JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 70, NO.

11, 2017

2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2017.07.755

Care Patterns and Outcomes in

Atrial Fibrillation Patients With and
Without Diabetes
ORBIT-AF Registry

Justin B. Echouffo-Tcheugui, MD, PHD,a Peter Shrader, MA,b Laine Thomas, PHD,b Bernard J. Gersh, MBCHB, DPHIL,c
Peter R. Kowey, MD,d Kenneth W. Mahaffey, MD,e Daniel E. Singer, MD,f Elaine M. Hylek, MD, MPH,g
Alan S. Go, MD,h Eric D. Peterson, MD, MPH,b Jonathan P. Piccini, MD, MHS,b Gregg C. Fonarow, MDi

ABSTRACT

BACKGROUND Diabetes is a well-established risk factor for thromboembolism in patients with atrial brillation (AF),
but less is known about how diabetes inuences outcomes among AF patients.

OBJECTIVES This study assessed whether symptoms, health status, care, and outcomes differ between AF patients
with and without diabetes.

METHODS The cohort study included 9,749 patients from the ORBIT-AF (Outcomes Registry for Better Informed
Treatment of Atrial Fibrillation) registry, a prospective, nationwide, outpatient registry of patients with incident and
prevalent AF. Outcomes included symptoms, health status, and AF treatment, as well as 2-year risk of death,
hospitalization, thromboembolic events, heart failure (HF), and AF progression.

RESULTS Patients with diabetes (29.5%) were younger, more likely to have hypertension, chronic kidney disease, HF,
coronary heart disease, and stroke. Compared to patients without diabetes, patients with diabetes also had a lower
Atrial Fibrillation Effects on Quality of Life score of 80 (interquartile range [IQR]: 62.5 to 92.6) versus 82.4 (IQR: 67.6
to 93.5; p 0.025) and were more likely to receive anticoagulation (p < 0.001). Diabetes was associated with higher
mortality risk, including overall (adjusted hazard ratio [aHR]: 1.63; 95% condence interval [CI]: 1.04 to 2.56, for
age <70 years vs. aHR: 1.25; 95% CI: 1.09 to 1.44, for age $70 years) and cardiovascular (CV) mortality (aHR: 2.20; 95% CI:
1.22 to 3.98, for age <70 years vs. 1.24; 95% CI: 1.02 to 1.51 for age $70 years). Diabetes conferred a higher risk of non-CV
death, sudden cardiac death, hospitalization, CV hospitalization, and non-CV and nonbleeding-related hospitalization, but
no increase in risks of thromboembolic events, bleeding-related hospitalization, new-onset HF, and AF progression.

CONCLUSIONS Among AF patients, diabetes was associated with worse AF symptoms and lower quality of life, and
increased risk of death and hospitalizations, but not thromboembolic or bleeding events. (J Am Coll Cardiol 2017;70:132535)
2017 by the American College of Cardiology Foundation.

From the aDepartment of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, Massachusetts; bDuke
University Medical Center and Duke Clinical Research Institute, Durham, North Carolina; cDepartment of Cardiovascular Medi-
cine, Mayo Clinic, Rochester, Minnesota; dLankenau Institute for Medical Research, Wynnewood, Pennsylvania; eStanford Center
for Clinical Research (SCCR), Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Med-
icine, Stanford, California; fDepartment of Medicine, Massachusetts General Hospital, Boston, Massachusetts; gDepartment of
h
Medicine, Division of General Internal Medicine, Boston University School of Medicine, Boston, Massachusetts; Division
Listen to this manuscripts
of Research, Kaiser Permanente of Northern California, Oakland, California; and the iDepartment of Medicine, Division of
audio summary by
Cardiology/Ahmanson-UCLA Cardiomyopathy Center, University of California, Los Angeles, Los Angeles, California. This project
JACC Editor-in-Chief
was supported in part by cooperative agreement 1U19 HS021092 from the Agency of Healthcare Research and Quality. The
Dr. Valentin Fuster.
Outcomes Registry for Better Informed Treatment of Atrial Fibrillation is sponsored by Janssen Scientic Affairs LLC, Raritan, New
Jersey. Dr. Piccini has received grants from the Agency for Healthcare Research and Quality and Janssen Pharmaceuticals; has
received consulting fees from Bristol-Myers Squibb/Pzer and Johnson & Johnson; has received research support from ARCA
Biopharma, Boston Scientic, GE Healthcare, and Johnson & Johnson/Janssen Scientic Affairs; and has received consultancy fees
from Forest Laboratories, Janssen Scientic Affairs, Pzer/Bristol-Myers Squibb, Spectranetics, and Medtronic. Dr. Fonarow has
served as a consultant for Novartis, Amgen, Bayer, Gambro, Medtronic, and Janssen; is a member of the GWTG steering committee;
1326 Echouffo-Tcheugui et al. JACC VOL. 70, NO. 11, 2017

