International Journal of Cardiology 187 (2015) 12–16
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Impact of gender on outcomes after atrial fibrillation ablation Ajay Vallakati a, Madhu Reddy b, Abhishek Sharma c,⁎, Arun Kanmanthareddy b, Arun Sridhar b, Jayasree Pillarisetti b, Donita Atkins b, Bhavana Konda d, Sudha Bommana b, Luigi Di Biase e,f, Pasquale Santangeli g, Andrea Natale e,f, Dhanunjaya Lakkireddy b a
Metrohealth Medical Center, Case Western Reserve University, Cleveland, OH, United States Division of Cardiovascular Diseases, Cardiovascular Research Institute, Mid-America Cardiology, University of Kansas Hospital & Medical Center, Kansas City, KS, United States Division of Cardiovascular Medicine, State University of New York Downstate Medical Center, NY, United States d Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, United States e Texas Cardiac Arrhythmia Institute, Austin, TX, United States f Department of Biomedical Engineering, University of Texas, Austin, TX, United States g Cardiovascular Division, Hospital of the University of Pennsylvania, Philadelphia, PA, United States b c
a r t i c l e
i n f o
Article history: Received 20 March 2015 Accepted 21 March 2015 Available online 24 March 2015 Keywords: Atrial fibrillation Atrial fibrillation ablation Women Gender
Dear Editor, There is no clear data on the relative efficacy of catheter ablation in women when compared to men [1,2]. We conducted this metaanalysis to compare the long-term outcomes of catheter ablation in both genders. We searched PubMed Central and Embase databases using search terms “atrial fibrillation” and “ablation” for studies, which reported outcomes of AF ablation in adult AF patients (aged ≥ 18 years), regardless of duration or severity of symptoms. Search was conducted from the inception of the databases to May 30, 2014. We used the published strengthening Meta-analysis Of Observational Studies in Epidemiology checklist to select the studies for this review [3]. We excluded studies with ≤100 patients, b1 month blanking period, b12 months follow-up and duplicate publications. Studies were also excluded if ablation of the atrioventricular node was attempted for rate control. We assess the risk of bias of the included studies using the recommended checklist of STROBE [4]. ⁎ Corresponding author at: 125 96th Street Apt 5B, Brooklyn, NY 11209, United States. E-mail address: [email protected] (A. Sharma).
http://dx.doi.org/10.1016/j.ijcard.2015.03.341 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
Mix 2.0 Pro (Biostat XL) software was used to analyze the data [5]. Random-effects model (inverse variance weighting method) was applied to calculate the pooled odds ratio and 95% confidence intervals (CI). Heterogeneity between studies was assessed using the Cochrane's Q test and I2 statistic, which describe the percentage of total variation across studies that is a result of heterogeneity rather than chance. Heterogeneity was considered significant if the p value was less than 0.1. Publication bias was assessed by the funnel and regression test of Egger. The influence of individual studies, from which the metaanalysis estimates are derived, was examined by omitting one study at a time to see the extent to which inferences depend on a particular study (sensitivity analysis). Meta-regression analysis was performed to answer the specific question whether the type of AF can predict recurrence rates. Meta-regression analysis was performed with the Open Meta analyst software (http://www.cebm.brown.edu/open_ meta). Twenty studies (N = 9968, with 2112 females (21.2%)) were selected for final analysis (Fig. 1) [1,2,6–23]. Quality and baseline characteristics of the studies included in our analysis are summarized in Tables 1 and 2. The definition of AF recurrence varies among different studies included in our analysis. In eleven studies, AF recurrence was defined as the occurrence of atrial tachyarrhythmia (including AF) lasting for more than 30 s [7,9–15,18,19,21,23]. In four studies, the maintenance of sinus rhythm with antiarrhythmic drugs was defined as treatment success [1,6,18,19]. Pooled analysis of 20 studies revealed that women have a higher risk of AF recurrence (OR 1.20, 95% CI 1.04–1.38, p = 0.01) (Fig. 2A). There was low heterogeneity across the studies (p = 0.14, I2 = 25%) (Fig. 2B). Egger's regression test did not show any publication bias (p = 0.06). We explored the robustness of our findings by omitting one study at a time or outlier studies and switching our meta-analysis model from a random- to a fixed-effects analysis. There was no change in summary effect with fixed effects analysis. Exclusion of any single study did not change the composite effect size (Fig. 2C). To further test whether the type of AF determines the outcomes, we performed a meta-regression analysis including the % of non-paroxysmal AF as a covariate. A trend
A. Vallakati et al. / International Journal of Cardiology 187 (2015) 12–16
13
Identification
PRISMA 2009 Flow Diagram
Records identified through database searching (n =6519)
Additional records identified through other sources (n =14)
Eligibility
Screening
Records after duplicates removed (n =6519)
Records screened (n =6519)
Records excluded (n = 6436)
Full-text articles assessed for eligibility (n = 84)
Full-text articles excluded (n = 64) Sample size less than 100 (34) Blanking period less than 1 month (10) Follow up less than 12 months (9) Same population sample (11)
Included
Studies included in qualitative synthesis (n = 20)
Studies included in quantitative synthesis (meta-analysis) (n =20)
Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow sheet.
