†These authors contributed equally.
Several observational studies have shown a survival benefit for patients with atrial fibrillation (AF) who are treated with catheter ablation (CA) rather than medical management (MM). However, data from randomized controlled trials (RCTs) are uncertain. Therefore, we performed a meta-analysis of RCTs that compared the benefits of CA and MM in treatment of AF. We searched the Cochrane Library, PubMed, and EMBASE databases for RCTs that compared AF ablation with MM from the time of database establishment up to January 2020. The risk ratio (RR) with a 95% confidence interval (CI) was used as a measure treatment effect. Twenty-six RCTs that enrolled a total of 5788 patients were included in the meta-analysis. In this meta-analysis, the effect of AF ablation depended on the baseline level of left ventricular ejection fraction (LVEF) in the heart failure (HF) patients. AF ablation appears to be of benefit to patients with a lesser degree of advanced HF and better LVEF by reducing mortality. Meanwhile, this mortality advantage was manifested in long-term follow-up. CA increased the risk for hospitalization when it was used as first-line therapy and decreased the risk when used as second-line therapy. CA reduced recurrence of atrial arrhythmia for different types of AF (paroxysmal or persistent AF) and CA-related complications were non-negligible. There was no convincing evidence for a reduction in long-term stroke risk after AF ablation, and additional high quality RCTs are needed to address that issue.
Atrial fibrillation (AF) is the most common type of cardiac arrhythmia
(Lloyd-Jones et al., 2004), and its prevalence and incidence gradually
increase with age. AF is more common in men than in women of all ages (Chugh et al., 2014). AF is the main cause of stroke, and is associated with higher rates
of mortality and cardiovascular disease. The major causes of death in patients
with AF are progressive heart failure (HF), cardiac arrest, and stroke (Chiang et al., 2017). AF occurs in
In addition to the risk factors and lifestyle management (e.g., alcohol, obesity, sleep apnoea, lack of exercise) as well as stroke prevention (Hart et al., 2007; Kirchhof et al., 2016), rate control and rhythm control are the most common strategies employed for treating AF. A previous large sample randomized controlled trial (RCT) revealed that the use of antiarrhythmic drugs (AADs) for rhythm control in AF treatment provides no survival advantage compared to a rate control strategy (Wyse et al., 2002). Subsequently, several RCTs showed that catheter ablation (CA) is a safe and better method for maintaining sinus rhythm (SR) and preventing AF recurrence than the use of AADs (Forleo et al., 2009; Jais et al., 2008; Pappone et al., 2006; Stabile et al., 2006). Similarly, data from non-randomized studies have consistently indicated that AF ablation provides greater benefits for treating AF as measured by clinical hard endpoints and cardiac function tests than treatment by medical management (MM) alone (Mansour et al., 2018; Reynolds et al., 2012). Despite the recent publication of several landmark RCTs that compared CA with MM among AF patients in clinical hard endpoints, the superiority of one strategy over the other remains in doubt. To fill this knowledge gap, we performed a meta-analysis of RCTs comparing CA and MM in patients with AF.
According to PICOS (Menzies, 2011), we searched the Cochrane Library, PubMed, and EMBASE databases from the time of their establishment up to January 2020 using the following Medical Subject Heading terms and key words: “atrial fibrillation”, “catheter ablation”, “randomized”, “medical therapy”, “rhythm control”, and “radiofrequency ablation”. In addition, we searched the website www.ClinicalTrials.gov to identify relevant information from ongoing trials that have not yet been published. The search strategies used were not restricted by year of publication or language.
All relevant RCTs that reported at least one outcome of interest were collected. The patients in those trials had either paroxysmal AF or persistent AF, and also included AF patients with HF. If outcome data for recurrence of atrial arrhythmia with both on-drug and off-drug therapy are available, the off-drug data are used. We excluded trials in which CA was used in both therapeutic arms, and as part of a surgical operation. The Cochrane risk of bias assessment tool was used to assess the risk of bias in the included trials (Higgins et al., 2011).