Diabetes and Outcomes of AF SEPTEMBER 12, 2017:132535

A trial brillation (AF) is the most

ABBREVIATIONS
AND ACRONYMS common clinically signicant
arrhythmia (1,2) and is associated
AF = atrial brillation
with increased morbidity, mortality, and
aHR = adjusted hazard ratio
health care costs (35). Diabetes is a common
CI = condence interval
comorbid illness in patients with AF; at least
CV = cardiovascular 1 in 7 patients with AF have diabetes (6).
HbA1c = glycosylated Diabetes has been shown to increase the
hemoglobin
risk of incident AF (7), as it promotes
HF = heart failure
maladaptive and probrillatory structural
HR = hazard ratio (mediated by oxidative stress, advanced
IQR = interquartile range glycosylation end products, and connective
OAC = oral anticoagulant tissue changes), electromechanical, and
OR = odds ratio autonomic nervous system changes (8).
QOL = quality of life
SEE PAGE 1336
SCD = sudden cardiac death
TIA = transient ischemic attack
Diabetes is also a risk factor for ischemic
stroke in patients with AF not receiving anti-
coagulation (911). Consequently, diabetes has been
included in the stroke risk scoring systems (CHADS 2
and CHA 2DS2-VASc), which are used to guide anti-
coagulation therapy in AF patients (12,13). However,
the extent to which diabetes inuences outcomes of
AF other than thromboembolic events, including
mortality, hospitalization, heart failure (HF), and AF
progression, as well as the use of AF targeted thera-
pies, is unclear. Despite the commonality of diabetes
and AF, this has not been a topic of previous investi-
gation. Such investigation may allow for a better un-
derstanding of the natural history, symptom burden,
concomitant risks, and clinical outcomes of patients
with both AF and diabetes (8).
Using the framework of the ORBIT-AF (Outcomes
Registry for Better Informed Treatment of Atrial
Fibrillation) registry, we examined the association of
diabetes and outcomes of AF. We hypothesized that
diabetes will be associated with greater symptoms,
more disease progression, and worse cardiovascular
(CV) outcomes in patients with AF.
METHODS
DATA SOURCE AND STUDY POPULATION. Our study
cohort was formed from the ORBIT-AF registry, which
is an observational, prospective, quality improve-
ment program. The rationale and design of ORBIT-AF
have been previously described in detail (14). In brief,
the registry enrolled adults older than 18 years with
electrocardiographic evidence of AF. Patients were
excluded if they were diagnosed as having AF
secondary to an easily reversible condition or if they
had a life expectancy <6 months. Patients were
enrolled from heterogeneous practices across the
United States, including internal medicine,
neurology, cardiology, and electrophysiology clinics.
Data were collected by various health care providers,
including internists, primary care physicians, neu-
rologists, cardiologists, and electrophysiologists. The
patients medical record was entered into an online
case report form, and patients were to be followed
every 6 months for 2 to 3 years. All participants gave
informed consent, and all study sites had approval
from an institutional review board for inclusion in the
ORBIT-AF registry.
We identied 10,137 patients with AF from a total
of 176 U.S. clinic practices enrolled between June 29,
2010, and August 9, 2011. We excluded those patients
without information on follow-up (n 388), leaving a
nal study sample of 9,749 patients.
Diabetes mellitus was dened by previous medical
history or new clinical diagnosis during the enroll-
ment visit.

