Incidence and risk factors for new-onset atrial ... - Kidney International

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Incidence and risk factors for new-onset atrial fibrillation among patients with end-stage renal disease undergoing renal replacement therapy Jo-Nan Liao1,2,7, Tze-Fan Chao1,2,7, Chia-Jen Liu3,4, Kang-Ling Wang1,2, Su-Jung Chen4,5, Yenn-Jiang Lin1,2, Shih-Lin Chang1,2, Li-Wei Lo1,2, Yu-Feng Hu1,2, Ta-Chuan Tuan1,2, Fa-Po Chung1,2, Tzeng-Ji Chen6 and Shih-Ann Chen1,2 1

Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; 2Institute of Clinical Medicine and Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan; 3Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; 4Institute of Public Health and School of Medicine, National Yang-Ming University, Taipei, Taiwan; 5Division of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan and 6Department of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

Atrial fibrillation (AF) is prevalent in end-stage renal disease (ESRD) patients and negatively impacts patient outcomes. We explored the incidence and risk factors for new-onset AF among patients with ESRD undergoing renal replacement therapy, without a prior history of AF, retrieved from Taiwan’s National Health Insurance Research Database (NHIRD). For each of 134,901 patients with ESRD, one age- and gender-matched control and one similarly matched patient with chronic kidney disease (CKD), a total of 404,703 patients, were selected from the NHIRD. The study endpoint was the occurrence of new-onset AF and patients were followed an average of 5.1 years. The incidence rates of AF were 12.1, 7.3, and 5.0 per 1000 person-years for ESRD, CKD, and control patients, respectively. Among patients with ESRD, age, hypertension, heart failure, coronary artery disease, peripheral arterial occlusive disease, and chronic obstructive pulmonary disease were significant risk factors for new-onset AF. Thus, patients with ESRD had a significantly higher risk of new-onset AF. The presence of multiple risk factors was associated with a higher possibility of AF occurrence. Kidney International (2015) 87, 1209–1215; doi:10.1038/ki.2014.393; published online 14 January 2015 KEYWORDS: atrial fibrillation; chronic kidney disease; end-stage renal disease; risk factors

Correspondence: Shih-Ann Chen, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei, Taiwan. E-mail: [email protected] 7

These authors contributed equally to this work.

Received 21 January 2014; revised 18 October 2014; accepted 23 October 2014; published online 14 January 2015 Kidney International (2015) 87, 1209–1215

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical practice,1 and carries a fivefold risk of stroke, a threefold incidence of heart failure (HF), and an increased mortality.2 It not only leads to multiple comorbidities and a poor prognosis,3,4 but also substantially increases health-care expenditures.5 AF is usually divided into valvular or non-valvular types according to the guidelines of the European Society of Cardiology2 and the American College of Cardiology/American Heart Association.1 The term valvular AF represents AF that is related to significant mitral valve disease, including mitral stenosis or regurgitation, or prosthetic mitral valves.2 Various classification systems have been developed for non-valvular AF, but none have been able to account for all types of AF.1 The most widely used classification divides AF into paroxysmal and non-paroxysmal, including persistent or permanent types, based on the duration and chronicity of each episode. With regard to AF-related thromboembolic events, the type of AF has not been taken into account in present practical guidelines, because previous studies have demonstrated that the risk of thromboembolism was similar for paroxysmal and non-paroxysmal AF.6,7 Risk factors for AF have been investigated and renal dysfunction has been documented to be significantly associated with new-onset AF and AF-related stroke.8–13 For patients with end-stage renal disease (ESRD) undergoing renal replacement therapy, both the risk of AF and AF-related systemic thromboembolism were substantially increased.9,14–16 However, the incidence of new-onset AF in patients with ESRD and the risk factors associated with this have been less well delineated. Although Korantzopoulos et al.17 reported the incidence of AF in ESRD patients to be 10–148 per 1000 person-years from literature review, most of the studies in this meta-analysis were either small in sample size or primarily derived from a limited population, such as the elderly or those with symptomatic AF requiring treatment. 1209


J-N Liao et al.: New-onset AF in ESRD undergoing dialysis

Table 1 | Baseline characteristics of subjects with different renal function status Matched controls (n ¼ 134,901)