The following information was recorded for each trial included in the meta-analysis: last name of the first author, publication year, sample size in each arm, mean age of the patients, proportion of males in each arm, percentage of patients who crossed-over from a MM group to a CA group, and patient follow-up duration. Additionally, data pertaining to left atrium diameter (LAD), left ventricular ejection fraction (LVEF), previous embolic events (PEEs), hypertension (HTN), coronary artery disease (CAD), and diabetes mellitus (DM) were also recorded. Two investigators independently extracted the data and then analyzed each trial for the outcomes of interest per treatment arm. Any differences of opinion were resolved via discussion.
The primary outcome was all-cause mortality. The secondary outcomes were recurrence of atrial arrhythmia, stroke/transient ischemic attack (TIA), hospitalization, major bleeding events, pulmonary vein stenosis, and pericardial complications (combination of tamponade, effusion, perforation, pericarditis, and hemorrhage). The definitions of the endpoints were taken as reported in the included trials.
Measurements of treatment effect for the endpoints are reported as a pooled risk
ratio (RR) with a 95% confidence interval (CI). Heterogeneity was evaluated
according to the I
The study selection steps are summarized in Fig. 1. A total of 2227 articles were identified during the literature search. After reviewing the full text of each possibly appropriate article, 26 articles that met the selection criteria were included in this meta-analysis.
Flow diagram showing the study selection process for the meta-analysis. The number of studies shown at the bottom of the flow chart represents studies that were ultimately considered eligible for inclusion in this meta-analysis.
The meta-analysis included 26 RCTs, with a total of 5788 patients (3054 in the
CA arm and 2734 in the MM arm). The 26 trials were published between 2000 and
2019 (Da Costa et al., 2006; Di Biase et al., 2016; Forleo et al., 2009; Hummel et al., 2014; Hunter et al., 2014; Jais et al., 2008; Jones et al., 2013; Krittayaphong et al., 2003; Kuck et al., 2019; MacDonald et al., 2011; Marrouche et al., 2018; Mont et al., 2014; Morillo et al., 2014; Natale et al., 2000; Nielsen et al., 2012; Oral et al., 2006; Packer et al., 2013, 2019; Pappone et al., 2006; Pokushalov et al., 2013; Prabhu et al., 2017; Sohara et al., 2016; Stabile et al., 2006; Wazni et al., 2005; Wilber et al., 2010; Zhang et al., 2014). Six trials were conducted at one center (Hunter et al., 2014; Jones et al., 2013; Krittayaphong et al., 2003; Pappone et al., 2006; Pokushalov et al., 2013; Zhang et al., 2014), and the remaining trials were
multicenter trials. One trial included only patients with diabetes (Forleo et al., 2009), and seven trials included patients with HF (Di Biase et al., 2016; Hunter et al., 2014; Jones et al., 2013; Kuck et al., 2019; MacDonald et al., 2011; Marrouche et al., 2018; Prabhu et al., 2017). Table 1 provides
the baseline characteristics of the included trials. The patients in 9 trials
were followed up for
Study/Year | Patients (n) | Mean age (years) | Male (%) | LAD (mm) | LVEF (%) | PEE (n) | CAD (n) | DM (n) | HTN (n) | Crossover to CA(%) | Follow up (months) |
Natale et al., 2000 | 31/30 | 67 |
65/73 | NR | 49.4 |