Table 1 Quality of included studies. Name of the study
State specific objectives of the study
Present key elements of study design
Gives the eligibility criteria
Clearly explains the characteristics of both sexes
Clearly explains recurrence rates
Explains how loss to follow-up was addressed
Score
Quality
Tang (2009) Montefusco (2010) Cai (2011) Hu (2012) Tokuda (2010) Park (2012) Den Ujil (2011) Blanche (2012) Forleo (2007) Patel (2010) Mulder (2012) Pokushalov (2012 Mohanty (2011) Themistoclakis (2008) Dixit (2008) Gertz (2011) Naruse (2011) Yagashita (2011) Shim (2011) Winkle (2011)
1 0 0 1 1 1 1 1 1 1 0 1 1 1 1 1 1 0 1 1
1 1 1 1 0 1 0 0 1 1 0 1 1 0 1 1 0 0 1 0
1 1 1 1 0 1 0 0 1 0 0 1 1 0 1 1 0 0 1 0
0 0 0 0 0 0 0 0 1 1 0 0 1 0 0 0 0 0 0 1
1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0
4 3 3 4 2 4 2 2 5 4 1 4 5 2 5 5 2 1 4 3
Intermediate Intermediate Intermediate Intermediate Low Intermediate Low Low High Intermediate Low Intermediate High Low High High Low Low Intermediate Intermediate
14
A. Vallakati et al. / International Journal of Cardiology 187 (2015) 12–16
Table 2 Characteristics of AF ablation studies with gender specific outcomes. Name of the study
(n)
Females Mean F/U duration
Patient population
Definition of arrhythmia recurrence
Blanking period
Atrial tachyarrhythmia (confirmed by Holter or ECG) 3 months after index catheter ablation Recurrences of AF or episodes of a new-onset common atrial flutter or a left atrial flutter/tachycardia lasting longer than 1 min that occurred after the second ablationa Episode lasting more than 30 s and confirmed on ECG or Holter, including atrial fibrillation and atrial tachyarrhythmia. Recurrence after 3 months defined as late recurrence Symptomatic recurrence or any occurrence of sustained atrial arrhythmia lasting N30 s No sustained atrial tachyarrhythmia lasting more than 30 sa
3 months
Any episode of AF or AT including atrial flutter of at least 30 s Recurrence of AF was defined as any recording of AF on ECG or an episode longer than 30 s on 24 h Holter registration. Documented AF (duration N 3 min) occurring after a blanking period after the ablation procedure
3 months 3 months
Tang (2009)
178
57
12 months
Only paroxysmal AF
Montefusco (2010)
240
39
30.3 +/− 9.2 months
Cai (2011)
186
63
24 months
Paroxysmal AF — 65.4% Non-paroxsymal AF — 34.6% Paroxysmal AF — 86.6% Non-paroxysmal AF — 13.4%
Hu (2012)
142
36
36 +/− 12 months
Only paroxysmal AF
Tokuda (2010)
224
37
37.4+/− 24.4
Only paroxysmal AF Only non-paroxsymal AF Non-paroxsymal AF — 22%
Park (2012) Den Ujil (2011)
140 213
20 48
months 18.7 +/− 7.6 months 13 +/− 3 months
Blanche (2012)
102
19
12 +/− 7 months
Forleo (2007)
221
71
22 +/− 11.8 months
Patel (2010)
3265 518
24 +/− 16 months
Mulder (2012) Pokushalov (2012)
120 29 613 157
24 months 12 months
Mohanty (2011)
568 414
12 months
Themistoclakis (2008) Dixit (2008)
1298 282 105
29
41 +/− 10 months 20 months
Gertz (2011)
190 138
12 months
Naruse (2011)
221
42
31.9 +/− 7.6 months
Yagashita (2011)
524
97
44 +/− 13 months
Shim (2011)
575 128
15 +/− 7 months
Winkle (2011)
843 235
28.8 +/− 18 months
a b
Paroxysmal AF — 59.8% Non-paroxysmal AF — 40.2% Paroxysmal AF — 59.7% Non-paroxysmal AF — 40.3% Paroxysmal AF — 53.4% Non-paroxysmal AF — 46.6% Only paroxysmal AF Paroxysmal AF — 82.9% Non-paroxysmal AF — 17.1% Paroxysmal AF — 25% Non-paroxysmal AF — 75% Paroxysmal AF — 54% Non-paroxysmal AF — 46% Paroxysmal AF — 73.3% Non-paroxysmal AF — 26.7% Paroxysmal AF — 50.5% Non-paroxysmal AF — 49.5% Paroxysmal AF — 58% Non-paroxysmal — 42% Paroxysmal AF — 69.1% Non-paroxysmal AF — 30.9% Paroxysmal AF — 65.7% Non-paroxysmal AF — 34.3% Paroxysmal AF — 32% Non-paroxysmal AF — 68%
2 months
3 months
3 months 3 months
2 months
Freedom from AF and left atrial tachycardia (LAT) with or without AAD therapya
1 month
Any episode of AF/atrial tachycardia without AADs that lasted longer than 1 minb
2 months
Absence of AF or any other LA arrhythmia lasting for N30 s AF N 0.5% during each monthly telemetry follow up
3 months 3 months
Freedom from atrial flutter, AF or atrial tachycardia of N30 sb
2 months
Recurrence of AF or episodes of new-onset left atrial flutter/ tachycardia lasting more than 1 min b90% reduction in AF burden on or off AADsb
3 months 1.5 months
Any documented electrocardiographic episode of atrial arrhythmia lasting N30 s
3 months
AF or any other atrial tachyarrhythmias lasting N30 s
3 months
Persistent or paroxysmal episode of AF/AT continuous for N30 s
3 months
Any episode of AF or atrial tachycardia of at least 30 s
3 months
AF, flutter, or tachycardia exceeding 30 s after blanking period off of antiarrhythmic drugsa,b
3 months
Recurrence rates after more than ablation. Recurrence rates calculated from success rates after AF ablation.
