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Gender differences in management and clinical outcomes of atrial fibrillation patients
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Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc
Original article
Gender differences in management and clinical outcomes of atrial fibrillation patients Natasha A. Kassim (MD), Andrew D. Althouse (PhD), Dingxin Qin (MD), George Leef (MD), Samir Saba (MD, FACC, FHRS)* Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 10 December 2015 Received in revised form 22 February 2016 Accepted 25 February 2016 Available online xxx
Background: Prior research has identified gender differences in the epidemiology and clinical management of atrial fibrillation (AF). The primary aim of this study is to systematically analyze a cohort of AF men and women and evaluate their baseline demographics, treatment, and clinical outcomes by gender. Methods: We examined the records of 5976 (42% women) consecutive AF patients who were prescribed at least one anti-arrhythmic drug between 2006 and 2013. From this cohort, 4311 (72%) patients had anticoagulation data available and were included in the final analysis. Time to clinical events was assessed using survival analysis and adjusted for covariates using Cox regression. Results: Compared to men, women were older (73 years vs. 67 years, p < 0.001), had higher CHADS2 scores (1.9 vs. 1.5, p < 0.001), and fewer cardiac comorbidities. Compared to men, women were more often prescribed sotalol and less often dofetilide (p < 0.001). Women were also less likely to be anticoagulated (76.8% vs. 82.5%, p < 0.001). Over a mean follow-up of 40 months, women were more likely to die (HR 1.21, p = 0.037) or to have an ischemic stroke (HR 1.35, p = 0.058). Women also had higher rates of atrioventricular-nodal ablation (adjusted HR 2.11, p < 0.001) and pacemaker implantation (adjusted HR 1.69, p < 0.001) procedures, but lower rates of electrical cardioversions, AF ablations, and maze surgeries. Conclusions: There are significant gender differences in baseline demographics and clinical outcomes of AF patients. Women have higher mortality and ischemic strokes and are less often prescribed anticoagulation therapy despite higher CHADS2 scores. These data have important clinical implications. ß 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Atrial fibrillation Gender Anticoagulation Stroke Mortality
Introduction Atrial fibrillation (AF) is the most common sustained arrhythmia in the USA and developed nations, with a predicted 2.5-fold increase in prevalence in the USA by 2050 [1,2]. There is a greater incidence of AF in men at all ages; however, the prevalence of AF in women 75 years and older is nearly twice that of men secondary to an average longer lifespan in women [3]. Although gender differences in the epidemiology, clinical management, and outcomes of AF have been described [4–8], leading to the development of the CHA2DS2-VASc scoring system which accounts for female gender as an independent risk predictor for stroke [9–11], no
* Corresponding author at: Electrophysiology Section, 200 Lothrop Street, UPMC Presbyterian, Suite B 535, Pittsburgh, PA 15213, USA. Tel.: +1 412 802 3372; fax: +1 412 647 7979. E-mail address: [email protected] (S. Saba).
studies have comprehensively evaluated the gender differences in baseline demographics, treatment strategies, and clinical outcomes of AF patients in the USA. This study was therefore designed to systematically analyze a cohort of patients with AF and examine by gender their baseline demographics, their treatment strategy focusing primarily on anticoagulation, and their clinical outcomes including mortality and stroke. Methods The original dataset consisted of 5976 consecutive patients diagnosed with paroxysmal (58%) or persistent (42%) AF, who were prescribed one or more anti-arrhythmic drug with the goal of achieving rhythm control, at the University of Pittsburgh Medical Center hospitals and clinics from January 2006 to November 2013. The cohort was created via examination of the electronic medical record for encounters classified under the diagnosis of AF (427.31) by the International Classification of Diseases, Ninth
http://dx.doi.org/10.1016/j.jjcc.2016.02.022 0914-5087/ß 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kassim NA, et al. Gender differences in management and clinical outcomes of atrial fibrillation patients. J Cardiol (2016), http://dx.doi.org/10.1016/j.jjcc.2016.02.022
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Revision, Clinical Modification (ICD-9-CM) [12]. Associated pharmacologic databases were searched for a prescription of Vaughan Williams Class IA, IC, or Class III anti-arrhythmic drug [13]. The cohort was prospectively followed starting from the date of first anti-arrhythmic drug prescription (after January 1st, 2006) through May 30th, 2014 with review of outpatient and inpatient medical records. Patients who died or were lost to follow-up during this period were censored at their date of death or last encounter. Demographic data were obtained from the clinical records and information on comorbidities was generated from ICD-9-CM codes in the clinical database [14]. For risk stratification, the CHADS2 score, CHA2DS2-VASc score, and Charlson comorbidity index were also calculated for each patient [15–17]. Information on anticoagulation therapy was obtained from the pharmacologic database search, which generated results for 4311 (72.1%) patients, which constituted the final cohort included for analysis in this study. Clinical outcomes included mortality, ischemic stroke, AF recurrence, admission for AF, admission for congestive heart failure, and need for AF-related procedures, including directcurrent electrical cardioversion, AF ablation, permanent pacemaker implantation, atrioventricular nodal ablation, and surgical maze procedures. AF recurrence was defined by recurrence of AF on surface