NR | 12/11 | NR | NR | NR | 33 |
Krittayaphong et al., 2003 | 15/15 | 55 |
73/53 | 39.6 |
63.7 |
0/0 | NR | NR | NR | NR | 12 |
Wazni et al., 2005 | 33/37 | 53 |
NR | 41 |
53 |
NR | NR | NR | 8/10 | NR | 12 |
Da Costa et al., 2006 | 52/51 | 78.5 |
79/82 | 43 |
56 |
NR | NR | 10/11 | 36/34 | NR | 13 |
Oral et al., 2006 | 77/69 | 55 |
67/62 | 45 |
55 |
0/0 | 3/4 | NR | NR | 77 | 12 |
Stabile et al., 2006 | 68/69 | 62 |
54/64 | 46 |
59.1 |
NR | NR | NR | 36/34 | 52 | 12 |
Pappone et al., 2006 | 99/99 | 55 |
70/65 | 40 |
60 |
NR | 2/2 | 5/4 | 56/57 | 42 | 12 |
Jais et al., 2008 | 53/59 | 50 |
85/83 | 39.5 |
63 |
1/7 | NR | 1/2 | 11/18 | 63 | 12 |
Forleo et al., 2009 | 35/35 | 63 |
57/65 | 44 |
54.6 |
5/3 | 7/7 | 35/35 | 22/24 | NR | 12 |
Wilber et al., 2010 | 106/61 | 56 |
69/62 | 40 |
62.3 |
2/2 | NR | 10/7 | 51/30 | 59 | 9 |
MacDonald et al., 2011 | 22/19 | 62 |
77/79 | NR | 16.1 |
2/2 | 11/9 | 7/4 | 14/11 | 0 | 6 |
Nielsen et al., 2012 | 146/148 | 56 |
68/72 | 40 |
6/5 | 6/2 | 6/10 | 43/53 | 36 | 24 | |
Packer et al., 2013 | 163/82 | 57 |
77/78 | 40 |
60 |
0/0 | 13/8 | 11/7 | 67/37 | 79 | 12 |
Pokushalov et al., 2013 | 77/77 | 56 |
73/77 | 45 |
57 |
5/6 | 8/10 | 9/7 | 24/29 | 56 | 36 |
Jones et al., 2013 | 26/26 | 64 |
81/92 | 50 |
22 |
NR | 11/13 | NR | NR | 3.8 | 12 |
Zhang et al., 2014 | 101/100 | 60 |
70/67 | 45.8 |
57.9 |
10/6 | 11/13 | 19/20 | 52/48 | 24 | 24 |
Mont et al., 2014 | 98/48 | 55 |
78/77 | 41 |
61 |
4/2 | NR | NR | 46/19 | 48 | 12 |
Hummel et al., 2014 | 138/72 | 60 |
83/83 | 45 |
54 |
0/0 | 28/12 | 22/8 | 84/40 | 60 | 6 |
Hunter et al., 2014 | 26/24 | 55 |
96/96 | 52 |
31.8 |
NR | NR | NR | 8/8 | 0 | 6 |
Morillo et al., 2014 | 66/61 | 56 |
77/74 | 40 |
61.4 |
3/4 | 6/2 | 1/4 | 28/25 | 43 | 24 |
Sohara et al., 2016 | 100/43 | 59 |
80/81 | 38.3 |
66.7 |
NR | 3/2 | 3/4 | 51/24 | 79 | 9 |
Di Biase et al., 2016 | 102/101 | 62 |
75/73 | 47 |
29 |
NR | 63/66 | 22/24 | 46/48 | NR | 24 |
Prabhu et al., 2017 | 33/33 | 59 |
94/88 | 48 |
32 |
2/0 | 0/0 | 4/5 | 13/12 | 9 | 6 |
Marrouche et al., 2018 | 179/184 | 64 |
87/84 | 48 |
31.5 |
21/21 | 72/96 | 43/67 | 129/136 | 15.6 | 38 |
Packer et al., 2019 | 1108/1096 | 68 |
63/63 | NR | NR | 117/103 | 201/216 | 280/281 | 876/900 | 27.5 | 48 |
Kuck et al., 2019 | 100/95 | 65 |
88/92 | 50 |
28 |
NR | 30/40 | 24/22 | 56/55 | 4 | 12 |
Data are presented as patients receiving CA/patients receiving MM. Age is given
as mean |
The medications used in the MM arms of the studies were mostly class I and class III AADs (single or combined use), and the AADs in three RCTs were limited to amiodarone (Da Costa et al., 2006; Di Biase et al., 2016; Krittayaphong et al., 2003). In four RCTs (Hunter et al., 2014; Jones et al., 2013; MacDonald et al., 2011; Prabhu et al., 2017), the patients in the MM arm used only rate control medications. In the CA arms, one trial used cryoballoon ablation technology (Packer et al., 2013) and another trial used hotballoon ablation (Sohara et al., 2016). CA was performed as first-line therapy in three trials (Morillo et al., 2014; Nielsen et al., 2012; Wazni et al., 2005), and as second-line therapy in the remaining trials. All trials included pulmonary vein isolation, and most reported additional linear ablation at the discretion of the operator. A complete summary of the risk of bias in the included trials is shown in Table 2.