towards a significant association between % of non-paroxysmal AF in each study and recurrence rates was detected (β = − 0.018 log OR, 95% CI: 0.000–0.011, p = 0.059) (Fig. 2D). The main findings of our study are that 1) there is a 20% greater risk of AF recurrence in women compared to men, 2) this difference in recurrence rates can be partly attributed to the type of AF. Our study also demonstrated that the recurrence might be related to percent of non-paroxysmal AF patients. Overall prevalence of AF in females is similar to that in males [24]. However, in our pooled analysis, women constituted only 21.2% of the composite population. This finding is in line with earlier studies, which showed the underrepresentation of women in AF ablation studies. This phenomenon was also observed across various cardiovascular conditions. Women were less likely to be referred for catheter ablation, coronary revascularization and defibrillator implantation [25,26]. The underlying mechanisms for increased recurrence in women are not established. At the time of ablation, women with AF are older with a greater prevalence of structural heart disease [1]. Women are referred
later in the course of the disease and after treatment failure with more antiarrhythmic medications [1,2]. In addition, women have a higher prevalence of non-paroxysmal AF and have more non-PV triggers [2]. Women have a higher prevalence of isolated atrial amyloidosis, which can in turn increase the susceptibility to AF and increases the likelihood of recurrence of AF after ablation [27]. Recurrence rates after catheter ablation are higher in patients with a longer duration of AF as there is greater structural and electrical remodeling with the duration of AF [28]. Additionally, catheter ablation in women at an advanced stage in the disease process may partly explain the higher recurrence rates. Our pooled analysis is limited by a lack of data regarding the duration of AF in the included studies. Our study has several limitations. The definition of AF recurrence varies among different studies included in our analysis. Various studies used different methods and protocols for surveillance and outcome measurement. Furthermore, follow up duration was different across the studies. In this meta-analysis only studies with a follow up duration of at least 12 months were included. Recurrence of AF in the period
A. Vallakati et al. / International Journal of Cardiology 187 (2015) 12–16
15
Fig. 2. A: Forest plot showing gender specific outcomes after AF ablation. B: Funnel plot to assess publication bias for studies in which gender specific outcomes were reported. C: Exclusion sensitivity analysis with the omission of one study at a time. D: Odds of recurrence with percent of non-paroxysmal AF. The line indicates predicted odds of recurrence. Meta-regression analysis shows a trend towards increased recurrence with an increase in percent of non-paroxysmal AF (β = −0.018 log OR, 95% CI: 0.000–0.011, p = 0.059).
shortly following catheter ablation is common but it does not reflect long-term outcome; therefore these recurrences are censored. Conventionally a postablation period ranging from 1 to 3 months is considered as a blanking period [29,30]. Therefore only studies with a blanking period duration of at least 1 month were included for analysis. In conclusion, our study shows that women have an increased risk of recurrence after AF ablation. This difference in recurrence rates may be related to the type of AF. Further studies with detailed patient level data are needed to evaluate gender specific outcomes of ablation in different types of AF. Conflicts of interest DL has received a modest speaker's honorarium from Boehringer Ingelheim. Other co-authors have no conflict of interest relevant to the topic in discussion. References [1] G.B. Forleo, C. Tondo, L. De Luca, A. Dello Russo, M. Casella, V. De Sanctis, F. Clementi, et al., Gender-related differences in catheter ablation of atrial fibrillation, Europace 9 (8) (Aug 2007) 613–620. [2] D. Patel, P. Mohanty, L. Di Biase, J.E. Sanchez, M.H. Shaheen, J.D. Burkhardt, M. Bassouni, et al., Outcomes and complications of catheter ablation for atrial fibrillation in females, Heart Rhythm. 7 (2) (2010) 167–172. [3] D.F. Stroup, J.A. Berlin, S.C. Morton, I. Olkin, G.D. Williamson, D. Rennie, D. Moher, et al., Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group, JAMA 283 (2008–2012). [4] E. von Elm, D.G. Altman, M. Egger, S.J. Pocock, P.C. Gotzsche, J.P. Vandenbroucke, The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies, Ann. Intern. Med. 147 (2007) 573–577. [5] Bax L, MIX 2.0 — Professional software for meta-analysis in Excel. Version 2.0.1.4. BiostatXL hwm-a-m-ec, 2014.
