ABSTRACT
Introduction: Increasing evidence has suggested improved
outcomes in atrial fibrillation (AF) patients with heart failure (HF)
undergoing catheter ablation (CA) as compared to medical therapy. We
sought to investigate the benefit of CA on outcomes of patients with AF
and HF as compared to medical therapy.
Methods and Results : A systematic review of PubMed, Embase, and
Cochrane Central Register of Clinical Trials was performed for clinical
studies evaluating the benefit of CA for patients with AF and HF.
Primary endpoint was all-cause mortality. Secondary endpoints included
atrial-arrhythmia recurrence and improvement in left ventricular
ejection fraction (LVEF).
Eight randomized controlled trials were included with a total of 2121
patients (mean age: 65 ± 5 years; 72% male). Mean follow-up duration
was 32.9 ± 14.5 months. All-cause mortality in patients who underwent CA
was significantly lower than in the medical treatment group (8.8% vs.
13.5%, RR 0.65, 95% CI 0.51-0.83, P=0.0005). A 35% relative risk
reduction and 4.7% absolute risk reduction in all-cause mortality was
observed with CA. Rates of atrial-arrhythmia recurrence were
significantly lower in the CA group (39.9% vs 69.6%, RR 0.55, 95% CI
0.40-0.76, P=0.0003). Improvement in LVEF was significantly higher in
patients undergoing CA (+9.4 ±7.6%) as compared to conventional
treatment (+3.3±8%) (Mean difference 6.2, 95% CI 3.6-8.8,
P<0.00001).
Conclusion: CA for AF in patients with HF decreases all-cause
mortality, improves atrial-arrhythmia recurrence rate and LVEF when
compared to medical management. CA should be considered the treatment of
choice to improve survival in this select group of patients.
KEYWORDS: heart failure, catheter ablation, atrial
fibrillation, all-cause mortality, left ventricular ejection fraction,
arrhythmia recurrence
INTRODUCTION
Atrial fibrillation (AF) and heart failure (HF) often occur
concomitantly in patients. While their interrelationship is not
completely understood, it has been evident that they share risk factors
and each of these conditions can worsen the progression of the other. AF
has been linked with a five-fold rise in incident HF;1it may also cause a reduction in left ventricular ejection fraction
(LVEF) by tachycardia-induced cardiomyopathy.2 On the
contrary, HF can escalate the risk of developing AF, propelled by high
left ventricular filling pressures and atrial stretch. Moreover, the
mortality associated with the coexistence of these conditions is higher
than in patients with either condition alone. Presence of AF in patients
with HF has been linked with a 40% increase in
mortality.3
HF is estimated to affect 6.5 million adults in the US, and accounts for
nearly 1 million emergency department visits and hospitalizations, 80
000 deaths, and $30 billion in healthcare costs annually. Similarly, AF
is the most commonly encountered cardiac arrhythmia in clinical
practice, and its prevalence is projected to increase from 5.2 million
in 2010 to 12.1 million cases in the US by 2030. Prevalence of AF in
patients with HF has been described to range from 6% to 35% in various
studies, with a higher prevalence being observed in patients with
symptomatic HF. With an aging population, the prevalence of these two
conditions is only expected to increase over time.
Restoring sinus rhythm in patients with AF and HF has shown to improve
survival and LVEF.4-6 In this meta-analysis, we sought
to evaluate the impact of catheter ablation (CA) on all-cause mortality
in patients with AF and HF as compared to medical therapy.
METHODS
The present meta-analysis was performed in accordance with the Cochrane
Collaboration and Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) statements.
Search strategy
We searched PubMed, Embase, and Cochrane Central Register of Clinical
Trials (Cochrane Library, Issue 02, 2017) databases from January
1st, 1996 through April 2022 to identify trials
evaluating the outcomes of AF ablation vs. medical therapy in patients
with CHF. We used the terms (“Atrial Fibrillation” OR “AF”) AND
(“Ablation” OR “Catheter Ablation” OR “CA” OR “Radiofrequency
Ablation” OR “RFA”) AND (“CHF” OR “Heart Failure” OR “Congestive
Heart Failure”). The language of the articles was restricted to English
only. The reference lists of identified articles were also reviewed.