Author/Study(year) | Random sequence generation (selection bias) | Allocation concealment (selection bias) | Blinding of participants and personnel (performance bias) | Blinding of outcome assessment (detection bias) | Incomplete outcome data (attrition bias) | Selective reporting (reporting bias) | Other bias |
Natale et al., 2000 | Unlcear | Low | High | High | Low | Low | Unlcear |
Krittayaphong et al., 2003 | Unclear | Unclear | Unclear | Unclear | Unclear | Unclear | Unclear |
Wazni et al., 2005 | Low | High | Unclear | Unclear | Low | Low | Unclear |
Da Costa et al., 2006 | Unclear | Unclear | Unclear | Unclear | Unclear | Unclear | Unclear |
Oral et al., 2006 | Low | Unclear | Unclear | Unclear | Low | Unclear | High |
Stabile et al., 2006 | Low | Unclear | High | Low | Low | Low | High |
Pappone et al., 2006 | Unclear | Unclear | High | Low | Low | Low | Unclear |
Jais et al., 2008 | Low | Unclear | Low | Unlcear | Low | Low | High |
Forleo et al., 2009 | Low | High | Unclear | Unlcear | Low | Low | Unlcear |
Wilber et al., 2010 | Low | Low | High | Unlcear | Low | Low | High |
MacDonald et al., 2011 | Low | Low | High | High | Low | Low | Unclear |
Nielsen et al., 2012 | Low | Low | High | Low | Low | Low | Unclear |
Packer et al., 2013 | Unlcear | Low | High | Unclear | High | Low | High |
Pokushalov et al., 2013 | Low | Low | High | Low | Low | Low | High |
Jones et al., 2013 | Low | High | High | Low | Low | Low | Unclear |
Zhang et al., 2014 | Low | High | High | Low | Low | Low | Unclear |
Mont et al., 2014 | Low | High | High | Unclear | Low | Low | Unclear |
Hummel et al., 2014 | Unclear | Unclear | Unclear | Unclear | Low | Unclear | High |
Hunter et al., 2014 | Low | Low | High | High | Low | Low | Unclear |
Morillo et al., 2014 | Low | Unclear | Unclear | Low | Low | Low | Unclear |
Sohara et al., 2016 | Unlcear | Unclear | High | Low | High | Low | High |
Di Biase et al., 2016 | Low | Low | High | High | High | Low | Unlcear |
Prabhu et al., 2017 | Low | Low | High | High | Low | Low | Unlcear |
Marrouche et al., 2018 | Low | Low | High | Unclear | High | Low | Unlcear |
Packer et al., 2019 | Low | Low | High | Low | Low | Low | Unlcear |
Kuck et al., 2019 | Low | Low | High | Low | High | Low | Unlcear |
A total of 274 deaths were reported (115 in the composite CA arm and 159 in the
composite MM arm), including 2 peri-procedural deaths. CA was associated with a
statistically significant reduction in all-cause mortality in AF patients when
compared with the MM patients, with a low degree of heterogeneity (RR: 0.72; 95%
CI: 0.57 to 0.90, P
The pooled outcome of all-cause mortality. A forest plot illustrating the all-cause mortality during follow-up among AF patients randomized to CA versus MM. Packer-(Non-HF), Packer-(HF), and Marrouche-(AHF) used composite endpoints.
The Packer-(Non-HF) and Packer-(HF) subgroup analysis used a composite endpoint (death, disabling stroke, serious bleeding, or cardiac arrest) (Packer et al., 2019), and the Marrouche-(AHF) subgroup analysis also used a composite endpoint (death or admission for worsening HF) (Marrouche et al., 2018). Therefore, in our subgroup analysis, we conducted an additional sensitivity analysis to test the stability of all-cause mortality results for Non-HF, HF, and AHF patients. The sensitivity analysis proved the results to be very stable (Fig. 3).
Sensitivity analysis for all-cause mortality. (A) Sensitivity analysis for all-cause mortality among patients without HF. (B) Sensitivity analysis for all-cause mortality among patients with HF. (C) Sensitivity analysis for all-cause mortality among patients with AHF.