and is supported by the Ahmanson Foundation (Los Angeles, California). Dr. Gersh has received personal fees from Mount Sinai
St. Lukes, Boston Scientic Corp., Teva Pharmaceuticals, Janssen Scientic Affairs, St. Jude Medical, Janssen Research &
Development LLC, Duke Clinical Research Institute, Duke University, Kowa Research Institute Inc., Sirtex Medical Ltd., Baxter
Healthcare Corp., Cardiovascular Research Foundation, Medtronic, Xenon Pharmaceuticals, Cipla Ltd., Thrombosis Research
Institute, and Armetheon Inc. Dr. Hylek has received personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb,
Daiichi-Sankyo, Janssen, Medtronic, Pzer, and Portola. Dr. Kowey has served as a consultant/advisory board member for
Boehringer Ingelheim, Bristol-Myers Squibb, Johnson & Johnson, Portola, Merck, Sano, and Daiichi-Sankyo. Dr. Mahaffey has
received research grants from Afferent, Amgen, AstraZeneca, Daiichi, Ferring, Google (Verily), Johnson & Johnson, Medtronic,
Merck, Novartis, Sano, and St. Jude; has served as a consultant or provided other services for Ablynx, AstraZeneca, BAROnova,
Bio2 Medical, Boehringer Ingelheim, Bristol-Myers Squibb, Cardiometabolic Health Congress, Cubist, Eli Lilly, Elsevier, Epson,
GlaxoSmithKline, Johnson & Johnson, Merck, Mt Sinai, Myokardia, Novartis, Oculeve, Portola, Radiomeer, Springer Publishing,
The Medicines Company, Theravance, UCSF, Vindico, and WebMD; and has equity in BioPrint Fitness. Dr. Peterson has received
personal fees from Boehringer Ingelheim, Sano, AstraZeneca, Valeant, and Bayer; grants and personal fees from Janssen; and
research support from Eli Lilly & Co. and Janssen Scientic Affairs. Dr. Singer has served as a consultant/advisory board for
Boehringer Ingelheim, Bristol-Myers Squibb, CVS Health, Merck, Johnson & Johnson, Medtronic, and Pzer; and has received
research grants from Boehringer Ingelheim, Bristol-Myers Squibb, and Medtronic. Dr. Go has received a research grant to his
institution from iRhythm Technologies. All other authors have reported that they have no relationships relevant to the contents of
this paper to disclose.

Manuscript received June 28, 2017; revised manuscript received July 9, 2017, accepted July 11, 2017.
JACC VOL. 70, NO. 11, 2017
SEPTEMBER 12, 2017:132535
OUTCOMES. Patients were followed at 6-month in-
tervals for up to 3 years. Outcomes assessed at follow-
up were all-cause mortality, CV death, non-CV death,
hospitalization (all-cause, CV-related, bleeding-
related, and non-CV and nonbleeding-related), stroke
or non-central nervous system systemic embolism or
transient ischemic attack (TIA), incident new-onset
HF, AF progression, bleeding events, AF symptoms,
health status, and use of targeted therapies. AF pro-
gression was dened as either: 1) progression from
paroxysmal AF at baseline to either persistent or
permanent AF reported at any subsequent follow-up
visit; or 2) progression from persistent AF at base-
line to permanent AF reported at any subsequent
follow-up visit (15,16). Paroxysmal AF was dened as
recurrent AF episodes that terminate spontaneously
within 7 days; persistent AF as recurrent AF that is
sustained for more than 7 days; and permanent AF as
AF in which the presence of the AF is accepted. The
assessment of the use of targeted therapies included
the management strategy (rate control, rhythm
control), medication use (warfarin, non-vitamin
K oral anticoagulants [OACs], aspirin, clopidogrel,
beta-blockers, calcium-channel blockers, digoxin,
amiodarone, sotalol, dofetilide, propafenone, ecai-
nide), and procedures (catheter ablation for AF or
atrial utter, atrioventricular node ablation
cardioversion).
STATISTICAL ANALYSIS. We compared patient (de-
mographic and clinical) and hospital characteristics,