[6] S. Themistoclakis, R.A. Schweikert, W.I. Saliba, A. Bonso, A. Rossillo, G. Bader, O. Wazni, et al., Clinical predictors and relationship between early and late atrial tachyarrhythmias after pulmonary vein antrum isolation, Heart Rhythm. 5 (5) (May 2008) 679–685. [7] R.B. Tang, J.Z. Dong, X.P. Liu, J.P. Kang, S.F. Ding, L. Wang, D.Y. Long, et al., Obstructive sleep apnoea risk profile and the risk of recurrence of atrial fibrillation after catheter ablation, Europace 11 (1) (Jan 2009) 100–105. [8] A. Montefusco, L. Biasco, A. Blandino, Y. Cristoforetti, M. Scaglione, D. Caponi, P. Di Donna, et al., Left atrial volume at MRI is the main determinant of outcome after pulmonary vein isolation plus linear lesion ablation for paroxysmal-persistent atrial fibrillation, J. Cardiovasc. Med. (Hagerstown) 11 (8) (Aug 2010) 593–598. [9] L. Cai, Y. Yin, Z. Ling, L. Su, Z. Liu, J. Wu, H. Du, et al., Predictors of late recurrence of atrial fibrillation after catheter ablation, Int. J. Cardiol. 164 (1) (Mar 20 2013) 82–87. [10] D.W. den Uijl, M. Gawrysiak, L.F. Tops, S.A. Trines, K. Zeppenfeld, M.J. Schalij, J.J. Bax, et al., Prognostic value of total atrial conduction time estimated with tissue Doppler imaging to predict the recurrence of atrial fibrillation after radiofrequency catheter ablation, Europace 13 (11) (Nov 2011) 1533–1540. [11] Z.M. Gertz, A. Raina, S.E. Mountantonakis, E.S. Zado, D.J. Callans, F.E. Marchlinski, M.G. Keane, et al., The impact of mitral regurgitation on patients undergoing catheter ablation of atrial fibrillation, Europace 13 (8) (Aug 2011) 1127–1132. [12] S. Mohanty, P. Mohanty, L. Di Biase, B. Rong, D. Burkhardt, J.G. Gallinghouse, R. Horton, et al., Baseline B-type natriuretic peptide: a gender-specific predictor of procedure-outcome in atrial fibrillation patients undergoing catheter ablation, J. Cardiovasc. Electrophysiol. 22 (8) (Aug 2011) 858–865. [13] Y. Naruse, H. Tada, Y. Sekiguchi, T. Machino, M. Ozawa, H. Yamasaki, M. Igarashi, et al., Concomitant chronic kidney disease increases the recurrence of atrial fibrillation after catheter ablation of atrial fibrillation: a mid-term follow-up, Heart Rhythm. 8 (3) (Mar 2011) 335–341. [14] M. Tokuda, T. Yamane, S. Matsuo, K. Ito, R. Narui, M. Hioki, S. Tanigawa, et al., Relationship between renal function and the risk of recurrent atrial fibrillation following catheter ablation, Heart 97 (2) (Jan 2011) 137–142. [15] A. Yagishita, Y. Takahashi, A. Takahashi, A. Fujii, S. Kusa, T. Fujino, T. Nozato, et al., Incidence of late thromboembolic events after catheter ablation of atrial fibrillation, Circ. J. 75 (10) (2011) 2343–2349. [16] C. Blanche, N. Tran, F. Rigamonti, H. Burri, M. Zimmermann, Value of P-wave signal averaging to predict atrial fibrillation recurrences after pulmonary vein isolation, Europace 15 (2) (Feb 2013) 198–204. [17] J.Q. Hu, J. Ma, F. Ouyang, Q. Yang, Z.L. Liao, Y. Hou, S. Zhang, Is selective ipsilateral PV isolation sufficient for focally triggered paroxysmal atrial fibrillation? Comparison of selective ipsilateral pulmonary vein isolation versus bilateral pulmonary vein isolation, J. Cardiovasc. Electrophysiol. 23 (2) (Feb 2012) 130–136.