Next, we analyzed the rates of hospitalization in 14 trials, and found a large
degree of heterogeneity (RR: 0.67; 95% CI: 0.52 to 0.87, P
The pooled outcome of hospitalization risk for patients treated with CA versus MM. A forest plot illustrating results of the subgroup analysis that was performed based on CA provided as first-line or second-line therapy (upper panel shows the pooled outcome for CA when used as first-line therapy; lower panel shows the pooled outcome for CA when used as second-line therapy).
The pooled outcome of hospitalization risk when CA was used as first-line therapy. A forest plot illustrating the risk of hospitalization when CA was performed as first-line treatment, after excluding the study by Wazni et al. (2005).
There were 34 strokes/TIAs in the CA arm and 27 in the MM arm (follow-up periods
ranged from 6 to 48 months).
No
difference was found in the risk for stroke/TIA directly induced by AF itself in
the two groups (RR: 0.70; 95% CI: 0.39 to 1.23, P
The pooled outcome of stroke/TIA risk associated with CA versus MM. The forest plot illustrates results of a subgroup analysis that was performed based on the source of stroke (upper panel shows the pooled outcome for stroke directly induced by AF itself; lower panel shows the pooled outcome for stroke caused by ablation procedure).
Similarly, CA significantly increased the risk of major bleeding
(RR: 3.88; 95% CI: 1.63 to 9.22, P
The pooled outcome of peri-procedural complications in the CA group versus the MM group. The forest plot illustrates results of the stratification analysis that was performed based on the types of complications (upper panel shows the pooled outcome for major bleeding, the middle panel shows the pooled outcome for pulmonary vein stenosis, and lower panel shows the pooled outcome for pericardial complications).
Death, N (%) | Stroke/ TIA, N (%) | Major bleeding, N (%) | Pulmonary vein stenosis, N (%) | Pericardial complications, N (%) | |
Natale (N |
0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
Krittayaphong (N |
0 (0.0%) | 1 (6.7%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
Wazni (N |
0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 2 (6.1%) | 0 (0.0%) |
Da Costa (N |
0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
Oral (N |
0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
Stabile (N |
0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 1 (1.5%) |
Pappone (N |
0 (0.0%) | 1 (1.0%) | 0 (0.0%) | 0 (0.0%) | 1 (1.0%) |
Jais (N |
0 (0.0%) | 0 (0.0%) | 2 (3.8%) | 1 (1.9%) | 2 (3.8%) |
Forleo (N |
0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
Wilber (N |
0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 1 (0.9%) |
MacDonald (N |
0 (0.0%) | 0 (0.0%) | 2 (9.1%) | 0 (0.0%) | 2 (9.1%) |
Nielsen (N |
1 (0.7%) | 1 (0.7%) | 0 (0.0%) | 1 (0.7%) | 3 (2.1%) |
Packer (2013) (N |
0 (0.0%) | 1 (0.6%) | 3 (1.8%) | 5 (3.1%) | 1 (0.6%) |
Pokushalov (N |
0 (0.0%) | 0 (0.0%) | 2 (2.6%) | 0 (0.0%) | 2 (2.6%) |
Jones (N |
0 (0.0%) | 0 (0.0%) | 1 (4.0%) | 0 (0.0%) | 1 (4.0%) |
Zhang (N |
0 (0.0%) | 2 (2.0%) | 1 (1.0%) | 0 (0.0%) | 1 (1.0%) |
Mont (N |
0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 1 (1.0%) | 3 (3.1%) |
Hummel (N |