Eligibility criteria
Studies with the following characteristics were considered eligible: 1.
Study design was a prospective, randomized controlled trial (RCT); 2.
Included HF patients with documented AF undergoing CA therapy; 3.
Compared the all-cause mortality between the ablation group and the
standard / medical therapy groups; 4. Compared improvement in LVEF; 5.
Compared other outcomes such as quality of life using Minnesota Living
with Heart Failure Questionnaire (MLWHFQ), change in 6-minute walk
distance (6-MWD), and atrial-arrhythmia recurrence. Abstracts, case
reports, conference presentations, editorials, reviews, and expert
opinions were excluded from our analysis.
Primary and secondary endpoints
The primary endpoint of our analysis was all-cause mortality during
follow-up after CA. The secondary endpoints included improvement in
LVEF, atrial-arrhythmia recurrence, change in MLWHFQ and 6-MWD.
Data extraction and quality appraisal
Three investigators (J.R., M.G. and L.D.B) independently screened all
titles, abstracts and manually searched the full text versions of all
relevant studies that fulfilled the inclusion criteria. References of
the retrieved articles were independently reviewed for further
identification of potentially relevant studies. Disagreements were
resolved arbitrarily (J.R. and L.D.B), and consensus was reached after
discussion. We extracted characteristics of each study including
methodology and baseline patient characteristics, all-cause mortality,
change in LVEF, atrial-arrhythmia recurrence rates, change in MLWHFQ and
6-MWD, ablation strategy, and duration of follow-up for our analysis. If
the above-mentioned information was not readily available in the written
article, the principal investigator of the study was contacted to obtain
pertinent information. Studies not including the aforementioned outcomes
in their analysis were not included in the analysis for that particular
outcome.
Quality assessment
The quality and reporting of the included RCTs were assessed using the
Cochrane Risk of Bias Tool. Quality of the included RCTs was summarized
visually.
Statistical analysis
Descriptive statistics are presented as number of cases (n) for
dichotomous and categorical variables. Statistical analysis was
performed in line with recommendations from the Cochrane Collaboration
and the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) guidelines, using Review Manager (RevMan version
5.3, the Cochrane Collaboration, 2014). Heterogeneity was assessed using
the I2 statistics, which is the proportion of
total variation observed among the studies attributable to differences
between studies rather than sampling error (chance). Data were
summarized across groups using the Mantel-Haenszel Risk Ratio (RR)
Fixed-Effect model if I2 <25. We
considered I2 less than 25% as low andI2 greater than 25% as high. The
Random-Effects Model was used if I2 ≥25%.
Publication bias was estimated visually by funnel plots.
RESULTS
Baseline characteristics
A total of 2929 studies were identified using the pre-specified search
criteria (Figure 1) . After a detailed evaluation of these
studies, 8 studies that comprised a total of 2121 participants were
included.4-10 Baseline characteristics of included
studies are summarized in Table 1 . Ablation strategy utilized
and details of follow-up have been summarized in Table 2 . The
largest study included 778 patients and the smallest included 50
patients. Mean follow-up duration was 32.9 ± 14.5 months. Mean age of
the study population was 65 ± 5 years; the majority of patients were
male (72%). Mean LVEF in the included studies was 41.6 ± 7.8% in the
ablation group and 42 ± 8.4 % in the medical therapy group.
Characteristics of included studies
All eight of the included studies were prospective, RCTs that compared
outcomes of patients with AF and HF undergoing CA as compared to medical
therapy.4-11 Of the 2121 patients included, 1056
patients underwent CA, while 1065 patients received medical therapy.
Five of the included studies only had patients with persistent
AF;4,7-10 in the three remaining studies, patients
with paroxysmal AF were also included.5,6,11
Quality assessment and publication bias
Funnel plots did not suggest publication bias in all studied outcomes(Figure 2) . All the studies included in this meta-analysis had
good methodological quality indicating “low risk of bias”. All 8
studies were classified as high-quality based on the Cochrane Risk of
Bias Tool (Figure 3).