CKD (n ¼ 134,901)

ESRD (n ¼ 134,901)

Age, years Age X65 years, n (%) Age X75 years, n (%) Male gender, n (%)

61.7±14.3 62,583 (46.4%) 27,163 (20.1%) 66,828 (49.5%)

61.7±14.3 62,670 (46.5%) 27,136 (20.1%) 66,828 (49.5%)

61.7±14.3 62,583 (46.4%) 27,163 (20.1%) 66,828 (49.5%)

Underlying diseases, n (%) HTN Diabetes mellitus HF CAD PAOD CVA COPD Cancer Liver cirrhosis

48,476 20,598 7703 9247 446 16,776 21,306 8320 2061

95,354 (70.7%)b 99,553 (73.8%)b 23,128 (17.1%)b 17,312 (12.8%)b 1792 (1.3%)b 33,248 (24.6%)b 30,018 (22.3%)b 12,918 (9.6%)b 5269 (3.9%)b

114,167 (84.6%)b,c 76,081 (56.4%)b,c 45,921 (34.0%)b,c 22,524 (16.7%)b,c 3057 (2.3%)b,c 36,572 (27.1%)b,c 28,032 (20.8%)b,c 16,321 (12.1%)b,c 8115 (6.0%)b,c

Variables

(35.9%) (15.3%) (5.7%) (6.9%) (0.3%) (12.4%) (15.8%) (6.2%) (1.5%)

P-valuea 0.963 0.928 0.989 1.000 o0.001 o0.001 o0.001 o0.001 o0.001 o0.001 o0.001 o0.001 o0.001

Abbreviations: ANOVA, analysis of variance; CAD, coronary artery disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVA, cerebral vascular accident; ESRD, end-stage renal disease; HF, heart failure; HTN, hypertension; PAOD, peripheral arterial occlusive disease. a Comparisons of the continuous variables were performed using one-way ANOVA. Nominal variables were compared by w2-test or Fisher’s exact test. b Po0.05, in comparison with matched controls group. c Po0.05 for ESRD group in comparison with CKD group.

The goal of the present study was to explore the incidence of AF in patients with ESRD undergoing renal replacement therapy, using a nationwide database with a large sample size and minimal selection bias. We also aimed to identify important risk factors of new-onset AF in this special population. Furthermore, the incidence of AF in patients with chronic kidney disease (CKD), not requiring renal replacement therapy, and non-CKD subjects was also analyzed and compared with that of ESRD patients.

Table 2 | Incidence (per 1000 person-years) of new-onset AF in patients with different renal function status Number Number of events of patients Person-years Incidencea

Renal function Matched controls Chronic kidney disease ESRD

4314 5056 6375

134,901 134,901 134,901

858,499 689,948 527,389

5.0 7.3 12.1

Abbreviations: AF, atrial fibrillation; ESRD, end-stage renal disease. a Number of new-onset atrial fibrillations per 1000 person-years of follow-up.

RESULTS Baseline characteristics of study subjects

The baseline characteristics of the study cohort are shown in Table 1. The mean patient age was 61.7±14.3 years, and 49.5% were male in all three groups. Compared with controls, ESRD and CKD patients had a higher percentage of hypertension (HTN), diabetes mellitus, HF, coronary artery disease (CAD), peripheral arterial occlusive disease (PAOD), cerebral vascular accident, chronic obstructive pulmonary disease (COPD), cancer, and liver cirrhosis. In addition, these comorbidities were more prevalent in patients with ESRD than in CKD patients.

18

1210

Cumulative event rate (%)

14 P < 0.0001

12 10 8 6 4 2

New-onset AF among ESRD, CKD, and control patients

During the mean follow-up of 5.1±4.1 years, 15,745 patients had new-onset AF (6,375 in the ESRD group, 5,056 in the CKD group, and 4,314 in controls). Among these 15,745 patients experiencing new-onset AF, there were only 168 (1.1%) patients who had newly diagnosed hyperthyroidism, significant mitral valve diseases, or had undergone major cardiac surgery (coronary artery bypass graft, valve replacement, or valve repair surgeries) within 3 months before the onset of AF. The incidence rates of AF were 12.1/1000 personyears for ESRD, 7.3/1000 person-years for patients with CKD, and 5.0/1000 person-years for controls (Table 2). Figure 1