0 (0.0%) | 4 (2.9%) | 0 (0.0%) | 5 (3.6%) | 5 (3.6%) |
Hunter (N |
0 (0.0%) | 1 (3.8%) | 1 (3.8%) | 0 (0.0%) | 1 (3.8%) |
Morillo (N |
0 (0.0%) | 0 (0.0%) | 4 (6.0%) | 1 (1.5%) | 4 (6.1%) |
Sohara (N |
0 (0.0%) | 2 (2.0%) | 0 (0.0%) | 7 (7.0%) | 0 (0.0%) |
Di Biase (N |
0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 1 (1.0%) |
Prabhu (N |
0 (0.0%) | 0 (0.0%) | 2 (6.0%) | 0 (0.0%) | 0 (0.0%) |
Marrouche (N |
0 (0.0%) | 0 (0.0%) | 4 (2.2%) | 1 (0.6%) | 3 (1.7%) |
Packer (2019) (N |
0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 1 (0.09%) | 8 (0.7%) |
Kuck (N |
1 (1.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 2 (2.0%) |
Total (N |
2 (0.06%) | 13 (0.4%) | 22 (0.7%) | 25 (0.8%) | 42 (1.4%) |
At the last follow-up, the pooled incidence of recurrent atrial arrhythmia was
41.1% after a single ablation and 34.5% after multiple ablations. The multiple
ablations long-term recurrence of atrial arrhythmia in paroxysmal AF was 33.2%
in 7 studies, and that in persistent AF was 38.4% in 8 studies. Patients
underwent multiple procedures with the mean number of ablations ranging from 1.19
to 1.7. The recurrence rate reached the maximum (49.9%) when the follow-up time
reached 48 months or more. Compared with rhythm control or rate control, CA was
associated with a significantly reduced risk of recurrent atrial arrhythmia at
follow-up [(RR: 0.38; 95% CI: 0.30 to 0.49, P
Recurrence of atrial arrhythmia | No. of studies | Patients CA/MM | Events CA/MM | P value | Effect estimate RR (95% CI) | I |
Incidence after CA/MM |
Overall | 26 | 2533/2249 | 882/1525 | 0.43 (0.37, 0.51) | 82% | 34.8%/67.8% | |
Follow-up duration | |||||||
---|---|---|---|---|---|---|---|
Follow-up |
20 | 2113/2003 | 730/1309 | 0.43 (0.36, 0.53) | 83% | 34.5%/65.4% | |
Follow-up |
8 | 1313/1330 | 531/858 | 0.58 (0.48, 0.69) | 72% | 40.4%/64.5% | |
Follow-up |
3 | 867/890 | 398/623 | 0.001 | 0.60 (0.45, 0.82) | 85% | 45.9%/70% |
Follow-up |
1 | 611/629 | 305/437 | 0.72 (0.65, 0.79) | — | 49.9%/69.5% | |
Type of MM | |||||||
CA vs. rhythm control | 14 | 992/863 | 291/617 | 0.38 (0.30, 0.49) | 76% | 29.3%/71.5% | |
CA vs. rate control | 4 | 104/101 | 18/99 | 0.008 | 0.17 (0.05, 0.63) | 88% | 17.3%/98% |
Number of ablation | |||||||
Single ablation | 12 | 756/606 | 311/481 | 0.51 (0.45, 0.58) | 46% | 41.1%/79% | |
Multiple ablations | 19 | 2330/2102 | 804/1401 | 0.45 (0.38, 0.54) | 83% | 34.5%/66.7% | |
Type of AF | |||||||
Paroxysmal AF | 7 | 864/799 | 287/527 | 0.0001 | 0.43 (0.29, 0.66) | 93% | 33.2%/66% |
Persistent AF | 8 | 803/743 | 308/475 | 0.54 (0.44, 0.68) | 66% | 38.4%/63.9% | |
Level of LVEF | |||||||
Normal LVEF | 19 | 1966/1675 | 696/1116 | 0.44 (0.37, 0.54) | 83% | 35.4%/66.6% | |
Reduced LVEF | 8 | 567/566 | 186/409 | 0.42 (0.30, 0.60) | 81% | 32.8%/72.2% | |
AF: atrial fibrillation; CA: catheter ablation; CI: confidence interval; LVEF: left ventricular ejection fraction; MM: medical management; RR: risk ratio. |
The probability of potential publication bias in the 26 studies was estimated by
using Begg’s funnel plots (Fig. 8) and Egger’s linear regression method (P
A Begg’s funnel plot of all studies included in the meta-analysis. The absence of asymmetry indicates that there was no publication bias.
