, Dorian P, Reda DJ, Harris CL, et al. Quality of life and
exercise performance in patients in sinus rhythm versus persistent atrial
fibrillation: a Veterans Affairs Cooperative Studies Program Substudy. J Am Coll
Cardiol 2006;48:721–30.
[60] Zuluaga MC, Guallar-Castillón P, López-García E, Banegas JR, Conde-Herrera M,
Olcoz-Chiva M, et al. Generic and disease-specific quality of life as a predictor of
long-term mortality in heart failure. Eur J Heart Fail 2010;12:1372–8.
[61] Rodríguez-Artalejo F, Guallar-Castillón P, Pascual CR, Otero CM, Montes AO,
García NA, et al. Health-related quality of life as a predictor of hospital
readmission and death among patients with heart failure. Arch Intern Med
2005;165:1274–9.
[62] Konstam V, Salem D, Pouleur H, Kostis J, Gorkin L, Shumaker S, et al. Baseline quality
of life as a predictor of mortality and hospitalization in 5,025 patients with congestive
heart failure. SOLVD Investigations. Studies of Left Ventricular Dysfunction Investigators. Am J Cardiol 1996;78:890–5.
[63] Jenkins LS, Brodsky M, Schron E, Chung M, Rocco Jr T, Lader E, et al. Quality of life in
atrial fibrillation: the Atrial Fibrillation Follow-up Investigation of Rhythm
Management (AFFIRM) study. Am Heart J 2005;149:112–20.
[64] Grönefeld GC, Lilienthal J, Kuck KH. Pharmacological Intervention in Atrial Fibrillation
(PIAF) Study investigators. Impact of rate versus rhythm control on quality of life in
patients with persistent atrial fibrillation. Results from a prospective randomized
study. Eur Heart J 2003;24:1430–6.
D. Caldeira et al. / European Journal of Internal Medicine 22 (2011) 448–455
[65] Tse HF, Lam YM, Lau CP, Cheung BM, Kumana CR, Tse HF, et al. Comparison of
digoxin versus low-dose amiodarone for ventricular rate control in patients with
chronic atrial fibrillation. Clin Exp Pharmacol Physiol 2001;28:446–50.
[66] Jaber J, Cirenza C, Jaber J, Amaral A, Almeida de Sousa JM, Oliveira Filho JA, et al.
Influence of heart rate on quality of life in patients with chronic atrial fibrillation.
Clin Cardiol 2010;33:E28–32.
[67] Tsuneda T, Yamashita T, Fukunami M, Kumagai K, Niwano S, Okumura K, et al. Rate
control and quality of life in patients with permanent atrial fibrillation: the Quality
of Life and Atrial Fibrillation (QOLAF) Study. Circ J 2006;70:965–70.
[68] Dorian P, Paquette M, Newman D, Green M, Connolly SJ, Talajic M, et al. Quality of
life improves with treatment in the Canadian Trial of Atrial Fibrillation. Am Heart J
2002;143:984–90.
[69] Sidorov J, Shull RD, Girolami S, Mensch D. Use of the short form 36 in a primary
care based disease management program for patients with congestive heart
failure. Dis Manag 2003;6:111–7.
[70] Krum H, Roecker EB, Mohacsi P, Rouleau JL, Tendera M, Coats AJ, et al. Effects of
initiating carvedilol in patients with severe chronic heart failure: results from the
COPERNICUS Study. JAMA 2003;289:712–8.
[71] Maragno I, Santostasi G, Gaion RM, Trento M, Grion AM, Miraglia G, et al. Low- and
medium-dose diltiazem in chronic atrial fibrillation: comparison with digoxin and
correlation with drug plasma levels. Am Heart J 1988;116:385–92.
[72] Li D, Fareh S, Leung TK, Nattel S. Promotion of atrial fibrillation by heart failure in
dogs: atrial remodeling of a different sort. Circulation 1999;100:87–95.
455
[73] von Lewinski D, Kockskämper J, Rübertus SU, Zhu D, Schmitto JD, Schöndube FA,
et al. Direct pro-arrhythmogenic effects of angiotensin II can be suppressed by AT1
receptor blockade in human atrial myocardium. Eur J Heart Fail 2008;10:1172–6.
[74] Fogari R, Zoppi A, Mugellini A, Corradi L, Lazzari P, Preti P, et al. Comparative
evaluation of effect of valsartan/amlodipine and atenolol/amlodipine combinations on atrial fibrillation recurrence in hypertensive patients with type 2 diabetes
mellitus. J Cardiovasc Pharmacol 2008;51:217–22.
[75] Tveit A, Grundvold I, Olufsen M, Seljeflot I, Abdelnoor M, Arnesen H, et al. Candesartan
in the prevention of relapsing atrial fibrillation. Int J Cardiol 2007;120:85–91.
[76] GISSI-AF InvestigatorsDisertori M, Latini R, Barlera S, Franzosi MG, Staszewsky L, et al.
Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med 2009;360:
1606–17.
[77] Cleland JG, Coletta AP, Yassin A, Buga L, Torabi A, Clark AL. Clinical trials update
from the European Society of Cardiology Meeting 2009: AAA, RELY, PROTECT,
ACTIVE-I, European CRT survey, German pre-SCD II registry, and MADIT-CRT. Eur J
Heart Fail 2009;11:1214–9.
[78] Khan MN, Jaïs P, Cummings J, Di Biase L, Sanders P, Martin DO, et al. Pulmonaryvein isolation for atrial fibrillation in patients with heart failure. N Engl J Med
2008;359:1778–85.
[79] Marrouche NF. CASTLE-AF Steering Committee. Catheter ablation versus
standard conventional treatment in patients with left ventricular dysfunction
and atrial fibrillation (CASTLE-AF) — study design. Pacing Clin Electrophysiol
2009;32:987–94.