electrocardiogram, electrocardiographic monitoring, or recurrence of AF symptoms. Causes for admission to the hospital were adjudicated by review of admission notes and were subclassified into AF, congestive heart failure, and other cardiovascular reasons. Patient death and occurrence of ischemic stroke were identified by review of the institutional electronic medical record. The University of Pittsburgh Institutional Review Board approved this study. Baseline characteristics are presented as means standard deviation for continuous variables and as occurrence rates for dichotomous variables and were compared using the Student’s t and chi-square tests, respectively. Clinical outcomes were reported as incidence rate (number of events per 100 person-years) and compared by gender using the log-rank test. Univariate and multivariate Cox proportional-hazard models were constructed to estimate the hazard ratio (HR) of females (vs. males) for each clinical outcome. In the multivariate models, the HR of females was adjusted for cofactors that were significantly different by gender. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). Results The study cohort comprised 4311 patients with AF, of whom 1774 patients (41.3%) were women. Mean follow-up time was 38.6 months for women and 42.0 months for men (p = 0.01). Baseline demographic information, clinical data, and medications are summarized in Table 1. Compared to men, women were older (72.5 years vs. 66.8 years, p < 0.001), had higher CHADS2 (1.9 vs. 1.5, p < 0.001) and CHA2DS2-VASc (3.7 vs. 2.2, p < 0.001) scores, and higher rates of hypertension and prior strokes, but lower rates of coronary artery disease, heart failure, prior percutaneous coronary interventions, and prior coronary artery bypass grafting. The most common anti-arrhythmic medication prescribed for both men and women was amiodarone (42.8% and 41.1%, respectively). Women had lower rates of dofetilide use (11.6% compared to 20.5%, p < 0.001) and higher rates of sotalol use (36.1% compared to 30.9%, p < 0.001). Rates of anticoagulation were significantly lower in women compared to men (76.8% compared to 82.5%, p < 0.001). Rates of warfarin use were similar between men and women (71.7% and 69.1%, respectively, p = 0.066) but the use of the direct oral anticoagulants (DOACs) was significantly lower in women (19.9% compared to 24.6%, p < 0.001). Rates of anticoagulation by age and gender are shown in Fig. 1. As demonstrated in that figure, there was no difference in
Table 1 Demographic and clinical characteristics of patient population by gender (Full Study Cohort). Male
Female Number of patients Age Race White Black Asian Other/not specified Atrial flutter CHADS2 score CHA2DS2-VASc score Charlson index Coronary artery disease Hypertension Diabetes mellitus Heart failure Chronic kidney disease Chronic pulmonary disease Depression Follow-up time (months) Prior medical events Prior stroke Prior cardioversion Prior atrioventricular nodal ablation Prior AF ablation Prior pacemaker implantation Prior maze surgery Prior defibrillator implantation Prior coronary intervention Prior coronary bypass surgery Anti-arrhythmic drugs Amiodarone Dronedarone Dofetilide Flecainide or propafenone Sotalol Anticoagulation Anticoagulation (any) Warfarin Enoxaparin Direct anticoagulation agents
1774 72.5 11.7
2537 66.8 12.4
1677 (94.6%) 2394 (94.3%) 72 (4.1%) 90 (3.5%) 4 (0.2%) 10 (0.4%) 21 (1.1%) 43 (1.8%) 106 (6.0%) 199 (7.8%) 1.9 1.3 1.5 1.3 3.7 1.6 2.2 1.6 1.5 1.8 1.4 1.6 468 (26.4%) 921 (36.3%) 1195 (67.4%) 1525 (60.1%) 346 (19.5%) 497 (19.6%) 351 (19.8%) 587 (23.1%) 122 (6.9%) 177 (7.0%) 176 (9.9%) 241 (9.5%) 279 (15.7%) 191 (7.5%) 38.6 (0.4–101.1) 42.0 (0.3–101.4)
p-Value
<0.001 0.131
0.019 <0.001 <0.001 0.006 <0.001 <0.001 0.944 0.009 0.899 0.645 <0.001 0.012
19 (1.1%) 2 (0.1%) 14 (0.8%)
9 (0.4%) 3 (0.1%) 31 (1.2%)
0.004 0.958 0.169
53 (3.0%) 171 (9.6%)
129 (5.1%) 189 (7.4%)
<0.001 0.011
27 (1.5%) 66 (3.7%)
45 (1.8%) 260 (10.2%)
0.526 <0.001
113 (6.4%) 140 (7.9%)
232 (9.1%) 386 (15.2%)
<0.001 <0.001
730 253 206 405 641
(41.1%) (14.3%) (11.6%) (22.8%) (36.1%)
1087 314 520 538 785
(42.8%) (12.4%) (20.5%) (21.2%) (30.9%)
0.267 0.072 <0.001 0.204 <0.001
1362 1226 83 353
(76.8%) (69.1%) (4.7%) (19.9%)
2092 1819 119 625
(82.5%) (71.7%) (4.7%) (24.6%)
<0.001 0.066 0.985 <0.001
AF, atrial fibrillation.
the rate of anticoagulation by gender in patients aged <75 years, whereas in patients aged 75 years, women were significantly less likely than men to be on anticoagulation. Table 2 summarizes the clinical outcomes of patients by gender. During follow-up, women had higher all-cause mortality rates (3.18 in women vs. 2.64 in men per 100 person-years, p = 0.037, Fig. 2A) and a strong trend toward a higher incidence of stroke (1.17 in women vs. 0.87 in men per 100 person-years, p = 0.057, Fig. 2B). There were no significant differences in AF recurrence or AF hospitalization rates between the two genders. Women had higher rates of atrioventricular nodal ablation and permanent pacemaker implantation than men, but had lower rates of electrical cardioversion, AF ablation, and maze surgery. The HRs by gender for various clinical outcomes by unadjusted and adjusted Cox proportional-hazard models are displayed in Table 3. In the multivariate models, the differences in the risk of death and stroke seen in univariate analyses were no longer significant (HR = 0.94, p = 0.50 for death; HR = 1.16, p = 0.37 for stroke). However, the increased rates of atrioventricular nodal ablation and permanent pacemaker implantation in women were still present in the multivariate models (HR of 2.11 and 1.69,
Please cite this article in press as: Kassim NA, et al. Gender differences in management and clinical outcomes of atrial fibrillation patients. J Cardiol (2016), http://dx.doi.org/10.1016/j.jjcc.2016.02.022
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Fig. 1. Bar graph showing the rate of anticoagulation for men and women <75 years and 75 years of age.