as well as proportional use of different AF manage-
ment strategies between patients with and without
diabetes. Categorical variables are presented as count
and proportion, and differences were tested using the
Pearson chi-square test. Continuous variables are
presented as median (interquartile range [IQR]), and
differences between groups were tested using the
Wilcoxon rank sum test.
The event rate for each outcome was estimated
both overall and by diabetes status, with rates pre-
sented as the number of events per 100 patient-years
of follow-up. We used Cox proportional hazards
survival models to test the association between dia-
betes and each clinical outcome. For AF progression,
we estimated the frequency and percentage of AF
progression, and a logistic regression model was used
to estimate the odds ratio (OR) for the association
between diabetes and AF progression. All models
used a robust variance estimate to account for
correlation within sites. Covariates for the multivari-
able modeling were chosen based on their clinical
relevance or known association with diabetes and
outcome(s). A common set of variables was used in
Echouffo-Tcheugui et al. 1327
Diabetes and Outcomes of AF
models for adjustment and is listed in the Online
Appendix. Adjusted associations for outcomes are
displayed as hazard ratio (HR) or OR with corre-
sponding 95% condence interval (CI). We assessed
the inuence of age, race (white vs. nonwhite), use of
anticoagulants, renal function (as dened by esti-
mated glomerular ltration rate), type of AF (parox-
ysmal vs. nonparoxysmal), history of ablation
procedure, and pulse pressure on the relationship
between diabetes and outcomes, by testing the
interaction of each of these factors with diabetes. In
models, all continuous variables were tested for
linearity with each outcome, and any nonlinear
associations are accounted for using linear splines.
Missing covariate data in the regression analysis were
handled by multiple imputation using Markov Chain
Monte Carlo and regression methods. Final estimates
and associated standard errors reect the combined
analysis over 5 imputed datasets.
Analyses were performed using SAS version 9.3
(SAS Institute Inc., Cary, North Carolina). All p values
were based on 2-sided tests and were considered
statistically signicant at p < 0.05.
RESULTS
The nal study sample from ORBIT-AF contained
9,749 patients from 174 practices, among whom 2,874
(29.5%) had diabetes, with median follow-up of 2.78
years (IQR: 1.95 to 3.00 years) and mean follow-up of
2.41  0.75 years. The proportion of surviving
patients by period of follow-up are 6.8% with <1 year
of follow-up, 12.5% with <1.5 years of follow-up,
17.6% with <1.8 years of follow-up, and 28.9%
with <2.0 years of follow-up.
Baseline clinical and demographic characteristics
of the study participants by diabetes status are given
in Table 1. Patients with diabetes were more likely to
be younger, male, from an ethnic minority (Hispanic
and black), a smoker, and have a higher body mass
index and a history of comorbidities, with the largest
differences from nondiabetic patients observed for
hypertension, obesity, hyperlipidemia, chronic kid-
ney disease or dialysis, chronic pulmonary obstruc-
tive disease, obstructive sleep apnea, coronary artery
disease, cerebrovascular disease, and HF. Patients
with diabetes had a higher stroke risk compared to
those without diabetes as estimated by media
CHADS2 (3 vs. 2; p < 0.001) and CHA2DS2 -VASc scores
(5 vs. 4; p < 0.001). Only 0.7% of patients with
diabetes had a CHA2DS 2-VASc score of 1 compared to
12.4% of patients without diabetes (p < 0.001).
Patients with diabetes also had a signicantly
1328 Echouffo-Tcheugui et al. JACC VOL. 70, NO. 11, 2017