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[18] A.A. Mulder, M.C. Wijffels, E.F. Wever, L.V. Boersma, Freedom from paroxysmal atrial fibrillation after successful pulmonary vein isolation with pulmonary vein ablation catheter-phased radiofrequency energy: 2-year follow-up and predictors of failure, Europace 14 (6) (Jun 2012) 818–825. [19] Y.M. Park, J.I. Choi, H.E. Lim, S.W. Park, Y.H. Kim, Is pursuit of termination of atrial fibrillation during catheter ablation of great value in patients with longstanding persistent atrial fibrillation? J. Cardiovasc. Electrophysiol. 23 (10) (Oct 2012) 1051–1058. [20] E. Pokushalov, A. Romanov, G. Corbucci, S. Bairamova, D. Losik, A. Turov, N. Shirokova, et al., Does atrial fibrillation burden measured by continuous monitoring during the blanking period predict the response to ablation at 12-month follow-up? Heart Rhythm. 9 (9) (Sep 2012) 1375–1379. [21] J. Shim, B. Joung, J.H. Park, J.S. Uhm, M.H. Lee, H.N. Pak, Long duration of radiofrequency energy delivery is an independent predictor of clinical recurrence after catheter ablation of atrial fibrillation: over 500 cases experience, Int. J. Cardiol. 167 (6) (Sep 10 2013) 2667–2672. [22] S. Dixit, E.P. Gerstenfeld, S.J. Ratcliffe, J.M. Cooper, A.M. Russo, S.E. Kimmel, D.J. Callans, et al., Single procedure efficacy of isolating all versus arrhythmogenic pulmonary veins on long-term control of atrial fibrillation: a prospective randomized study, Heart Rhythm. 5 (2) (Feb 2008) 174–181. [23] R.A. Winkle, R.H. Mead, G. Engel, R.A. Patrawala, Long-term results of atrial fibrillation ablation: the importance of all initial ablation failures undergoing a repeat ablation, Am. Heart J. 162 (1) (Jul 2011) 193–200.
[24] W.M. Feinberg, J.L. Blackshear, A. Laupacis, R. Kronmal, R.G. Hart, Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications, Arch. Intern. Med. 155 (5) (Mar 13 1995) 469–473. [25] S.S. Rathore, J.M. Foody, M.J. Radford, H.M. Krumholz, Sex differences in use of coronary revascularization in elderly patients after acute myocardial infarction: a tale of two therapies, Chest 124 (6) (Dec 2003) 2079–2086. [26] A.F. Hernandez, G.C. Fonarow, L. Liang, S.M. Al-Khatib, L.H. Curtis, K.A. LaBresh, C.W. Yancy, et al., Sex and racial differences in the use of implantable cardioverterdefibrillators among patients hospitalized with heart failure, JAMA 298 (13) (Oct 3 2007) 1525–1532. [27] C. Rocken, B. Peters, G. Juenemann, W. Saeger, H.U. Klein, C. Huth, A. Roessner, et al., Atrial amyloidosis: an arrhythmogenic substrate for persistent atrial fibrillation, Circulation 106 (16) (Oct 15 2002) 2091–2097. [28] Y. Takahashi, A. Takahashi, T. Kuwahara, T. Fujino, K. Okubo, S. Kusa, A. Fujii, et al., Clinical characteristics of patients with persistent atrial fibrillation successfully treated by left atrial ablation, Circ. Arrhythm. Electrophysiol. 3 (5) (Oct 2010) 465–471. [29] S. Joshi, A.D. Choi, G.S. Kamath, F. Raiszadeh, D. Marrero, A. Badheka, S. Mittal, et al., Prevalence, predictors, and prognosis of atrial fibrillation early after pulmonary vein isolation: findings from 3 months of continuous automatic ECG loop recordings, J. Cardiovasc. Electrophysiol. 20 (10) (Oct 2009) 1089–1094. [30] H. Oral, B.P. Knight, M. Ozaydin, H. Tada, A. Chugh, S. Hassan, C. Scharf, et al., Clinical significance of early recurrences of atrial fibrillation after pulmonary vein isolation, J. Am. Coll. Cardiol. 40 (1) (Jul 3 2002) 100–104.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Impact of gender on outcomes after atrial fibrillation ablation Ajay Vallakati a, Madhu Reddy b, Abhishek Sharma c,⁎, Arun Kanmanthareddy b, Arun Sridhar b, Jayasree Pillarisetti b, Donita Atkins b, Bhavana Konda d, Sudha Bommana b, Luigi Di Biase e,f, Pasquale Santangeli g, Andrea Natale e,f, Dhanunjaya Lakkireddy b a
Metrohealth Medical Center, Case Western Reserve University, Cleveland, OH, United States Division of Cardiovascular Diseases, Cardiovascular Research Institute, Mid-America Cardiology, University of Kansas Hospital & Medical Center, Kansas City, KS, United States Division of Cardiovascular Medicine, State University of New York Downstate Medical Center, NY, United States d Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, United States e Texas Cardiac Arrhythmia Institute, Austin, TX, United States f Department of Biomedical Engineering, University of Texas, Austin, TX, United States g Cardiovascular Division, Hospital of the University of Pennsylvania, Philadelphia, PA, United States b c
a r t i c l e