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respectively, p < 0.001). Conversely, women still had lower rates of electrical cardioversion and AF ablation procedures after adjusting for unbalanced covariates (HR of 0.74 and 0.64, respectively, p < 0.001). Fig. 3A and B shows the mortality and stroke outcomes in our cohort by gender and anticoagulation status. A significant interaction was noted between gender and anticoagulation status for mortality (p < 0.001), with women not on anticoagulation having a significantly higher mortality rate compared to women on anticoagulation and all men regardless of anticoagulation status. Women on anticoagulation therapy were significantly younger than women not on anticoagulation (72.0 years vs. 73.9 years, p = 0.004), but had no difference in CHADS2 score or medical comorbidities. When adjusting for age, this interaction between gender and anticoagulation on mortality disappears (p = 0.235) but not when adjusting for other baseline characteristics, suggesting that age is the primary driving force in this relationship. Refer to Supplementary Table 1 for full demographics and clinical characteristics of these gender cohorts. The study cohort was divided into three stroke risk groups according to the CHADS2 score as follows: 0 considered low risk, 1 considered intermediate risk, and 2 or greater considered high risk for stroke. Within each risk group, there was no observed difference in mortality by gender. There was a slightly higher risk
Table 2 Outcome incidence per 100 person-years by gender and age. Female
Overall # patients/person-years Death Stroke AF recurrence AF hospitalization Heart failure hospitalization Cardioversion Atrioventricular nodal ablation AF ablation Pacemaker implantation Maze surgery
6471 Events/100 PY
2537 Total # events
9731 Events/100 PY
206 76 883 472 159 220 148 131 201 29
3.18 1.17 13.65 7.29 2.46 3.40 2.29 2.02 3.11 0.45
257 85 1331 696 195 470 112 385 161 71
2.64 0.87 13.68 7.15 2.00 4.83 1.15 3.96 1.65 0.73
Age <75 years # patients/person-years Death Stroke AF recurrence AF hospitalization Heart failure hospitalization Cardioversion Atrioventricular nodal ablation AF ablation Pacemaker implantation Maze surgery
Female
Death Stroke AF recurrence AF hospitalization Heart failure hospitalization Cardioversion Atrioventricular nodal ablation AF ablation Pacemaker implantation Maze surgery
Male
918 Total # events
3370 Events/100 PY
1800 Total # events
7014 Events/100 PY
52 29 516 293 60 147 83 126 96 26
1.54 0.86 15.31 8.69 1.78 4.36 2.46 3.74 2.85 0.77
110 53 1035 559 101 400 78 373 88 64
1.57 0.76 14.76 7.97 1.44 5.70 1.11 5.32 1.25 0.91
856 Total # events
3101 Events/100 PY
737 Total # events
2717 Events/100 PY
154 47 367 179 99 73 65 5 105 3
4.97 1.52 11.83 5.77 3.19 2.35 2.10 0.16 3.39 0.10
147 32 296 137 94 70 34 12 73 7
5.41 1.18 10.89 5.04 3.46 2.58 1.25 0.44 2.69 0.26
Age 75 years # patients/person-years
Male
1774 Total # events
Female
Male
AF, atrial fibrillation; PY, person-years.
Please cite this article in press as: Kassim NA, et al. Gender differences in management and clinical outcomes of atrial fibrillation patients. J Cardiol (2016), http://dx.doi.org/10.1016/j.jjcc.2016.02.022
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Fig. 2. Kaplan–Meier survival curves demonstrating freedom from death (panel A) and stroke (panel B) by gender.
Fig. 3. Kaplan–Meier survival curves demonstrating freedom from death (panel A) and stroke (panel B) by gender and anticoagulation status.
of stroke in women vs. men in the intermediate risk group, but there were no significant differences in the low-risk group or the high-risk group. Men were more often anticoagulated than women in all three groups, although this difference was only statistically significant in the high-risk group. Refer to Supplemental Table 2 for full data on anticoagulation rates by risk of stroke cohort.
outcomes in a cohort of patients with AF in the USA. Our results show that women with AF are older, have less comorbid heart disease including coronary disease and heart failure but higher CHADS2 and CHA2DS2-VASc scores. Women also have higher rates of ischemic stroke and death compared to men. However, this increased risk for death and ischemic stroke in women is accounted for by a higher CHADS2 score driven primarily by older age. Despite their higher risk of stroke and higher CHADS2 scores, women were less likely to be on anticoagulation, which may have contributed to increased mortality. Although other studies have documented the lower anticoagulation rates and higher rates of
Discussion In this study, we report important gender differences in baseline demographics, anticoagulation management, and clinical Table 3 Outcomes hazard ratios for women vs. men (Full Study Cohort).
Adjustedb
Unadjusted Hazard ratio Death Stroke AF recurrence AF hospitalization CHF hospitalization Cardioversion AVN ablation AF ablation Pacemaker Maze surgery
1.21 1.35 0.93 0.99 1.23 0.66 2.05 0.47 1.89 0.61
95% CI (1.01, (0.98, (0.85, (0.88, (0.99, (0.56, (1.60, (0.30, (1.53, (0.39,
1.46) 1.84) 1.02) 1.11) 1.51) 0.78) 2.63) 0.57) 2.33) 0.94)
p-Value
Hazard ratio
0.037 0.058 0.115 0.884 0.056 <0.001 <0.001 <0.001 <0.001 0.025
0.94 1.16 1.02 1.09 1.20 0.74 2.11 0.64 1.69 0.81
95% CI (0.77, (0.83, (0.93, (0.90, (0.96, (0.62, (1.62, (0.52, (1.35, (0.51,
1.13) 1.61) 1.11) 1.23) 1.50) 0.87) 2.73) 0.79) 2.11) 1.26)
p-Value 0.497 0.366 0.699 0.164 0.108 <0.001 <0.001 <0.001 <0.001 0.350
AF, atrial fibrillation; AVN, atrioventricular nodal; CHF, congestive heart failure. a Estimates calculated using Cox proportional-hazards models. b Adjusted for age, hypertension, coronary artery disease, congestive heart failure, depression, and any prior cardiac event/procedure (stroke, cardioversion, ablation, pacemaker, maze, defibrillator, percutaneous coronary intervention, or coronary artery bypass graft).