Diabetes and Outcomes of AF SEPTEMBER 12, 2017:132535

elevated bleeding risk no matter which scoring

T A B L E 1 Patient Characteristics
system was used (Table 1).
Overall No Diabetes Diabetes
(N 9,749) (n 6,875) (n 2,874) p Value
SYMPTOMS, FUNCTIONAL STATUS, AND QUALITY
Demographics OF LIFE. In the ORBIT-AF cohort, patients with dia-
Age, yrs 75 (6782) 75 (6782) 74 (6781) <0.001
betes had greater functional impairment as reected
Race or ethnicity <0.001
by higher European Heart Rhythm Association scores
White 8,719 (89.6) 6,250 (91.0) 2,469 (86.1)
Black 477 (4.9) 278 (4.0) 199 (6.9)
(Table 1). Across the AF symptom checklist, patients
Hispanic 398 (4.1) 242 (3.5) 156 (5.4) with diabetes less often reported palpitations (29.2%
Other 139 (1.4) 95 (1.4) 44 (1.5) vs. 33.6%; p < 0.001) or syncope (3.3% vs. 4.9%;
Sex 0.033 p < 0.001), but they reported signicantly more dys-
Male 5,599 (57.4) 3,901 (56.7) 1,698 (59.1) pnea upon exertion (29.7% vs. 26.6%; p 0.002) or at
Female 4,150 (42.6) 2,974 (43.3) 1,176 (40.9)
rest (11.1% vs. 9.8%; p 0.06), exercise intolerance
Medical history
(11.9% vs. 9.2%; p < 0.001), and fatigue (27.9% vs.
Dialysis 124 (1.3) 69 (1.0) 55 (1.9) <0.001
25.6%; p 0.02). There were no differences between
Hyperlipidemia 7,042 (72.2) 4,670 (67.9) 2,372 (82.5) <0.001
Cognitive impairment or 293 (3.0) 186 (2.7) 107 (3.7) 0.007 the diabetes and nondiabetes groups in terms of
dementia lightheadedness or dizziness and chest tightness or
Frailty 575 (5.9) 400 (5.8) 175 (6.1) 0.585 discomfort.
COPD 1,605 (16.5) 1,022 (14.9) 583 (20.3) <0.001
Regarding health-related quality of life (QOL)
Alcohol abuse 380 (3.9) 252 (3.7) 128 (4.5) 0.067
(Table 1), patients with diabetes had a slightly lower
Hypertension 8,103 (83.1) 5,463 (79.5) 2,640 (91.9) <0.001
Chronic kidney disease* 3,361 (37.2) 2,169 (34.2) 1,192 (44.3) <0.001
overall median Atrial Fibrillation Effect on Quality-
Smoking 4,717 (48.4) 3,265 (47.5) 1,452 (50.5) 0.006 of-Life scores compared to those without diabetes
Thyroid disease 2,190 (22.5) 1,531 (22.3) 659 (22.9) 0.476 (80.6; IQR: 62.5 to 92.6 vs. 82.4; IQR: 67.6 to 93.6;
Hyperthyroidism 199 (2.0) 127 (1.9) 72 (2.5) 0.036 p 0.03). This difference was mainly driven by the
Hypothyroidism 1,990 (20.4) 1,403 (20.4) 587 (20.4) 0.9873 daily activities domain score, as the symptoms and
Gastrointestinal bleed 893 (9.2) 564 (8.2) 329 (11. 5) <0.001
treatment concern domain scores were similar.
Obstructive sleep apnea 1,783 (18.3) 1,040 (15.1) 743 (25.9) <0.001
These differences persisted at 12- and 24-month
Cardiovascular history
follow-up.
Family history of AF 1,444 (15.0) 1,047 (15.4) 397 (14.0) 0.863
Peripheral vascular 1,309 (13.4) 772 (11.2) 537 (18.7) <0.001
disease AF MANAGEMENT AND OUTCOMES. Patients with
Prior cerebrovascular 1,557 (16.0) 1,035 (15.1) 522 (18.2) <0.001 diabetes had persistent and permanent AF or a com-
events
bination of persistent or permanent AF (47.9% vs.
Stroke or TIA 1,479 (15.2) 983 (14.3) 496 (17.3) <0.001
43.6%) more frequently than did those without dia-
Congestive heart failure 3,204 (32.9) 1,969 (28.6) 1,235 (43.0) <0.001
betes (p < 0.001) (Table 1), but they were less likely to
Signicant valvular 2,510 (25.8) 1,800 (26.2) 710 (24.7) 0.131
disease have undergone cardioversion or ablation (Table 2).
Prior mechanical valve 803 (8.2) 567 (8.3) 236 (8.2) 0.953 The use of rate-control strategies was higher among
replacement or repair
people with diabetes compared to those without
History of CAD 3,535 (36.3) 2,226 (32.4) 1,309 (45.6) <0.001
2 diabetes contrary to use of rhythm-control therapies,
BMI, kg/m 29.1 (25.434.0) 28.2 (24.832.5) 31.7 (27.337.3) <0.001
Heart rate, beats/min 70 (6380) 70 (6279) 71 (6480) <0.001 which was lower (Table 2). Among rate-control
Diastolic blood pressure, 72 (6680) 72 (6880) 70 (6480) <0.001 agents, the use of beta-blockers (67.8% vs. 62.8%;
mm Hg p < 0.001), calcium-channel blockers (31.8% vs.
Systolic blood pressure, 126 (116138) 124 (116136) 127 (116140) <0.001
29.8%; p 0.05), and digoxin (29.0% vs. 21.3%;
mm Hg
Pulse pressure, mm Hg 52 (4362) 50 (4260) 54 (4564) <0.001 p < 0.001) was more prevalent among people with
LVEF, % 55 (5061) 57 (5061) 55 (4960) <0.001 diabetes. For rhythm-control therapies, ecainide
LA diameter, cm 4.4 (3.95.0) 4.4 (3.94.9) 4.5 (4.15.1) <0.001 was less commonly used among people with diabetes
Type of AF <0.001 (1.0% vs. 3.7%; p < 0.001). The overall use of antico-
First detected or new 438 (4.5) 320 (4.7) 118 (4.1) agulants (warfarin or dabigatran) was signicantly
onset
Paroxysmal 4,940 (50.7) 3,561 (51.8) 1,379 (48.0)
greater among people with diabetes. The use of
Persistent 1,635 (16.8) 1,147 (16.7) 488 (17.0) warfarin only was higher among those with diabetes
Permanent 2,736 (28.1) 1,847 (26.9) 889 (30.9) compared to those without diabetes (74.3% vs. 70.4%;
Continued on the next page p < 0.001), but use of dabigatran was similar in the
JACC VOL. 70, NO. 11, 2017 Echouffo-Tcheugui et al. 1329
SEPTEMBER 12, 2017:132535 Diabetes and Outcomes of AF