Our meta-analysis gave the following results:
(1) There was no significant difference in all-cause mortality among AF patients with non-HF or AHF in the two arms of the analysis, while patients with HF receiving CA treatment and patients who were followed up for more than 12 months had a significantly lower rate of all-cause mortality.
(2) CA increased the risk of hospitalization when used as first-line therapy but decreased the risk for hospitalization when used as second-line therapy.
(3) There was no significant difference regarding the risk for stroke directly induced by AF itself between the treatment groups. AF patients treated with CA had a higher incidence of peri-procedural stroke, major bleeding, pulmonary vein stenosis, and pericardial complications, while recurrent atrial arrhythmia was a lower risk.
AF and HF are common forms of heart disease which are associated with high rates
of mortality and morbidity. AF patients with HF have even higher mortality and
hospitalization rates, irrespective of which disease occurred first (Dyrda et al., 2015; Steinberg et al., 2014). Current data shows that successful AF
ablation has improved LVEF in such patients (Khan et al., 2018; Prabhu et al., 2017). A possible reason for that finding is an improvement in cardiac
hemodynamics achieved by restoring SR since HF patients rely more on atrial
contraction to maintain an adequate cardiac output, and reduce the likelihood of
developing tachycardia-mediated cardiomyopathy (Redfield et al., 2000). Our
meta-analysis showed a significant reduction in mortality when CA rather than MM
was used for treating AF patients with HF. Meanwhile, this survival benefit of CA
was mainly in trials with a follow-up time
Our preliminary analysis favored CA over MM for decreasing the risk for hospitalization when CA was used as second-line therapy. Data shows that while the average length of a hospital stay has remained unchanged, the cost of inpatient care has increased in recent years (Patel et al., 2014). As a result, it is very important to reduce the current hospitalization rate and associated treatment costs. Similarly, data also suggest that a reduction in hospitalizations, a core indicator of health care utilization, could have important socioeconomic effects (Nisar et al., 2018). On the other hand, when performed as initial therapy, CA may not be more expensive than MM (Khaykin et al., 2009), and result in a lower rate of recurrent atrial arrhythmias (Morillo et al., 2014). However, our meta-analysis revealed that CA, when used as first-line therapy, increased the risk for hospitalization. Furthermore, our report also suggested a significantly higher incidence of peri-procedure stroke, major bleeding, pulmonary vein stenosis, and pericardial complications with CA. These CA-related complications usually are more immediate and dramatic than those with MM. Therefore, the risks and benefits of performing CA as initial treatment for AF should be fully considered and understood. The current ongoing early invasive intervention study of AF (EARLY-AF trail) will once again evaluate the optimal first management approach for patients with AF (Andrade et al., 2018).
Regarding the result for stroke, 13 strokes/TIAs were associated with an ablation procedure, and 4 occurred in the study by Hummel et al. (2014), which used a phased radiofrequency ablation approach. Evidence exists for an increased peri-procedural stroke risk (Herrera et al., 2011). In our analysis, the peri-procedural stroke risk was 0.4%, which is similar to that documented by Arbelo et al. (2014), and suggests that stroke remains a significant complication of AF ablation. It has been suggested that successful CA and recovery of SR, although closely related to an increased risk for asymptomatic cerebral infarction, may subsequently reduce the burden of embolism over time (Asirvatham and Friedman, 2006; Thakur et al., 2016). Indeed, in a study by Nademanee et al. (2008), the stroke/TIA regression models showed significant differences in events between groups after one year of follow-up. However, our meta-analysis failed to show any strong evidence for a reduction in long-term stroke risk. The high crossover rate from MM to CA and relatively low number of cerebrovascular events may in our included studies have made the reduction in long-term stroke risk unrecognizable. These results should be interpreted with caution because some of the included trials did not report the type of anticoagulation strategy used during follow-up. The current ongoing Early Treatment of AF for Stroke Prevention (EAST) trial will provide much-needed evidence in this field (Kirchhof et al., 2013).