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stroke in women with AF in the USA and Canada [11,18,19], no studies have been able to identify the exact cause of this disparity. It has been speculated that older women are more often at risk of falling, which is why they are less likely to be prescribed anticoagulation therapy. In addition, some studies have demonstrated that physicians, in general, tend to overestimate the risk of falls and major bleeding in older patients therefore abstaining from prescribing anticoagulation therapy [20]. In our cohort, women were less likely to be prescribed a DOAC. Recent studies demonstrate that women may have improved outcomes with DOAC compared to warfarin therapy. Subgroup analyses of the ARISTOTLE trial demonstrated a lower risk of mortality and less clinically relevant bleeding in women compared to men on apixaban [21]. Furthermore, a recent meta-analysis that included five randomized control trials with gender data on warfarin and on DOACs found improved reduction in rate of ischemic stroke and reduced major bleeding with DOACs compared to warfarin therapy in women [22]. Our findings of women in our cohort being less likely to be on anticoagulation and even then being less likely to be prescribed a DOAC have important clinical implications as they could be contributing to gender disparities in outcomes. Furthermore, women who are admitted with embolic stroke have more severe neurological deficits on admission and worse functional outcome at discharge [23], further emphasizing the importance of understanding gender disparities in AF management. It is of interest that the rates of anticoagulation were higher in men (79%) and women (73%) in the lowest CHADS2 score risk category in our cohort compared to other reports [24]. This may reflect a more aggressive strategy of anticoagulation by physicians at our institution or other high-risk features in our patient population not captured by the present analysis. The EORP-AF Pilot registry study had previously documented that women are less likely to be on a rhythm control strategy for AF, despite the fact that women in that study were more symptomatic and had poorer quality of life [4]. In our study, although all patients were initially prescribed an anti-arrhythmic medication, the rate of conversion to a rate control strategy with pacemaker implantation and atrioventricular nodal ablation was significantly higher in women compared to men. In fact, procedural pursuit of rhythm management in men was evident through the higher rates of electrical cardioversion, AF ablations, and maze surgeries compared to women. A recent study looking at new onset AF in >500,000 Medicare beneficiaries found similar disparities in the treatment of AF by gender with men having higher rates of AF ablations [18]. It is not clear why women are less likely to receive AF ablation since current guidelines recommend AF ablation as a viable first-line treatment option for patients with paroxysmal AF regardless of gender [25]. It has been found that women often receive less aggressive care with lower procedural interventions for other cardiac diseases such as coronary disease and heart failure [26–30]. It is possible that gender differences in preference regarding medical care may play a role in this significant difference [31]. In addition, physician biases toward older patients may have contributed to the less aggressive attempts at restoring sinus rhythm in our cohort of women. This study is subject to some limitations inherent to observational studies. Selection and referral bias cannot be excluded. Our study was performed at a single center and therefore our results may not be reproducible at other institutions with different patient populations and clinical settings. It is worth noting, however, that the University of Pittsburgh Medical Center comprises a network of more than 25 hospitals, ranging from rural and suburban community hospitals to tertiary care urban centers, as well as many outpatient clinics encompassing a large geographical area in western Pennsylvania. With a cohort of more than 4000 AF patients derived from all these sites, this study has a wide
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representation of varying practice settings and patient demographics. Furthermore, all patients in our cohort were patients with AF who were initially prescribed an anti-arrhythmic medication. This may not accurately represent the demographics and management of the general AF population. Misclassification of baseline comorbidities and accidental omissions of clinical outcomes is possible. Reviewers evaluated the medical records prospectively for all patients in this study, looking for the clinical events of AF recurrence, hospitalizations, ischemic stroke, death, and procedures. It is possible that not all events were captured if patients did not continue to seek care at our institution. Lastly, women and men with AF are inherently different cohorts with multiple differences in baseline demographics and comorbidities. We felt that because this represents real-life practice in caring for patients, adjusting for too many potential confounders or doing a propensity-matched analysis would not be appropriate nor provide useful clinical information. However, it is possible that some of the associations we report are due to unmeasured confounders due to the inherent differences between men and women with AF. Funding This research received no grant from any funding agency in the public, commercial or not-for-profit sectors. Disclosures Samir Saba: Research support from St. Jude Medical, Boston Scientific, and Medtronic Inc. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jjcc.2016.02.022. References [1] Wolf PA, Benjamin EJ, Belanger AJ, Kannel WB, Levy D, D’Agostino RB. Secular trends in the prevalence of atrial fibrillation: the Framingham Study. Am Heart J 1984;131:790–5. [2] Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. J Am Med Assoc 2001;285:2370–5. [3] Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med 1995;155:469–73. [4] Lip GY, Laroche C, Boriani G, Cimaglia P, Dan GA, Santini M, Kalarus Z, Rasmussen LH, Popescu MI, Tica O, Hellum CF, Mortensen B, Tavazzi L, Maggioni AP. Sex-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe: a report from the Euro Observational Research Programme Pilot survey on Atrial Fibrillation. Europace 2015;17:24–31. [5] Dagres N, Nieuwlaat R, Vardas PE, Andresen D, Le´vy S, Cobbe S, Kremastinos DT, Breithardt G, Cokkinos DV, Crijns HJ. Gender-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe: a report from the Euro Heart Survey on Atrial Fibrillation. J Am Coll Cardiol 2007;49:572–7. [6] Wagstaff AJ, Overvad TF, Lip GYH, Lane DA. Is female sex a risk factor for stroke and thromboembolism in patients with atrial fibrillation? A systematic review and meta-analysis. Q J Med 2014;107:955–67. [7] Hart RG, Pearce LA, McBride R, Rothbar RM, Asinger RW. Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I–III clinical trials. The Stroke Prevention in Atrial Fibrillation (SPAF) investigators. Stroke 1999;30:1223–9. [8] Wang TJ, Massaro JM, Levy D, Vasan RS, Wolf PA, D’Agostino RV, Larson MG, Kannel WB, Benjamin EJ. A risk score for predicting stroke or death in individuals with new-onset atrial fibrillation in the community: the Framingham Heart Study. J Am Med Assoc 2003;290:1049–56. [9] Lip GYH, Nieuwlaat R, Pisters R, Lane DA, Crijins HG. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on Atrial Fibrillation. Chest 2010;137:263–72.