2 groups. Aspirin was more commonly used among

T A B L E 1 Continued
people with diabetes (46.5% vs. 43.4%; p 0.006).
The incidence rates for all outcomes during follow- Overall No Diabetes Diabetes
(N 9,749) (n 6,875) (n 2,874) p Value
up are given in Table 3. Over the 2-year period,
EHRA score 0.019
mortality rates were higher among people with
No symptoms 3,726 (38.3) 2,626 (38.3) 1,100 (38.5)
diabetes compared to those without diabetes. The Mild (normal daily 4,390 (45.2) 3,139 (45.8) 1,251 (43.7)
rates of CV death, non-CV death, and sudden cardiac activity not
affected)
death (SCD) also were higher among patients with
Severe (normal daily 1,430 (14.7) 965 (14.1) 465 (16.3)
diabetes than in those without diabetes (Table 3, activity affected)
Central Illustration, Figure 1, and Online Figures 1 to 12). Disabling (normal daily 175 (1.8) 131 (1.9) 44 (1.5)
activity discontinued)
There was a signicant interaction between
CHADS2 score 2 (13) 2 (13) 3 (24) <0.001
diabetes and age for all-cause death (p 0.025) and
CHA2DS2-VASc score 4 (35) 4 (25) 5 (46) <0.001
CV mortality (p 0.002) outcomes. After multivari- CHA2DS2-VASc score <0.001
able adjustment, diabetes was associated with a 0 212 (2.2) 212 (3.1) 0 (0.0)
higher risk of mortality, both among those age <70 1 659 (6.8) 639 (9.3) 20 (0.7)
years (adjusted hazard ratio [aHR]: 1.63; 95% CI: 1.04 2 1,174 (12.0) 1,036 (15.1) 138 (4.8)
to 2.56) and among those age $70 years (aHR: 1.25; 3 1,807 (18.5) 1,437 (20.9) 370 (12.9)
4 2,298 (23.6) 1,686 (24.5) 612 (21.3)
95% CI: 1.09 to 1.44) (Table 3). Diabetes was also
5 1,817 (18.6) 1,077 (15.7) 740 (25.8)
related to a higher risk of CV death, more so among
6 1,045 (10.7) 505 (7.4) 540 (18.8)
those <70 years than in those $70 years, as well as an
7 505 (5.2) 225 (3.3) 280 (9.7)
increased risk of non-CV death or SCD. Diabetes was 8 189 (1.9) 58 (0.8) 131 (4.6)
similarly associated with a higher risk of all-cause 9 43 (0.4) 0 (0.0) 43 (1.5)
(aHR: 1.15; 95% CI: 1.09 to 1.22), CV (aHR: 1.13; 95% ATRIA score 3 (14) 3 (14) 3 (15) <0.001
CI: 1.05 to 1.22) and non-CV and nonbleeding-related ORBIT score 2 (14) 2 (13) 3 (14) <0.001

hospitalizations (aHR: 1.19; 95% CI: 1.10 to 1.30). HAS-BLED score 2 (12) 2 (12) 2 (13) <0.001
Functional status <0.001
However, diabetes was not associated with a higher
Living independently 8,882 (91.1) 6,321 (91.9) 2,561 (89.1)
risk of thromboembolic events (including stroke, TIA,
Living with assistance or 864 (8.9) 551 (8.0) 313 (10.9)
and non-central nervous system embolism) or hos- resides in assisted
pitalization related to bleeding (Table 3). Also, there living facility or
skilled nursing
was no association between diabetes and incident home or is
new-onset HF (aHR: 1.08; 95% CI: 0.80 to 1.47) or AF bedbound
AFEQT overall score
progression (adjusted OR: 0.96; 95% CI: 0.85 to 1.08).
Baseline 82.4 (66.793.5) 82.4 (67.693.5) 80.6 (62.592.6) 0.025
OAC use modied the association of diabetes and all-
12 months 84.3 (70.494.4) 85.2 (71.694.4) 80.6 (66.794.4) 0.008
cause hospitalization (p for interaction 0.018). 24 months 83.3 (66.794.4) 84.3 (69.494.4) 79.6 (60.794.4) 0.009
Diabetes was more strongly related to all-cause hos-
pitalization (aHR: 1.21; 95% CI: 1.12 to 1.29) among Values are median (interquartile range) or n (%). *Chronic kidney disease was dened using the Modication of
Diet in Renal Disease equation.
those using an OAC than among those not using OAC AF atrial brillation; AFEQT Atrial Fibrillation Effect on QualiTy-of-life; ATRIA AnTicoagulation and Risk
(aHR: 0.98; 95% CI: 0.85 to 1.13). Among patients with Factors in Atrial Fibrillation; BMI body mass index; CAD coronary artery disease; CHA2DS2-VASc congestive
heart failure, hypertension, age $75 years, diabetes mellitus, prior stroke, transient ischemic attack, or throm-
diabetes, there were no signicant differences in boembolism, vascular disease, age 6574 years, sex category (female); CHADS2 congestive heart failure,
outcomes of AF between patients using both OAC and hypertension, age $75 years, diabetes mellitus, prior stroke or transient ischemic attack; COPD chronic
obstructive pulmonary disease; EHRA European Heart Rhythm Association HAS-BLED Hypertension,
antiplatelet therapy and those taking an OAC alone Abnormal renal and liver function, Stroke, Bleeding, Labile INR, Elderly, Drugs or alcohol; LA left atrial;
LVEF left ventricular ejection fraction; ORBIT Outcomes Registry for Better Informed Treatment;
(Online Table 1). TIA transient ischemia attack.
There was a signicant interaction of diabetes and
pulse pressure (#60 mm Hg vs. >60 mm Hg) for the
following outcomes (Online Table 2): new-onset HF
(p < 0.001), CV hospitalization (p 0.015), bleeding patients in the ORBIT-AF registry. Overall, 30% of
hospitalization (p 0.029), and non-CV or non- patients had diabetes. Key ndings included the
bleeding hospitalization (p 0.002). following: use of anticoagulation and rate-control
strategies was signicantly greater among patients
DISCUSSION with diabetes, but this was not the case for rhythm-
control strategies (including pharmacotherapy and
We examined outcomes of AF in patients with dia- cardioversion and catheter-based ablation proced-
betes in a large, real-world population of 9,749 ures); patients with diabetes had more AF symptoms
1330 Echouffo-Tcheugui et al. JACC VOL. 70, NO. 11, 2017