Current published reports indicate variable efficacy of CA for different groups
of patients with AF (i.e., paroxysmal or persistent AF) (Ganesan et al., 2013; Shi et al., 2015). Subsequently, the superior efficacy of CA in reducing the
risk of recurrent atrial arrhythmia in patients with paroxysmal or persistent AF
in our analysis suggests that CA can be considered as a suitable treatment for
all types of AF. However, significant heterogeneity was also found in this result
(
Previous studies have shown that CA is superior to MM alone for preventing a recurrence of AF, improving a patient’s quality of life, and reducing morbidity (Choi et al., 2010; Gentlesk et al., 2007). Therefore, it may seem legitimate believe that successful AF ablation will lead to reductions in clinical hard endpoints. In fact, our meta-analysis showed contradictory results. Rhythm control and rate control are two highly debated topics in AF management. In theory, rhythm control with better atrial pump function, a relatively normal ventricular rate, and regular rhythm should provide for a better prognosis. However, the studies by Hagens et al. (2005), Roy et al. (2008) and Wyse et al. (2002) indicate that regardless of whether it is implemented by use of AADs or cardioversion, a rhythm control strategy does not provide an advantage in terms of clinical hard endpoints. One reason may be that a rhythm control strategy does not completely maintain SR. With advances in technology, CA has become an effective method for treating AF. Our meta-analysis supporting the use of CA for reducing mortality was mostly confined to HF patients with moderately depressed LVEF. In this subgroup of patients, and especially those treated with ablation technology at skilled research centers, ablation rather than MM can be used for the objective of improving a patient’s prognosis. The study by Packer et al. (2019) remains the largest RCT to compare CA with MM for treatment of AF. Patients enrolled in that trial who had a risk factor for stroke were relatively “low risk” patients when compared to patients enrolled in two trials conducted by Di Biase et al. (2016) and Marrouche et al. (2018), and the results showed that although CA had a higher SR maintenance rate, it did not benefit clinical hard endpoints. One on hand, this suggests that rhythm control may be just a type of symptomatic treatment that does not address the underlying cause of AF. On the other hand, the technical bottleneck of CA needs to be broken (e.g., additional ganglion ablation, rotor ablation, experience and data on cryoablation by ice balloon), as only in this manner can we fully understand the advantages and limitations of a rhythm control strategy.
This is the latest pooled analysis with a large sample size and enhanced statistical power. All the RCTs included in our analysis were of high methodological quality. Because recent meta-analyses have only assessed AF patients with HF (Asad et al., 2019; Chen et al., 2019; Ruzieh et al., 2019; Virk et al., 2019), we included studies that enrolled AF patients without HF and with AHF. In addition, a sensitivity analysis was conducted, and the results showed very good stability regarding our findings for all-cause mortality. Furthermore, we explored the source of the heterogeneity regarding hospitalization rates. Despite these advantages, our analysis still has some limitations that cannot be ignored. First, a number of small sample-size studies and studies with short follow-up periods were included in the pooled analysis. Second, due to the lack of individual patient data, a meta-regression could not be performed to assess the impact of confounding factors. Our findings were also likely affected by several other factors, including the technique used for ablation, the drugs used, the type or dose of anticoagulant used, the pattern of AF, and the follow-up duration, which may have led to the heterogeneity encountered in our analysis.
In this meta-analysis, the effect of AF ablation depended on the baseline level of LVEF in the HF patients. AF ablation appears to be of benefit to patients with a lesser degree of AHF and better LVEF by reducing mortality. Meanwhile, this mortality advantage was manifested in long-term follow-up. CA increased the risk for hospitalization when it was used as first-line therapy and decreased the risk when used as second-line therapy. CA reduced recurrence of atrial arrhythmia for different types of AF (paroxysmal or persistent AF) and CA-related complications were non-negligible. There was no convincing evidence for a reduction in long-term stroke risk after AF ablation, and additional high quality RCTs are needed to address that issue.
M-YJ and WH made the primary contribution in literature search, data collection, table drawing, and manuscript drafting/revisions. C-JX made main contribution in language editing, references sorting, and manuscript drafting/revisions. H-PF made the contribution to study conception, data interpretation and manuscript revisions. All authors contributed to the interpretation of results, revising themanuscript critically for important intellectual content, and all approved the final manuscript.
I would like to express my gratitude to all those who assisted me with writing this manuscript. I also thank the peer reviewers and editors for their comments and suggestions.
All authors declare having no conflict of interest.