Matched controls Chronic kidney disease (CKD) End-stage renal disease (ESRD)

16

0 0

3

Number at risk

9 6 Years of follow-up

12

15

Controls

134,901

96,594

64,899

38,657

17,944

3523

CKD

134,901

82,556

49,587

25,797

9355

1040

ESRD

134,901

63,970

33,319

15,883

6137

984

Figure 1 | Cumulative event rate of new-onset atrial fibrillation (AF) in end-stage renal disease (ESRD), chronic kidney disease (CKD), and control patients. Log-rank test demonstrated a significantly different risk of new-onset AF among the three groups. As the cumulative incidence curve demonstrates, the ESRD group had a higher incidence rate than the CKD and control group. Kidney International (2015) 87, 1209–1215



Table 3 | Hazard ratio of new-onset AF in patients with renal function impairment in comparison with matched controls

Renal function Matched controls CKD ESRD

Number Number of of patients new-onset AF (n ¼ 404,703) (n ¼ 15,745) HRa 134,901 134,901 134,901

4314 5056 6375

95% CI

P-value

1 — — 1.28 1.22–1.34 o0.001 2.26 2.16–2.37 o0.001

Abbreviations: AF, atrial fibrillation; CAD, coronary artery disease; CI, confidence interval; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; ESRD, end-stage renal disease; HF, heart failure; HTN, hypertension; PAOD, peripheral arterial occlusive disease. a Adjusted according to age, gender, HTN, diabetes mellitus, HF, CAD, PAOD, cerebral vascular accident, COPD, cancer, liver cirrhosis in the multivariable regression analysis.

Variables Age Male gender HTN Diabetes mellitus HF CAD PAOD CVA COPD Cancer Liver cirrhosis

Hazard ratio (95% CI)

P-value

1.06 (1.06–1.06) 1.06 (1.01–1.11) 1.63 (1.52–1.75) 1.40 (1.33–1.47) 1.95 (1.85–2.05) 1.92 (1.81–2.05) 1.99 (1.68–2.35) 1.63 (1.54–1.72) 1.87 (1.76–1.98) 1.42 (1.31–1.53) 1.12 (0.99–1.26)

o0.001 0.029 o0.001 o0.001 o0.001 o0.001 o0.001 o0.001 o0.001 o0.001 0.072

Number of risk factors 0 1 2 3 4 5 6

Number of patients (n ¼ 134,901)

Number of new-onset AF (n ¼ 6375)

Hazard ratio

95% CI

P-value

11,655 40,081 37,384 26,680 14,438 4335 328

452 1465 1874 1472 839 254 19

1 1.47 3.11 4.66 6.17 7.28 10.35

— 1.32–1.63 2.80–3.46 4.17–5.20 5.48–6.96 6.22–8.53 6.53–16.41

— o0.001 o0.001 o0.001 o0.001 o0.001 o0.001

Abbreviations: AF, atrial fibrillation; CI, confidence interval; ESRD, end-stage renal disease.

patients without risk factors (Table 5). With an increase in the number of risk factors in ESRD patients, the incidence of AF multiplied (Figure 2a) and the cumulative event rate increased significantly (Figure 2b).

Table 4 | Predictors of new-onset AF in ESRD patients Univariate analysis

Table 5 | Risk of new-onset AF in ESRD patients with different number of risk factors

Multivariable analysisa Hazard ratio (95% CI) 1.05 1.01 1.17 1.02 1.38 1.25 1.24 1.02 1.12 1.05 1.04

(1.05–1.06) (0.98–1.03) (1.08–1.26) (0.97–1.08) (1.31–1.46) (1.16–1.33) (1.05–1.47) (0.96–1.08) (1.05–1.19) (0.97–1.14) (0.92–1.17)

P-value o0.001 0.641 o0.001 0.477 o0.001 o0.001 0.011 0.623 o0.001 0.219 0.533

Abbreviations: AF, atrial fibrillation; CAD, coronary artery disease; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CVA, cerebral vascular accident; ESRD, end-stage renal disease; HF, heart failure; HTN, hypertension; PAOD, peripheral arterial occlusive disease. a Variables with P-valueo0.1 in the univariate Cox proportional hazards models were included in the multivariable analysis, including age, gender, HTN, diabetes mellitus, HF, CAD, PAOD, CVA, COPD, cancer, and liver cirrhosis.