Impact on all-cause mortality
All-cause mortality in patients with HF who underwent CA for AF was
significantly lower compared to patients who received medical treatment
alone (8.8% vs. 13.5 %, respectively, risk ratio (RR) 0.65, 95%
confidence interval (CI) 0.51-0.83, P=0.0005). A 34.8% relative risk
reduction and 4.7% absolute risk reduction in all-cause mortality was
observed with CA (Figure 4A, Figure 5A) .
Impact on LVEF
Improvement in the LVEF was significantly higher in patients
undergoing CA (+9.4±7.6%) compared to conventional treatment (+3.3±8%)
(mean difference 6.2, 95% CI 3.6-8.8, P<0.00001)(Figure 4B, Figure 5B) .
Atrial-arrhythmia recurrence
At a mean follow-up duration of 34.3 ± 14.7 months for this outcome in
studies that reported it, atrial-arrhythmia recurrence was significantly
lower in patients who underwent CA compared to medical therapy (39.9%
vs 69.6%, RR 0.55, 95% CI 0.40-0.76, P=0.0003) (Figure 4C,
Figure 5C) .
Change in quality of life assessment and functional
capacity
Improvement in quality of life, as evaluated by decrease in MLWHFQ, was
significantly better in CA group (mean decrease -15.1±12 vs -10.6±12,
Mean difference -4.8, 95% CI -8.6 to -1, P=0.01) (Figure 6A) .
Change in functional capacity, as assessed by 6-MWD, showed a
significant improvement in the CA group compared to medical therapy
group (39 ± 43 meters vs. 22 ± 41 meters, Mean difference 19.3, 95% CI
5.8 - 32.8, P=0.005) (Figure 6B) .
DISCUSSION
To the best of our knowledge, this is the largest meta-analysis of
randomized controlled trials evaluating the outcomes of patients with AF
and HF undergoing CA as compared to medical therapy to date. The
principal findings are as follows:
- At a mean follow-up of 32.9 ± 14.5 months, a 35% relative risk
reduction and 4.7% absolute reduction in all-cause mortality was
observed with CA of AF compared to medical therapy in patients with
HF.
- CA for AF in HF was associated with a significantly higher improvement
in LVEF compared to medical therapy (+9±8% compared to +3±8,
respectively).
- CA for AF in HF was associated with a significant reduction in
atrial-arrhythmia recurrence as compared to medical therapy.
- CA for AF in HF was associated with a significant improvement in
quality of life as opposed to medical therapy.
Multiple RCTs have demonstrated an improvement in the outcomes of
patients with AF and HF, with CA when compared to medical
therapy.4-8 According to the 2019 AHA/ACC/HRS
guidelines for the management of patients with AF, CA is considered
reasonable in select patients with heart failure with a reduced ejection
fraction (HFrEF) for its potential benefit in decreasing mortality and
hospitalization rates (Class IIb recommendation).12More recently, the European society of cardiology guidelines assigned
catheter ablation a class I recommendation in patients with paroxysmal
AF and HF with reduced ejection fraction.13 However,
CA has not yet been adopted as the standard of care for rhythm control
in HF.
Over a decade ago, AFFIRM (Atrial Fibrillation Follow-up Investigation
of Rhythm Management) sub-analysis noted that maintenance of sinus
rhythm was an important determinant of survival.14Anti-arrhythmic drugs (AADs) are not linked with improved survival
indicating that any beneficial effect of these drugs is offset by their
adverse effects. In patients with AF and HF, the available AADs
recommended by current guidelines are amiodarone and dofetilide.