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Contents lists available at ScienceDirect
Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc
Original article
Gender differences in management and clinical outcomes of atrial fibrillation patients Natasha A. Kassim (MD), Andrew D. Althouse (PhD), Dingxin Qin (MD), George Leef (MD), Samir Saba (MD, FACC, FHRS)* Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 10 December 2015 Received in revised form 22 February 2016 Accepted 25 February 2016 Available online xxx
Background: Prior research has identified gender differences in the epidemiology and clinical management of atrial fibrillation (AF). The primary aim of this study is to systematically analyze a cohort of AF men and women and evaluate their baseline demographics, treatment, and clinical outcomes by gender. Methods: We examined the records of 5976 (42% women) consecutive AF patients who were prescribed at least one anti-arrhythmic drug between 2006 and 2013. From this cohort, 4311 (72%) patients had anticoagulation data available and were included in the final analysis. Time to clinical events was assessed using survival analysis and adjusted for covariates using Cox regression. Results: Compared to men, women were older (73 years vs. 67 years, p < 0.001), had higher CHADS2 scores (1.9 vs. 1.5, p < 0.001), and fewer cardiac comorbidities. Compared to men, women were more often prescribed sotalol and less often dofetilide (p < 0.001). Women were also less likely to be anticoagulated (76.8% vs. 82.5%, p < 0.001). Over a mean follow-up of 40 months, women were more likely to die (HR 1.21, p = 0.037) or to have an ischemic stroke (HR 1.35, p = 0.058). Women also had higher rates of atrioventricular-nodal ablation (adjusted HR 2.11, p < 0.001) and pacemaker implantation (adjusted HR 1.69, p < 0.001) procedures, but lower rates of electrical cardioversions, AF ablations, and maze surgeries. Conclusions: There are significant gender differences in baseline demographics and clinical outcomes of AF patients. Women have higher mortality and ischemic strokes and are less often prescribed anticoagulation therapy despite higher CHADS2 scores. These data have important clinical implications. ß 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Atrial fibrillation Gender Anticoagulation Stroke Mortality
Introduction Atrial fibrillation (AF) is the most common sustained arrhythmia in the USA and developed nations, with a predicted 2.5-fold increase in prevalence in the USA by 2050 [1,2]. There is a greater incidence of AF in men at all ages; however, the prevalence of AF in women 75 years and older is nearly twice that of men secondary to an average longer lifespan in women [3]. Although gender differences in the epidemiology, clinical management, and outcomes of AF have been described [4–8], leading to the development of the CHA2DS2-VASc scoring system which accounts for female gender as an independent risk predictor for stroke [9–11], no
* Corresponding author at: Electrophysiology Section, 200 Lothrop Street, UPMC Presbyterian, Suite B 535, Pittsburgh, PA 15213, USA. Tel.: +1 412 802 3372; fax: +1 412 647 7979. E-mail address: [email protected] (S. Saba).
studies have comprehensively evaluated the gender differences in baseline demographics, treatment strategies, and clinical outcomes of AF patients in the USA. This study was therefore designed to systematically analyze a cohort of patients with AF and examine by gender their baseline demographics, their treatment strategy focusing primarily on anticoagulation, and their clinical outcomes including mortality and stroke. Methods The original dataset consisted of 5976 consecutive patients diagnosed with paroxysmal (58%) or persistent (42%) AF, who were prescribed one or more anti-arrhythmic drug with the goal of achieving rhythm control, at the University of Pittsburgh Medical Center hospitals and clinics from January 2006 to November 2013. The cohort was created via examination of the electronic medical record for encounters classified under the diagnosis of AF (427.31) by the International Classification of Diseases, Ninth
http://dx.doi.org/10.1016/j.jjcc.2016.02.022 0914-5087/ß 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kassim NA, et al. Gender differences in management and clinical outcomes of atrial fibrillation patients. J Cardiol (2016), http://dx.doi.org/10.1016/j.jjcc.2016.02.022
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Revision, Clinical Modification (ICD-9-CM) [12]. Associated pharmacologic databases were searched for a prescription of Vaughan Williams Class IA, IC, or Class III anti-arrhythmic drug [13]. The cohort was prospectively followed starting from the date of first anti-arrhythmic drug prescription (after January 1st, 2006) through May 30th, 2014 with review of outpatient and inpatient medical records. Patients who died or were lost to follow-up during this period were censored at their date of death or last encounter. Demographic data were obtained from the clinical records and information on comorbidities was generated from ICD-9-CM codes in the clinical database [14]. For risk stratification, the CHADS2 score, CHA2DS2-VASc score, and Charlson comorbidity index were also calculated for each patient [15–17]. Information on anticoagulation therapy was obtained from the pharmacologic database search, which generated results for 4311 (72.1%) patients, which constituted the final cohort included for analysis in this study. Clinical outcomes included mortality, ischemic stroke, AF recurrence, admission for AF, admission for congestive heart failure, and need for AF-related procedures, including directcurrent electrical cardioversion, AF ablation, permanent pacemaker implantation, atrioventricular nodal ablation, and surgical maze procedures. AF recurrence was