DISCUSSION Main findings

We analyzed a nationwide cohort in Taiwan, to study the incidence of new-onset AF in patients with CKD and ESRD. Several important risk factors for the new-onset AF in ESRD patients were identified. The main findings were as follows: (1) the incidence rate of AF was B12.1/1000 person-years among patients with ESRD, which was 1.66-fold higher than in CKD patients and 2.42-fold higher than in control patients; (2) advanced age, HTN, HF, CAD, PAOD, and COPD were independent risk factors for the occurrence of AF in ESRD patients; and (3) the incidence rate of AF was 5.3/ 1000 person-years for ESRD patients without risk factors and increased to 47.6/1000 person-years for those with all 6 risk factors. Incidence rate of AF in patients with ESRD

demonstrates the higher occurrence of AF in ESRD patients than in the other two groups during the follow-up period. Compared with controls, the hazard ratios for AF occurrence were 2.26 (95% confidence interval ¼ 2.16–2.37, Po0.001) for ESRD and 1.28 (95% confidence interval ¼ 1.22–1.34, Po0.001) for CKD after adjusting for age, gender, HTN, diabetes mellitus, HF, CAD, PAOD, cerebral vascular accident, COPD, cancer, and liver cirrhosis (Table 3). Predictors of new-onset AF in ESRD patients

Among patients with ESRD, age, HTN, HF, CAD, PAOD, and COPD were identified to be independent risk factors for the new-onset AF (Table 4). AF incidence was proportional to the number of risk factors a patient displayed. The risk of new-onset AF increased from an hazard ratio of 1.47 (95% confidence interval ¼ 1.32–1.63, Po0.001) to 10.35 (95% confidence interval ¼ 6.53–16.41, Po0.001), when the number of risk factors increased from 1 to 6 in comparison with Kidney International (2015) 87, 1209–1215

Previously, several studies have reported the incidence of AF in patients with ESRD to range from 1.0 to 14.8 per 100 person-years (Table 6).18–23 The largest study was performed by Goldstein et al.23 using a Medicare database with a total of 258,605 elderly ESRD patients. They reported an AF incidence of 148/1000 person-years, which was higher than the results seen in all other studies. However, only patients older than 67 years were enrolled in this study, and this hardly represents the incidence in the ESRD group as a whole. It should also be noted that Goldstein et al.23 defined AF events to include both AF and atrial flutter, while we recognized only cases with AF in our study. Notably, most studies regarding AF incidence in ESRD have been performed in Europe or the United States, and statistical data in Asians were scarce. Wizemann et al.22 conducted the only analysis comparing the incidence of AF in different countries using data from the International Dialysis Outcomes and Practice Patterns Study. A wide range of variation in AF incidence was observed, ranging from 0.5/100 person-years in Japan to 3.0/100 person-years in Sweden. Based on these observations, 1211



50

47.6

45 Incidence of AF*

40 35

33.0

30

27.9

25

21.2

20 14.5

15 10 5.3

5

7.2

0 0

Cumulative event rate (%)

60

1

2 3 4 5 Number of risk factors

6

P < 0.0001

50 40 30 20 10 0 0

3

Number at risk 0 risk factor 1 risk factor 2 risk factors 3 risk factors 4 risk factors 5 risk factors 6 risk factors

6

9

12

15

Years of follow-up 11,655 40,081 37,384 26,680 14,438 4335 328

8669 24,518 16,842 9188 3794 927 32

6608 14,870 7642 3052 976 170 1

4673 7729 2636 697 128 20 0

2725 2750 570 82 10 0 0

598 346 38 2 0 0 0

Figure 2 | Incidence and cumulative event rate of new-onset atrial fibrillation (AF) in end-stage renal disease (ESRD) patients with multiple risk factors. (a) The incidence of AF continuously increased in patients with multiple risk factors. (b) Patients were stratified into seven groups based on the number of risk factors they had. The cumulative incidence curve with log-rank test showed that patients with more risk factors had a higher rate of new-onset AF. *Number of new-onset AF per 1000 person-years of follow-up.