Long-term utilization of amiodarone is linked with hepatic, pulmonary
and thyroid toxicity. Dofetilide requires hospitalization due to risk of
severe QTc prolongation and torsades de pointes in up to 3% of
patients. In addition, its utilization is restricted in patients with
renal dysfunction, a common condition that preexists with HF. The AF-CHF
(Atrial Fibrillation and Congestive Heart Failure)15and DIAMOND-CHF (Danish Investigators of Arrhythmia and Mortality on
Dofetilide in Congestive Heart Failure) trials16 with
predominant and exclusive utilization of amiodarone and dofetilide,
respectively, noted that use of neither of these AADs was associated
with a reduction in mortality despite reduction in AF burden.
CA offers an appealing alternative therapy to restore sinus rhythm while
avoiding the adverse effects associated with the use of AADs. In
PABA-CHF (Pulmonary Vein Isolation for Atrial Fibrillation in Patients
with Heart Failure) trial, a prospective, multicenter RCT published by
our group, CA for AF and HF (EF ≤ 40%) was demonstrated to be superior
to atrioventricular-node ablation with biventricular pacing for the
composite endpoint of improvement in LVEF (35% vs 28%,
P<0.001), 6-MWD (340m vs 297m, P<0.001) and MLWHF
score (60 vs 82, P<0.001).17 CAMTAF (A
Randomized Controlled Trial of Catheter Ablation Versus Medical
Treatment of Atrial Fibrillation in Heart Failure), demonstrated
significant improvement in LVEF in patients with persistent AF and HF
(EF <50%), at 6-month follow-up (40±12% vs 31±13%,
P=0.015).8 Subsequently, AATAC (Ablation Versus
Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients
With Congestive Heart Failure and an Implanted
Device),4 a multicenter, RCT published by our group
noted superiority of CA for persistent AF and HF over amiodarone in
improving freedom from atrial-arrhythmia recurrence (70% vs 34%,
P< 0.001), at 2-year follow-up. A significant reduction in the
unplanned hospitalization rate (31% vs 57%, P<0.001) and
mortality rate (8% vs 18%, P=0.037) was also noted.4In CAMERA-MRI (Catheter Ablation Versus Medical Rate Control in Atrial
Fibrillation and Systolic Dysfunction), a RCT of patients with
persistent AF and HF (EF ≤45%), significant improvement in LVEF
(18±13% vs 4.4±13%, P<0.0001) was noted in the ablation arm,
with the absence of late gadolinium enhancement predicting greater
improvement in LVEF (10.7%, P=0.0069).10 CASTLE-AF
(Catheter Ablation for Atrial Fibrillation with Heart Failure) trial, a
RCT, which enrolled patients with paroxysmal or persistent AF and HF (EF
≤ 35%) demonstrated a significant improvement in the primary composite
endpoint of all-cause mortality or HF hospitalization rate (28.5% vs.
44.6%, p=0.007), at a mean follow-up of 37.8 months.6
In CABANA (Effect of Catheter Ablation vs Antiarrhythmic Drug Therapy on
Mortality, Stroke, Bleeding, and Cardiac Arrest Among Patients With
Atrial Fibrillation) trial, the largest RCT to date comparing CA for AF
to medical therapy in 2204 patients, CA did not significantly improve
the primary composite outcome of death, serious bleeding, cardiac
arrest, or disabling stroke per intention-to-treat analysis (8% vs.