defined by recurrence of AF on surface electrocardiogram, electrocardiographic monitoring, or recurrence of AF symptoms. Causes for admission to the hospital were adjudicated by review of admission notes and were subclassified into AF, congestive heart failure, and other cardiovascular reasons. Patient death and occurrence of ischemic stroke were identified by review of the institutional electronic medical record. The University of Pittsburgh Institutional Review Board approved this study. Baseline characteristics are presented as means standard deviation for continuous variables and as occurrence rates for dichotomous variables and were compared using the Student’s t and chi-square tests, respectively. Clinical outcomes were reported as incidence rate (number of events per 100 person-years) and compared by gender using the log-rank test. Univariate and multivariate Cox proportional-hazard models were constructed to estimate the hazard ratio (HR) of females (vs. males) for each clinical outcome. In the multivariate models, the HR of females was adjusted for cofactors that were significantly different by gender. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). Results The study cohort comprised 4311 patients with AF, of whom 1774 patients (41.3%) were women. Mean follow-up time was 38.6 months for women and 42.0 months for men (p = 0.01). Baseline demographic information, clinical data, and medications are summarized in Table 1. Compared to men, women were older (72.5 years vs. 66.8 years, p < 0.001), had higher CHADS2 (1.9 vs. 1.5, p < 0.001) and CHA2DS2-VASc (3.7 vs. 2.2, p < 0.001) scores, and higher rates of hypertension and prior strokes, but lower rates of coronary artery disease, heart failure, prior percutaneous coronary interventions, and prior coronary artery bypass grafting. The most common anti-arrhythmic medication prescribed for both men and women was amiodarone (42.8% and 41.1%, respectively). Women had lower rates of dofetilide use (11.6% compared to 20.5%, p < 0.001) and higher rates of sotalol use (36.1% compared to 30.9%, p < 0.001). Rates of anticoagulation were significantly lower in women compared to men (76.8% compared to 82.5%, p < 0.001). Rates of warfarin use were similar between men and women (71.7% and 69.1%, respectively, p = 0.066) but the use of the direct oral anticoagulants (DOACs) was significantly lower in women (19.9% compared to 24.6%, p < 0.001). Rates of anticoagulation by age and gender are shown in Fig. 1. As demonstrated in that figure, there was no difference in
Table 1 Demographic and clinical characteristics of patient population by gender (Full Study Cohort). Male
Female Number of patients Age Race White Black Asian Other/not specified Atrial flutter CHADS2 score CHA2DS2-VASc score Charlson index Coronary artery disease Hypertension Diabetes mellitus Heart failure Chronic kidney disease Chronic pulmonary disease Depression Follow-up time (months) Prior medical events Prior stroke Prior cardioversion Prior atrioventricular nodal ablation Prior AF ablation Prior pacemaker implantation Prior maze surgery Prior defibrillator implantation Prior coronary intervention Prior coronary bypass surgery Anti-arrhythmic drugs Amiodarone Dronedarone Dofetilide Flecainide or propafenone Sotalol Anticoagulation Anticoagulation (any) Warfarin Enoxaparin Direct anticoagulation agents
1774 72.5 11.7
2537 66.8 12.4
1677 (94.6%) 2394 (94.3%) 72 (4.1%) 90 (3.5%) 4 (0.2%) 10 (0.4%) 21 (1.1%) 43 (1.8%) 106 (6.0%) 199 (7.8%) 1.9 1.3 1.5 1.3 3.7 1.6 2.2 1.6 1.5 1.8 1.4 1.6 468 (26.4%) 921 (36.3%) 1195 (67.4%) 1525 (60.1%) 346 (19.5%) 497 (19.6%) 351 (19.8%) 587 (23.1%) 122 (6.9%) 177 (7.0%) 176 (9.9%) 241 (9.5%) 279 (15.7%) 191 (7.5%) 38.6 (0.4–101.1) 42.0 (0.3–101.4)
p-Value
<0.001 0.131
0.019 <0.001 <0.001 0.006 <0.001 <0.001 0.944 0.009 0.899 0.645 <0.001 0.012
19 (1.1%) 2 (0.1%) 14 (0.8%)
9 (0.4%) 3 (0.1%) 31 (1.2%)
0.004 0.958 0.169
53 (3.0%) 171 (9.6%)
129 (5.1%) 189 (7.4%)
<0.001 0.011
27 (1.5%) 66 (3.7%)
45 (1.8%) 260 (10.2%)
0.526 <0.001
113 (6.4%) 140 (7.9%)
232 (9.1%) 386 (15.2%)
<0.001 <0.001
730 253 206 405 641
(41.1%) (14.3%) (11.6%) (22.8%) (36.1%)
1087 314 520 538 785
(42.8%) (12.4%) (20.5%) (21.2%) (30.9%)
0.267 0.072 <0.001 0.204 <0.001
1362 1226 83 353
(76.8%) (69.1%) (4.7%) (19.9%)
2092 1819 119 625
(82.5%) (71.7%) (4.7%) (24.6%)
<0.001 0.066 0.985 <0.001
AF, atrial fibrillation.
the rate of anticoagulation by gender in patients aged <75 years, whereas in patients aged 75 years, women were significantly less likely than men to be on anticoagulation. Table 2 summarizes the clinical outcomes of patients by gender. During follow-up, women had higher all-cause mortality rates (3.18 in women vs. 2.64 in men per 100 person-years, p = 0.037, Fig. 2A) and a strong trend toward a higher incidence of stroke (1.17 in women vs. 0.87 in men per 100 person-years, p = 0.057, Fig. 2B). There were no significant differences in AF recurrence or AF hospitalization rates between the two genders. Women had higher rates of atrioventricular nodal ablation and permanent pacemaker implantation than men, but had lower rates of electrical cardioversion, AF ablation, and maze surgery. The HRs by gender for various clinical outcomes by unadjusted and adjusted Cox proportional-hazard models are displayed in Table 3. In the multivariate models, the differences in the risk of death and stroke seen in univariate analyses were no longer significant (HR = 0.94, p = 0.50 for death; HR = 1.16, p = 0.37 for stroke). However, the increased rates of atrioventricular nodal ablation and permanent pacemaker implantation in women were still present in the multivariate models (HR of 2.11 and 1.69,
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Fig. 1. Bar graph showing the rate of anticoagulation for men and women <75 years and 75 years of age.