racial and geographical factors were considered to be likely to influence AF incidence and this may explain the difference in incidence rates between our study and others. The present study analyzed 499% of Taiwan’s ESRD patients without history of AF from the National Health Insurance Research Database (NHIRD); the mean age of patients was 61.7±14.3 years. To our knowledge, this is the first nationwide study in Asia to analyze the incidence of AF in the Asian ESRD population. In addition to reporting the incidence of newonset AF, we compared the risk of new-onset AF for control, CKD, and ESRD patients using the same database, which has rarely been discussed at a single study. Our analysis allows a clearer and more accurate understanding of the AF risk carried by CKD and ESRD patients. 1212

Risk factors for new-onset AF among ESRD patients

AF-related ischemic stroke is a serious adverse event that may occur in ESRD patients. In a large registry of elderly ESRD patients undergoing renal replacement therapy (age X67 years) with newly diagnosed AF, 10% of patients were hospitalized for ischemic stroke each year.23 The ATRIA (Anticoagulation and Risk Factors In Atrial Fibrillation) study reported a graded, increasing risk of thromboembolism with reduced estimated glomerular filtration rate,24 while Olesen et al.9 demonstrated a higher risk of ischemic stroke in AF patients with ESRD requiring renal replacement therapy, which can be decreased by warfarin therapy. In contrast, a previous cohort study suggested that warfarin use among AF patients undergoing dialysis may not provide benefits regarding risk reduction of ischemic stroke. In addition, the risk of intracranial hemorrhage must be taken into account, as these patients demonstrate a significant bleeding tendency.25 Although the optimal strategy for stroke prevention in AF patients with ESRD remains uncertain, identifying subjects who are at a high risk of AF occurrence is an important issue when caring for ESRD patients because of the increased risk of cardiovascular death, higher total mortality, and increased frequency of hospitalization.20 Several previous studies have reported risk factors associated with new-onset AF in patients with CKD,26 including age, Black or Hispanic race, and comorbid diseases such as diabetes mellitus and HTN. However, the risk factors for the new-onset of AF in ESRD patients, who have a higher risk than CKD patients, have not been well investigated in a large cohort. In the present study, several important factors associated with new-onset AF among ESRD subjects were identified, including advanced age, HTN, HF, CAD, PAOD, and COPD. Most of these factors have been shown to be related to electrical and structural remodeling of the right and left atria, which could have an important role in the promotion and perpetuation of AF.17,27–35 The incidence of new-onset AF increased as more risk factors were present, increasing to 47.6/1000 person-years for patients with all 6 risk factors, constituting a 10.4 times risk for the development of AF in comparison with patients without risk factors. The recognition of important risk factors of new-onset AF among ESRD could provide important information for risk stratification, accurate disease monitoring, detection, and prevention. Potential clinical implications

As a considerable number of patients had AF, which was paroxysmal in nature and without obvious symptoms, the correct and timely diagnosis of AF was difficult and challenging for clinical physicians. Ambulatory electrocardiographic monitoring systems are frequently used in the evaluation of symptoms suggestive of a cardiac arrhythmia. However, these tools have a low diagnostic rate due to the limited duration and presence of some asymptomatic AF events. The implantation of a loop recorder can provide a higher yield,36 but this is an invasive procedure with a risk of complications. Kidney International (2015) 87, 1209–1215



Table 6 | Summary of incidence of AF in ESRD patients in serial studies Study, year

Study population

Country/racial distribution

Study type

Age, years

Ansari et al., 200118

106 Dialysis patients

United States

Retrospective review

53.7±6.1

Spain

Prospective observational study Prospective observational study

164 Dialysis patients Vazquez-Ruiz de Castroviejo et al., 200619 476 Dialysis patients Genovesi et al., 200820 (127 had AF when enrollment) 256 Dialysis patients Vazquez et al., 200921 (31 had AF when enrollment) Wizemann et al., 201022 17,513 Dialysis patients (2188 had AF when enrollment) 258,605 Older Goldstein et al., 201223 dialysis patients