i n f o
Article history: Received 20 March 2015 Accepted 21 March 2015 Available online 24 March 2015 Keywords: Atrial fibrillation Atrial fibrillation ablation Women Gender
Dear Editor, There is no clear data on the relative efficacy of catheter ablation in women when compared to men [1,2]. We conducted this metaanalysis to compare the long-term outcomes of catheter ablation in both genders. We searched PubMed Central and Embase databases using search terms “atrial fibrillation” and “ablation” for studies, which reported outcomes of AF ablation in adult AF patients (aged ≥ 18 years), regardless of duration or severity of symptoms. Search was conducted from the inception of the databases to May 30, 2014. We used the published strengthening Meta-analysis Of Observational Studies in Epidemiology checklist to select the studies for this review [3]. We excluded studies with ≤100 patients, b1 month blanking period, b12 months follow-up and duplicate publications. Studies were also excluded if ablation of the atrioventricular node was attempted for rate control. We assess the risk of bias of the included studies using the recommended checklist of STROBE [4]. ⁎ Corresponding author at: 125 96th Street Apt 5B, Brooklyn, NY 11209, United States. E-mail address: [email protected] (A. Sharma).
http://dx.doi.org/10.1016/j.ijcard.2015.03.341 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
Mix 2.0 Pro (Biostat XL) software was used to analyze the data [5]. Random-effects model (inverse variance weighting method) was applied to calculate the pooled odds ratio and 95% confidence intervals (CI). Heterogeneity between studies was assessed using the Cochrane's Q test and I2 statistic, which describe the percentage of total variation across studies that is a result of heterogeneity rather than chance. Heterogeneity was considered significant if the p value was less than 0.1. Publication bias was assessed by the funnel and regression test of Egger. The influence of individual studies, from which the metaanalysis estimates are derived, was examined by omitting one study at a time to see the extent to which inferences depend on a particular study (sensitivity analysis). Meta-regression analysis was performed to answer the specific question whether the type of AF can predict recurrence rates. Meta-regression analysis was performed with the Open Meta analyst software (http://www.cebm.brown.edu/open_ meta). Twenty studies (N = 9968, with 2112 females (21.2%)) were selected for final analysis (Fig. 1) [1,2,6–23]. Quality and baseline characteristics of the studies included in our analysis are summarized in Tables 1 and 2. The definition of AF recurrence varies among different studies included in our analysis. In eleven studies, AF recurrence was defined as the occurrence of atrial tachyarrhythmia (including AF) lasting for more than 30 s [7,9–15,18,19,21,23]. In four studies, the maintenance of sinus rhythm with antiarrhythmic drugs was defined as treatment success [1,6,18,19]. Pooled analysis of 20 studies revealed that women have a higher risk of AF recurrence (OR 1.20, 95% CI 1.04–1.38, p = 0.01) (Fig. 2A). There was low heterogeneity across the studies (p = 0.14, I2 = 25%) (Fig. 2B). Egger's regression test did not show any publication bias (p = 0.06). We explored the robustness of our findings by omitting one study at a time or outlier studies and switching our meta-analysis model from a random- to a fixed-effects analysis. There was no change in summary effect with fixed effects analysis. Exclusion of any single study did not change the composite effect size (Fig. 2C). To further test whether the type of AF determines the outcomes, we performed a meta-regression analysis including the % of non-paroxysmal AF as a covariate. A trend
A. Vallakati et al. / International Journal of Cardiology 187 (2015) 12–16
13
Identification
PRISMA 2009 Flow Diagram
Records identified through database searching (n =6519)
Additional records identified through other sources (n =14)
Eligibility
Screening
Records after duplicates removed (n =6519)
Records screened (n =6519)
Records excluded (n = 6436)
Full-text articles assessed for eligibility (n = 84)
Full-text articles excluded (n = 64) Sample size less than 100 (34) Blanking period less than 1 month (10) Follow up less than 12 months (9) Same population sample (11)
Included
Studies included in qualitative synthesis (n = 20)
Studies included in quantitative synthesis (meta-analysis) (n =20)
Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow sheet.