Diabetes and Outcomes of AF SEPTEMBER 12, 2017:132535

individuals with AF (1921). The present study

T A B L E 2 Utilization of Care
demonstrated that, even after extensive covariate
Overall No Diabetes Diabetes adjustment, diabetes is independently associated
(N 9,749) (n 6,875) (n 2,874) p Value*
with an increased risk of all-cause and CV mortality in
Current AF management strategy <0.001
community-based patients with AF. These ndings
Rate control 6,641 (68.3) 4,590 (67.0) 2,051 (71.5)
Rhythm control 3,083 (31.7) 2,265 (33.0) 818 (28.5) were consistent with previous studies, which also
Current medications suggested that diabetes among patients with non-
OAC (warfarin or 7,445 (76.4) 5,175 (75.3) 2,270 (79.0) <0.001 valvular AF is associated with an increased risk of
dabigatran)
all-cause mortality (19,20), including among patients
Warfarin 6,965 (71.4) 4,829 (70.2) 2,136 (74.3) <0.001
already on anticoagulation (21). This suggests that the
Dabigatran 483 (5.0) 349 (5.1) 134 (4.7) 0.391
Aspirin 4,318 (44.3) 2,983 (43.4) 1,335 (46.5) 0.006
inuence of diabetes on outcomes of AF might extend
Past warfarin treatment 7,999 (82.0) 5,559 (80.9) 2,440 (84.9) <0.001 beyond its relation to thromboembolic events, as
OAC (warfarin or 1,438 (76.3) 1,393 (76.2) 45 (80.4) 0.467 evidenced by the increased overall, CV, and SCD risks
dabigatran) among
in our data.
CHADS2 1 and no OAC
contraindications Diabetes was also associated with increased use of
OAC (warfarin or 5,337 (88.0) 3,234 (89.1) 2,103 (86.5) 0.002 targeted therapies, as well as with higher risk of CV
dabigatran) among
CHADS2 $1 and no
and all-cause hospitalization. In contrast, diabetes in
OAC contraindications the setting of contemporary management, including
Beta-blockers 6,268 (64.3) 4,319 (62.8) 1,949 (67.8) <0.001 OAC in approximately 80% of patients, was not
Calcium-channel blockers 2,965 (30.4) 2,051 (29.8) 914 (31.8) 0.055
associated with increased risk of stroke (19,20). Our
Digoxin 2,296 (23.6) 1,464 (21.3) 832 (29.0) <0.001
ndings of a lack of difference in thromboembolic
Amiodarone 967 (9.9) 671 (9.8) 296 (10.3) 0.417
events between patients with and without diabetes
Sotalol 593 (6.1) 420 (6.1) 173 (6.0) 0.866
Dofetilide 189 (1.9) 143 (2.1) 46 (1.6) 0.118 were consistent with previous reports in patients
Propafenone 228 (2.3) 169 (2.5) 59 (2.1) 0.227 receiving anticoagulation (19). The latter was also
Flecainide 286 (2.9) 256 (3.7) 30 (1.0) <0.001 observed in clinical trials of newer anticoagulants, in
Disopyramide 12 (0.1) 8 (0.1) 4 (0.1) 0.770 which stroke risk did not differ between those with
Ranolazine 32 (0.3) 15 (0.2) 17 (0.6) 0.0046 or without diabetes (22,23). The lack of association of
Dronedarone 451 (4.6) 334 (4.9) 117 (4.1) 0.092
diabetes with the risk of stroke may be partially
Angiotensin-converting 3,465 (35.5) 2,239 (32.6) 1,226 (42.7) <0.001
enzyme inhibitor explained by the inclusion of diabetes in the stroke
Angiotensin receptor 1,738 (17.8) 1,114 (16.2) 624 (21.7) <0.001 risk calculators (CHADS 2 and CHA2 DS2-VASc).
blocker Indeed, virtually all the patients with AF and dia-
Statins 5,401 (55.4) 3,483 (50.7) 1,918 (66.7) <0.001