Italy

AF incidence

1/100 Person-years (episodes of symptomatic AF requiring treatment) 64±11 in AF group, 3.1/100 Person-years 56±20 in SR group 72.8 in AF patients 4.1/100 Person-years, (35/349 new cases)

Spain

Prospective observational study

65±15.9

5.9/100 Person-years

North America (US/Canada), Japan, Europe/Australia/ New Zealand United States (non-Hispanic Whites, Hispanics, AfricanAmericans, Asians and native Americans, 2–3% Asians)

Prospective, longitudinal, observational study Medicare system

N/A

1/100 Person-years (0.5 in Japan)

75.9±6

148/1,000 Person-years

Abbreviations: AF, atrial fibrillation; ESRD, end-stage renal disease; N/A, not available; SR, sinus rhythm.

Therefore, risk stratification based on AF incidence could identify patients at higher potential risk of AF occurrence, who could then be more closely followed. Although several scoring models have been proposed to predict new-onset AF in previous studies,37–39 these schemes were derived from the general population and did not focus on ESRD patients. The recognition of important factors associated with new-onset AF should lead physicians to remain vigilant about the possibility of AF occurrence when ESRD patients with risk factors exhibit symptoms of cardiac arrhythmias or suffer from an ischemic stroke. Study limitations

The present study had several limitations. First, personal information, such as smoking habits, alcohol intake, and physical activity, were not available in the nationwide registry database. The echocardiographic parameters, such as the left atrial dimension, left ventricular systolic and diastolic functions, and valvular status were also lacking. Some important pre-existing comorbidities, which could predispose patients to the development of AF, such as thyroid diseases and valvular heart diseases, were not taken into consideration. Nevertheless, we have tried to adjust partly for lifestyle factors by including COPD, CAD, cerebral vascular accident, liver cirrhosis, and malignancy in the multivariable Cox proportional hazards model. Second, the occurrence of AF was based on the diagnostic code registered by the physicians responsible for the treament of patients, and was not verified in any other manner. Besides, the bias of medical utilization might be present in our study and confound the comparisons of AF incidences among three groups. However, this is a common limitation that has been noted in previous studies, and the diagnostic accuracy of AF using the present definition in the Taiwan NHIRD has been validated. Third, Kidney International (2015) 87, 1209–1215

arrhythmia monitoring such as 24-h Holter monitoring or cardiac event recording was not routinely performed for every patient to dectect asymptomatic AF, and the true incidence of new-onset AF may have been underestimated. Fourth, the types of AF, paroxysmal, or non-paroxysmal, were not available from this nationwide data set. As the risk of stroke did not differ between patients with paroxysmal or non-paroxysmal AF,6,7 the lack of this information should not significantly affect the value of the present study. Finally, we analyzed CKD and control patients according to their baseline conditions, and the status of their renal function after entry into the study was not continuously recorded. It is probable that the renal function of some patients in the CKD and control groups declined during the follow-up period, and that these patients may have become misclassified. However, this type of misclassification would not occur in the ESRD group, which was the main target in the present study, and this should not significantly affect our findings. Owing to the limitations mentioned above, a further large-scale and prospective trial is necessary to confirm the findings presented here. In conclusion, the incidence rate of new-onset AF was B12.1/1000 person-years among patients with ESRD in a nationwide cohort study in Taiwan. Advanced age, HTN, HF, CAD, PAOD, and COPD were significant risk factors for the occurrence of new-onset AF in ESRD patients. METHODS Study cohort We performed a nationwide cohort analysis, retrieving all patients with ESRD undergoing renal replacement therapy from Taiwan’s NHIRD released by the Taiwan National Health Research Institutes. The National Health Insurance system is a mandatory universal health insurance program that offers comprehensive medical care 1213



NHIRD cohort (1996–2011) more than 23 million enrollees

ESRD patients older than 20 years old without AF (n =134,901)

Age and gender matching at the same index date at 1:1 ratio

CKD patients without AF (n =134,901)

Matched controls without AF (n =134,901)

Figure 3 | Flowchart of study enrollment. From 1996 to 2011, a total of 134,901 end-stage renal disease (ESRD) patients without a history of atrial fibrillation (AF) were identified from the National Health Insurance Research Database (NHIRD). For each ESRD patient, one age- and gender-matched subject with chronic kidney disease (CKD) and one similarly matched patient without CKD were selected from the NHIRD on the same date that the ESRD patient was enrolled.