Table 1 Quality of included studies. Name of the study
State specific objectives of the study
Present key elements of study design
Gives the eligibility criteria
Clearly explains the characteristics of both sexes
Clearly explains recurrence rates
Explains how loss to follow-up was addressed
Score
Quality
Tang (2009) Montefusco (2010) Cai (2011) Hu (2012) Tokuda (2010) Park (2012) Den Ujil (2011) Blanche (2012) Forleo (2007) Patel (2010) Mulder (2012) Pokushalov (2012 Mohanty (2011) Themistoclakis (2008) Dixit (2008) Gertz (2011) Naruse (2011) Yagashita (2011) Shim (2011) Winkle (2011)
1 0 0 1 1 1 1 1 1 1 0 1 1 1 1 1 1 0 1 1
1 1 1 1 0 1 0 0 1 1 0 1 1 0 1 1 0 0 1 0
1 1 1 1 0 1 0 0 1 0 0 1 1 0 1 1 0 0 1 0
0 0 0 0 0 0 0 0 1 1 0 0 1 0 0 0 0 0 0 1
1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0
4 3 3 4 2 4 2 2 5 4 1 4 5 2 5 5 2 1 4 3
Intermediate Intermediate Intermediate Intermediate Low Intermediate Low Low High Intermediate Low Intermediate High Low High High Low Low Intermediate Intermediate
14
A. Vallakati et al. / International Journal of Cardiology 187 (2015) 12–16
Table 2 Characteristics of AF ablation studies with gender specific outcomes. Name of the study
(n)
Females Mean F/U duration
Patient population
Definition of arrhythmia recurrence
Blanking period
Atrial tachyarrhythmia (confirmed by Holter or ECG) 3 months after index catheter ablation Recurrences of AF or episodes of a new-onset common atrial flutter or a left atrial flutter/tachycardia lasting longer than 1 min that occurred after the second ablationa Episode lasting more than 30 s and confirmed on ECG or Holter, including atrial fibrillation and atrial tachyarrhythmia. Recurrence after 3 months defined as late recurrence Symptomatic recurrence or any occurrence of sustained atrial arrhythmia lasting N30 s No sustained atrial tachyarrhythmia lasting more than 30 sa
3 months
Any episode of AF or AT including atrial flutter of at least 30 s Recurrence of AF was defined as any recording of AF on ECG or an episode longer than 30 s on 24 h Holter registration. Documented AF (duration N 3 min) occurring after a blanking period after the ablation procedure
3 months 3 months
Tang (2009)
178
57
12 months
Only paroxysmal AF
Montefusco (2010)
240
39
30.3 +/− 9.2 months
Cai (2011)
186
63
24 months
Paroxysmal AF — 65.4% Non-paroxsymal AF — 34.6% Paroxysmal AF — 86.6% Non-paroxysmal AF — 13.4%
Hu (2012)
142
36
36 +/− 12 months
Only paroxysmal AF
Tokuda (2010)
224
37
37.4+/− 24.4
Only paroxysmal AF Only non-paroxsymal AF Non-paroxsymal AF — 22%
Park (2012) Den Ujil (2011)
140 213
20 48
months 18.7 +/− 7.6 months 13 +/− 3 months
Blanche (2012)
102
19
12 +/− 7 months
Forleo (2007)
221
71
22 +/− 11.8 months
Patel (2010)
3265 518
24 +/− 16 months
Mulder (2012) Pokushalov (2012)
120 29 613 157
24 months 12 months
Mohanty (2011)
568 414
12 months
Themistoclakis (2008) Dixit (2008)
1298 282 105
29
41 +/− 10 months 20 months
Gertz (2011)
190 138
12 months
Naruse (2011)
221
42
31.9 +/− 7.6 months
Yagashita (2011)
524
97
44 +/− 13 months
Shim (2011)
575 128
15 +/− 7 months
Winkle (2011)
843 235
28.8 +/− 18 months
a b
Paroxysmal AF — 59.8% Non-paroxysmal AF — 40.2% Paroxysmal AF — 59.7% Non-paroxysmal AF — 40.3% Paroxysmal AF — 53.4% Non-paroxysmal AF — 46.6% Only paroxysmal AF Paroxysmal AF — 82.9% Non-paroxysmal AF — 17.1% Paroxysmal AF — 25% Non-paroxysmal AF — 75% Paroxysmal AF — 54% Non-paroxysmal AF — 46% Paroxysmal AF — 73.3% Non-paroxysmal AF — 26.7% Paroxysmal AF — 50.5% Non-paroxysmal AF — 49.5% Paroxysmal AF — 58% Non-paroxysmal — 42% Paroxysmal AF — 69.1% Non-paroxysmal AF — 30.9% Paroxysmal AF — 65.7% Non-paroxysmal AF — 34.3% Paroxysmal AF — 32% Non-paroxysmal AF — 68%
2 months
3 months
3 months 3 months
2 months
Freedom from AF and left atrial tachycardia (LAT) with or without AAD therapya
1 month
Any episode of AF/atrial tachycardia without AADs that lasted longer than 1 minb
2 months
Absence of AF or any other LA arrhythmia lasting for N30 s AF N 0.5% during each monthly telemetry follow up
3 months 3 months
Freedom from atrial flutter, AF or atrial tachycardia of N30 sb
2 months
Recurrence of AF or episodes of new-onset left atrial flutter/ tachycardia lasting more than 1 min b90% reduction in AF burden on or off AADsb
3 months 1.5 months
Any documented electrocardiographic episode of atrial arrhythmia lasting N30 s
3 months
AF or any other atrial tachyarrhythmias lasting N30 s
3 months
Persistent or paroxysmal episode of AF/AT continuous for N30 s
3 months
Any episode of AF or atrial tachycardia of at least 30 s
3 months
AF, flutter, or tachycardia exceeding 30 s after blanking period off of antiarrhythmic drugsa,b
3 months
Recurrence rates after more than ablation. Recurrence rates calculated from success rates after AF ablation.