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respectively, p < 0.001). Conversely, women still had lower rates of electrical cardioversion and AF ablation procedures after adjusting for unbalanced covariates (HR of 0.74 and 0.64, respectively, p < 0.001). Fig. 3A and B shows the mortality and stroke outcomes in our cohort by gender and anticoagulation status. A significant interaction was noted between gender and anticoagulation status for mortality (p < 0.001), with women not on anticoagulation having a significantly higher mortality rate compared to women on anticoagulation and all men regardless of anticoagulation status. Women on anticoagulation therapy were significantly younger than women not on anticoagulation (72.0 years vs. 73.9 years, p = 0.004), but had no difference in CHADS2 score or medical comorbidities. When adjusting for age, this interaction between gender and anticoagulation on mortality disappears (p = 0.235) but not when adjusting for other baseline characteristics, suggesting that age is the primary driving force in this relationship. Refer to Supplementary Table 1 for full demographics and clinical characteristics of these gender cohorts. The study cohort was divided into three stroke risk groups according to the CHADS2 score as follows: 0 considered low risk, 1 considered intermediate risk, and 2 or greater considered high risk for stroke. Within each risk group, there was no observed difference in mortality by gender. There was a slightly higher risk
Table 2 Outcome incidence per 100 person-years by gender and age. Female
Overall # patients/person-years Death Stroke AF recurrence AF hospitalization Heart failure hospitalization Cardioversion Atrioventricular nodal ablation AF ablation Pacemaker implantation Maze surgery
6471 Events/100 PY
2537 Total # events
9731 Events/100 PY
206 76 883 472 159 220 148 131 201 29
3.18 1.17 13.65 7.29 2.46 3.40 2.29 2.02 3.11 0.45
257 85 1331 696 195 470 112 385 161 71
2.64 0.87 13.68 7.15 2.00 4.83 1.15 3.96 1.65 0.73
Age <75 years # patients/person-years Death Stroke AF recurrence AF hospitalization Heart failure hospitalization Cardioversion Atrioventricular nodal ablation AF ablation Pacemaker implantation Maze surgery
Female
Death Stroke AF recurrence AF hospitalization Heart failure hospitalization Cardioversion Atrioventricular nodal ablation AF ablation Pacemaker implantation Maze surgery
Male
918 Total # events
3370 Events/100 PY
1800 Total # events
7014 Events/100 PY
52 29 516 293 60 147 83 126 96 26
1.54 0.86 15.31 8.69 1.78 4.36 2.46 3.74 2.85 0.77
110 53 1035 559 101 400 78 373 88 64
1.57 0.76 14.76 7.97 1.44 5.70 1.11 5.32 1.25 0.91
856 Total # events
3101 Events/100 PY
737 Total # events
2717 Events/100 PY
154 47 367 179 99 73 65 5 105 3
4.97 1.52 11.83 5.77 3.19 2.35 2.10 0.16 3.39 0.10
147 32 296 137 94 70 34 12 73 7
5.41 1.18 10.89 5.04 3.46 2.58 1.25 0.44 2.69 0.26
Age 75 years # patients/person-years
Male
1774 Total # events
Female
Male
AF, atrial fibrillation; PY, person-years.
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Fig. 2. Kaplan–Meier survival curves demonstrating freedom from death (panel A) and stroke (panel B) by gender.
Fig. 3. Kaplan–Meier survival curves demonstrating freedom from death (panel A) and stroke (panel B) by gender and anticoagulation status.
of stroke in women vs. men in the intermediate risk group, but there were no significant differences in the low-risk group or the high-risk group. Men were more often anticoagulated than women in all three groups, although this difference was only statistically significant in the high-risk group. Refer to Supplemental Table 2 for full data on anticoagulation rates by risk of stroke cohort.
outcomes in a cohort of patients with AF in the USA. Our results show that women with AF are older, have less comorbid heart disease including coronary disease and heart failure but higher CHADS2 and CHA2DS2-VASc scores. Women also have higher rates of ischemic stroke and death compared to men. However, this increased risk for death and ischemic stroke in women is accounted for by a higher CHADS2 score driven primarily by older age. Despite their higher risk of stroke and higher CHADS2 scores, women were less likely to be on anticoagulation, which may have contributed to increased mortality. Although other studies have documented the lower anticoagulation rates and higher rates of
Discussion In this study, we report important gender differences in baseline demographics, anticoagulation management, and clinical Table 3 Outcomes hazard ratios for women vs. men (Full Study Cohort).
Adjustedb
Unadjusted Hazard ratio Death Stroke AF recurrence AF hospitalization CHF hospitalization Cardioversion AVN ablation AF ablation Pacemaker Maze surgery
1.21 1.35 0.93 0.99 1.23 0.66 2.05 0.47 1.89 0.61
95% CI (1.01, (0.98, (0.85, (0.88, (0.99, (0.56, (1.60, (0.30, (1.53, (0.39,
1.46) 1.84) 1.02) 1.11) 1.51) 0.78) 2.63) 0.57) 2.33) 0.94)
p-Value
Hazard ratio
0.037 0.058 0.115 0.884 0.056 <0.001 <0.001 <0.001 <0.001 0.025
0.94 1.16 1.02 1.09 1.20 0.74 2.11 0.64 1.69 0.81
95% CI (0.77, (0.83, (0.93, (0.90, (0.96, (0.62, (1.62, (0.52, (1.35, (0.51,
1.13) 1.61) 1.11) 1.23) 1.50) 0.87) 2.73) 0.79) 2.11) 1.26)
p-Value 0.497 0.366 0.699 0.164 0.108 <0.001 <0.001 <0.001 <0.001 0.350
AF, atrial fibrillation; AVN, atrioventricular nodal; CHF, congestive heart failure. a Estimates calculated using Cox proportional-hazards models. b Adjusted for age, hypertension, coronary artery disease, congestive heart failure, depression, and any prior cardiac event/procedure (stroke, cardioversion, ablation, pacemaker, maze, defibrillator, percutaneous coronary intervention, or coronary artery bypass graft).