9.2%, p=0.30).18 However, in the sub-group analysis
of 778 patients with HF, the results were favorable for CA, with a 36%
relative reduction in the primary composite outcome (HR: 0.64, 95% CI:
0.41-0.99) and 43% relative reduction in all-cause mortality (HR: 0.57,
95% CI: 0.33-0.96), at a median follow-up of 48.5
months.5 In addition, more recently, RAFT-AF
(Randomized Ablation-based Rhythm-control Versus Rate-control Trial in
Patients with Heart Failure and Atrial Fibrillation), reported results
from a RCT of 411 patients.11 In the study’s analysis,
the primary composite outcome of all-cause mortality and heart failure
events was not significantly different between the catheter ablation and
medical therapy groups (23.4% vs 32.5% events, respectively, p=0.066),
despite a trend for improved outcomes. On the other hand, CA compared to
medical therapy was associated with statistically significant
improvement in LVEF (10.1±1.2% vs 3.8±1.2%, p=0.017), six minute walk
distance (44.9±9.1 meters 27.5±9.7 meters, p=0.025), MLWHFQ (LSMD of
-5.4, 95%CI (-10.5, -0.3), p=0.0036), and NT-proBNP (mean change
-77.1% vs -39.2%, p<0.0001). Results from AMICA (Catheter
Ablation Versus Best Medical Therapy in Patients With Persistent Atrial
Fibrillation and Congestive Heart Failure) trial,9 and
a study by MacDonald et al,19 contrasted the largely
positive results seen in other studies. AMICA trial, a RCT comparing CA
to medical therapy in patients with persistent or longstanding
persistent AF with HF, described no significant improvement in LVEF
between the ablation group and medical therapy group at 12-month
follow-up.9 MacDonald et al, in a RCT of patients with
persistent AF and advanced HF (EF <35%) also did not
demonstrate a significant improvement in LVEF on cardiac magnetic
resonance imaging, at 6-month follow-up.19 Both of
these trials enrolled majority of patients with advanced HF which may
have led to a lower benefit from CA.9,19 This was also
noted in CASTLE-AF sub-analysis, where CA in patients with NYHA classes
I and II was associated with a stronger improvement in outcomes as
compared to NYHA classes III and IV.20 As such, early
CA to achieve rhythm control in HF patients could be crucial in
achieving significant benefits, similar to what has been recently been
described in non-HF populations. Moreover, the short duration of
follow-up could have been insufficient to detect the beneficial outcomes
of CA. This was evident, for instance, in the CASTLE-AF study, where the
beneficial effect of CA on all-cause mortality, and HF hospitalization
rates were seen at a significantly longer follow-up duration (median:
~37 months).6 Finally, significant
cost reductions could result from AF CA in HF patients. Lima et al
recently described a significant reduction in 30-day readmissions
(16.8% vs 18.8%, P = 0.02) in patients with HF undergoing CA for AF
compared with a propensity score matched group receiving medical
therapy.21 Importantly, although the costs of the
index hospitalization were significantly higher for the CA group, after
readmission, overall costs were similar between the two groups. Field et
al found significant reductions in AF-related hospitalizations (64%),
emergency department 22 visits (51%), and HF related
hospitalizations (22%), all of which translated into a reduction in AF
related costs and ED related costs. As such, increasing the use of CA
for AF in HF is expected to be highly cost effective, with an
incremental cost of $38,496-74,403 per QALY gained compared to medical
therapy.23
In a meta-analysis of 856 patients with AF and HFrEF, CA demonstrated
significant improvement in all-cause mortality (10% vs. 19%, OR: 0.46,
95% CI: 0.29-0.72) and freedom from AF (70% vs. 18%, OR: 0.03, 95%
CI: 0.01-0.11).24 The results of the present
meta-analysis are also consistent with other meta-analyses published on
this subject.
Limitations
Several limitations must be taken into consideration while interpreting
the results of our meta-analysis. The sample size for some of the
included studies along with the number of studies assessing some of the
reported outcomes was relatively small. In addition, there was
considerable variability amongst studies in terms of inclusion of
patients with different NYHA classification subtypes, HF types
(preserved versus reduced), etiology of cardiomyopathy, and type of AF
included, making it difficult to stipulate which population derives the
greatest benefit from CA. Moreover, although pulmonary vein isolation
was the main approach in all the studies, there was significant
variation in additional ablation strategies utilized. Additionally,
there was variability in the intervention used in the control groups,
with some studies adopting amiodarone alone for rhythm control, a rate
control strategy, or a combination of rate and rhythm control. There was
also variation in the duration of AAD utilization after CA for AF.
CONCLUSION
CA for AF in patients with HF significantly decreases all-cause
mortality, improves LVEF, reduces atrial-arrhythmia recurrence and
improves quality of life in comparison to medical management. CA should
be considered the treatment of choice for rhythm control to in this
select group of patients with AF and HF.