towards a significant association between % of non-paroxysmal AF in each study and recurrence rates was detected (β = − 0.018 log OR, 95% CI: 0.000–0.011, p = 0.059) (Fig. 2D). The main findings of our study are that 1) there is a 20% greater risk of AF recurrence in women compared to men, 2) this difference in recurrence rates can be partly attributed to the type of AF. Our study also demonstrated that the recurrence might be related to percent of non-paroxysmal AF patients. Overall prevalence of AF in females is similar to that in males [24]. However, in our pooled analysis, women constituted only 21.2% of the composite population. This finding is in line with earlier studies, which showed the underrepresentation of women in AF ablation studies. This phenomenon was also observed across various cardiovascular conditions. Women were less likely to be referred for catheter ablation, coronary revascularization and defibrillator implantation [25,26]. The underlying mechanisms for increased recurrence in women are not established. At the time of ablation, women with AF are older with a greater prevalence of structural heart disease [1]. Women are referred
later in the course of the disease and after treatment failure with more antiarrhythmic medications [1,2]. In addition, women have a higher prevalence of non-paroxysmal AF and have more non-PV triggers [2]. Women have a higher prevalence of isolated atrial amyloidosis, which can in turn increase the susceptibility to AF and increases the likelihood of recurrence of AF after ablation [27]. Recurrence rates after catheter ablation are higher in patients with a longer duration of AF as there is greater structural and electrical remodeling with the duration of AF [28]. Additionally, catheter ablation in women at an advanced stage in the disease process may partly explain the higher recurrence rates. Our pooled analysis is limited by a lack of data regarding the duration of AF in the included studies. Our study has several limitations. The definition of AF recurrence varies among different studies included in our analysis. Various studies used different methods and protocols for surveillance and outcome measurement. Furthermore, follow up duration was different across the studies. In this meta-analysis only studies with a follow up duration of at least 12 months were included. Recurrence of AF in the period
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Fig. 2. A: Forest plot showing gender specific outcomes after AF ablation. B: Funnel plot to assess publication bias for studies in which gender specific outcomes were reported. C: Exclusion sensitivity analysis with the omission of one study at a time. D: Odds of recurrence with percent of non-paroxysmal AF. The line indicates predicted odds of recurrence. Meta-regression analysis shows a trend towards increased recurrence with an increase in percent of non-paroxysmal AF (β = −0.018 log OR, 95% CI: 0.000–0.011, p = 0.059).
shortly following catheter ablation is common but it does not reflect long-term outcome; therefore these recurrences are censored. Conventionally a postablation period ranging from 1 to 3 months is considered as a blanking period [29,30]. Therefore only studies with a blanking period duration of at least 1 month were included for analysis. In conclusion, our study shows that women have an increased risk of recurrence after AF ablation. This difference in recurrence rates may be related to the type of AF. Further studies with detailed patient level data are needed to evaluate gender specific outcomes of ablation in different types of AF. Conflicts of interest DL has received a modest speaker's honorarium from Boehringer Ingelheim. Other co-authors have no conflict of interest relevant to the topic in discussion. References [1] G.B. Forleo, C. Tondo, L. De Luca, A. Dello Russo, M. Casella, V. De Sanctis, F. Clementi, et al., Gender-related differences in catheter ablation of atrial fibrillation, Europace 9 (8) (Aug 2007) 613–620. [2] D. Patel, P. Mohanty, L. Di Biase, J.E. Sanchez, M.H. Shaheen, J.D. Burkhardt, M. Bassouni, et al., Outcomes and complications of catheter ablation for atrial fibrillation in females, Heart Rhythm. 7 (2) (2010) 167–172. [3] D.F. Stroup, J.A. Berlin, S.C. Morton, I. Olkin, G.D. Williamson, D. Rennie, D. Moher, et al., Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group, JAMA 283 (2008–2012). [4] E. von Elm, D.G. Altman, M. Egger, S.J. Pocock, P.C. Gotzsche, J.P. Vandenbroucke, The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies, Ann. Intern. Med. 147 (2007) 573–577. [5] Bax L, MIX 2.0 — Professional software for meta-analysis in Excel. Version 2.0.1.4. BiostatXL hwm-a-m-ec, 2014.
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