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stroke in women with AF in the USA and Canada [11,18,19], no studies have been able to identify the exact cause of this disparity. It has been speculated that older women are more often at risk of falling, which is why they are less likely to be prescribed anticoagulation therapy. In addition, some studies have demonstrated that physicians, in general, tend to overestimate the risk of falls and major bleeding in older patients therefore abstaining from prescribing anticoagulation therapy [20]. In our cohort, women were less likely to be prescribed a DOAC. Recent studies demonstrate that women may have improved outcomes with DOAC compared to warfarin therapy. Subgroup analyses of the ARISTOTLE trial demonstrated a lower risk of mortality and less clinically relevant bleeding in women compared to men on apixaban [21]. Furthermore, a recent meta-analysis that included five randomized control trials with gender data on warfarin and on DOACs found improved reduction in rate of ischemic stroke and reduced major bleeding with DOACs compared to warfarin therapy in women [22]. Our findings of women in our cohort being less likely to be on anticoagulation and even then being less likely to be prescribed a DOAC have important clinical implications as they could be contributing to gender disparities in outcomes. Furthermore, women who are admitted with embolic stroke have more severe neurological deficits on admission and worse functional outcome at discharge [23], further emphasizing the importance of understanding gender disparities in AF management. It is of interest that the rates of anticoagulation were higher in men (79%) and women (73%) in the lowest CHADS2 score risk category in our cohort compared to other reports [24]. This may reflect a more aggressive strategy of anticoagulation by physicians at our institution or other high-risk features in our patient population not captured by the present analysis. The EORP-AF Pilot registry study had previously documented that women are less likely to be on a rhythm control strategy for AF, despite the fact that women in that study were more symptomatic and had poorer quality of life [4]. In our study, although all patients were initially prescribed an anti-arrhythmic medication, the rate of conversion to a rate control strategy with pacemaker implantation and atrioventricular nodal ablation was significantly higher in women compared to men. In fact, procedural pursuit of rhythm management in men was evident through the higher rates of electrical cardioversion, AF ablations, and maze surgeries compared to women. A recent study looking at new onset AF in >500,000 Medicare beneficiaries found similar disparities in the treatment of AF by gender with men having higher rates of AF ablations [18]. It is not clear why women are less likely to receive AF ablation since current guidelines recommend AF ablation as a viable first-line treatment option for patients with paroxysmal AF regardless of gender [25]. It has been found that women often receive less aggressive care with lower procedural interventions for other cardiac diseases such as coronary disease and heart failure [26–30]. It is possible that gender differences in preference regarding medical care may play a role in this significant difference [31]. In addition, physician biases toward older patients may have contributed to the less aggressive attempts at restoring sinus rhythm in our cohort of women. This study is subject to some limitations inherent to observational studies. Selection and referral bias cannot be excluded. Our study was performed at a single center and therefore our results may not be reproducible at other institutions with different patient populations and clinical settings. It is worth noting, however, that the University of Pittsburgh Medical Center comprises a network of more than 25 hospitals, ranging from rural and suburban community hospitals to tertiary care urban centers, as well as many outpatient clinics encompassing a large geographical area in western Pennsylvania. With a cohort of more than 4000 AF patients derived from all these sites, this study has a wide
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representation of varying practice settings and patient demographics. Furthermore, all patients in our cohort were patients with AF who were initially prescribed an anti-arrhythmic medication. This may not accurately represent the demographics and management of the general AF population. Misclassification of baseline comorbidities and accidental omissions of clinical outcomes is possible. Reviewers evaluated the medical records prospectively for all patients in this study, looking for the clinical events of AF recurrence, hospitalizations, ischemic stroke, death, and procedures. It is possible that not all events were captured if patients did not continue to seek care at our institution. Lastly, women and men with AF are inherently different cohorts with multiple differences in baseline demographics and comorbidities. We felt that because this represents real-life practice in caring for patients, adjusting for too many potential confounders or doing a propensity-matched analysis would not be appropriate nor provide useful clinical information. However, it is possible that some of the associations we report are due to unmeasured confounders due to the inherent differences between men and women with AF. Funding This research received no grant from any funding agency in the public, commercial or not-for-profit sectors. Disclosures Samir Saba: Research support from St. Jude Medical, Boston Scientific, and Medtronic Inc. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jjcc.2016.02.022. References [1] Wolf PA, Benjamin EJ, Belanger AJ, Kannel WB, Levy D, D’Agostino RB. Secular trends in the prevalence of atrial fibrillation: the Framingham Study. Am Heart J 1984;131:790–5. [2] Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. J Am Med Assoc 2001;285:2370–5. [3] Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med 1995;155:469–73. [4] Lip GY, Laroche C, Boriani G, Cimaglia P, Dan GA, Santini M, Kalarus Z, Rasmussen LH, Popescu MI, Tica O, Hellum CF, Mortensen B, Tavazzi L, Maggioni AP. Sex-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe: a report from the Euro Observational Research Programme Pilot survey on Atrial Fibrillation. Europace 2015;17:24–31. [5] Dagres N, Nieuwlaat R, Vardas PE, Andresen D, Le´vy S, Cobbe S, Kremastinos DT, Breithardt G, Cokkinos DV, Crijns HJ. Gender-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe: a report from the Euro Heart Survey on Atrial Fibrillation. J Am Coll Cardiol 2007;49:572–7. [6] Wagstaff AJ, Overvad TF, Lip GYH, Lane DA. Is female sex a risk factor for stroke and thromboembolism in patients with atrial fibrillation? A systematic review and meta-analysis. Q J Med 2014;107:955–67. [7] Hart RG, Pearce LA, McBride R, Rothbar RM, Asinger RW. Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I–III clinical trials. The Stroke Prevention in Atrial Fibrillation (SPAF) investigators. Stroke 1999;30:1223–9. [8] Wang TJ, Massaro JM, Levy D, Vasan RS, Wolf PA, D’Agostino RV, Larson MG, Kannel WB, Benjamin EJ. A risk score for predicting stroke or death in individuals with new-onset atrial fibrillation in the community: the Framingham Heart Study. J Am Med Assoc 2003;290:1049–56. [9] Lip GYH, Nieuwlaat R, Pisters R, Lane DA, Crijins HG. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on Atrial Fibrillation. Chest 2010;137:263–72.
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Please cite this article in press as: Kassim NA, et al. Gender differences in management and clinical outcomes of atrial fibrillation patients. J Cardiol (2016), http://dx.doi.org/10.1016/j.jjcc.2016.02.022