coverage to all residents in Taiwan. NHIRD consists of detailed health-care data from 423 million enrollees, representing 499% of Taiwan’s population. In this cohort data set, the patients’ original identification numbers were encrypted to protect privacy, and the encrypting procedure was consistent so that a linkage of the claims belonging to each patient was feasible within the National Health Insurance database and could be followed continuously. Numerous scientific research papers have been published using data from NHIRD (http://nhird.nhri.org.tw/en/Research.html). The large sample size of this database provided a good opportunity to study AF incidence in patients with ESRD. From 1 January 1996 to 31 December 2011, a total of 134,901 ESRD patients undergoing renal replacement therapy with age X20 years and no history of AF were identified from the NHIRD as the study population. As the record of the NHIRD can be traced back to 1995, we excluded individuals with any recorded diagnosis of AF, significant mitral valve disease, or hyperthyroidism for at least 1 year preceding study enrollment. Diagnosis of ESRD requiring renal replacement therapy was confirmed by specific International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes and inclusion in the Registry for Catastrophic Illness Patient Database, a sub-classification of the NHIRD. According to the rules of the National Health Insurance system, only patients with ESRD undergoing renal replacement therapy can be registered in the Registry for Catastrophic Illness Patient Database. We defined the date of first documented ESRD as the index date. The control subjects, without a history of kidney disease, and CKD patients without ESRD were matched for comparison (ICD-9-CM codes of history of kidney disease: 580.x–588.x, 250.4x, 274.1x, 283.11, 403.x1, 404.x2, 404.x3, 440.1, 442.1, 447.3, 572.4, 642.1x, and 646.2x. ICD-9-CM codes of CKD: 582.0, 582.4, 582.8x, 586, 250.4x, 274.1,403.x1, 404.x2, and 404.x3).40 We also excluded individuals with a history of AF, significant mitral valve disease, or hyperthyroidism. One CKD patient and one non-CKD individual of the same age and gender as the ESRD patient were sampled from the 1214

risk set on the same index date. The flow chart of the enrollment of the study population is shown in Figure 3. The study endpoint was the new onset of AF (ICD-9-CM: 427.31). We did not include patients with the occurrence of atrial flutter (ICD-9-CM: 427.32), because previous studies have documented a different pathogenesis between AF and atrial flutter.41,42 Primarily, atrial flutter demonstrated a macroreentrant circuit localizing to the right atrium, while AF originated from ectopic beats initiating from pulmonary veins. To ensure the accuracy of diagnosis, we defined patients with AF only when it was listed as a discharge diagnosis or confirmed more than twice in the outpatient department.43 The diagnostic accuracy of AF using this definition in the NHIRD has been validated.44,45 The date of AF occurrences was the date of the second AF claim if the first claim was an outpatient claim, or the date when AF was listed as a discharge diagnosis. The duration of AF occurrence was defined as the period between the index date and AF occurrence date. Statistical analysis Data were presented as the mean value and s.d. for continuous variables and proportions for categorical variables. Comparisons of the continuous variables among three groups were performed using one-way analysis of variance. Nominal variables were compared by w2-test or Fisher’s exact test. The risk of AF occurrence was assessed using the Cox proportional hazards models. The time to event for alive subjects without the AF occurrence was censored at death, follow-up until dropout from the National Health Insurance program, or the end of the year of 2011. A multivariable Cox proportional hazards model was built with the variables with a P-valueo0.1 on univariate Cox proportional hazards models. The cumulative incidence curve of new-onset AF was plotted via the Kaplan–Meier method, with statistical significance examined by the log-rank test. All statistical significances were set at a Po0.05 using the SPSS version 17.0 statistical software (SPSS, Chicago, IL). DISCLOSURE

All the authors declared no competing interest. ACKNOWLEDGMENTS

This work was supported in part by grants from the National Science Council (NSC98-2410-H-010-003-MY2) and Taipei Veterans General Hospital (V99C1-140, V99A-153, V100D-002-3, V101D-001-2, and V102B-025). REFERENCES 1.

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