betes had CHA 2DS2-VASc >1 and thus were eligible
Prior procedures
for OAC based on current guidelines. It is possible,
Catheter ablation of AF 450 (10.1) 342 (10.6) 108 (8.8) 0.077
Atrial utter ablation 255 (2.6) 176 (2.6) 79 (2.8) 0.594
however, that diabetic patients with AF present at a
AV node or His-bundle 218 (2.2) 152 (2.2) 66 (2.3) 0.795 younger age and are more symptomatic and there-
ablation fore are more likely to receive these evidence-based
Cardioversion 2,939 (30.2) 2,128 (31.0) 811 (28.2) 0.007
disease-modifying therapies. Yet the design of the
present study, which analyzed diabetes as a single
Values are n (%). *p < 0.05 indicates that the care differs signicantly between those with and without diabetes.
AV atrioventricular; OAC oral anticoagulant; other abbreviations as in Table 1. cohort, may not fully capture the totality of the ef-
fect of abnormal glucose tolerance on the risk of
stroke. Indeed, previous studies have suggested that
the degree of blood glucose (as measured by glyco-
and worse health status; those with diabetes had a sylated hemoglobin [HbA1c]) (24) and diabetes
signicantly higher risk of death (overall, CV, and duration are determinants of the risk of stroke and
non-CV death) and of hospitalization, but similar risk thromboembolic events among patients with AF
of thromboembolic events (with close to 80% of (10,11).
patients receiving anticoagulation); and patients with The nding of a greater burden of permanent and
diabetes experienced more new-onset HF and AF persistent AF, severe to disabling symptoms, and
progression. worse QOL among patients with diabetes was
Although the association of diabetes and incident consistent with previous ndings. There have been
AF has been reported in several community-based studies suggesting that the burden of AF-related
(7,17) and hospital-based studies (18), a limited symptoms is higher among patients with diabetes
number of studies have evaluated the association (25). The lower frequency of rhythm-control strate-
between diabetes and clinical outcomes among gies among patients with diabetes could be
JACC VOL. 70, NO. 11, 2017 Echouffo-Tcheugui et al. 1331
SEPTEMBER 12, 2017:132535 Diabetes and Outcomes of AF

T A B L E 3 Association Between Diabetes and 2-Year Outcomes

Events per 100 Patient-Years

(No. of Events) Unadjusted Adjusted

No Diabetes Diabetes
(n 6,875) (n 2,874) HR (95% CI) p Value HR* (95% CI) p Value

All-cause death
Age <70 yrs (n 3,216) 1.68 (88) 4.03 (92) 2.41 (1.823.20) <0.001 1.63 (1.042.56) 0.033
Age $70 yrs (n 6,533) 6.46 (686) 9.22 (378) 1.43 (1.261.63) <0.001 1.25 (1.091.44) 0.001
Cardiovascular death
Age <70 yrs (n 3,199) 0.50 (26) 1.67 (38) 3.41 (2.165.39) <0.001 2.20 (1.223.98) 0.009
Age $70 yrs (n 6,436) 2.58 (272) 4.04 (164) 1.57 (1.281.93) <0.001 1.24 (1.021.51) 0.03
Non-CV death 2.59 (409) 3.49 (221) 1.41 (1.181.67) <0.001 1.29 (1.061.56) 0.009
Sudden cardiac death 0.43 (68) 0.81 (51) 1.87 (1.282.73) 0.001 1.53 (1.042.26) 0.032
Stroke, non-CNS embolism, TIA 1.55 (242) 1.72 (108) 1.11 (0.871.42) 0.393 0.98 (0.761.26) 0.856
All-cause hospitalization 30.70 (3,420) 41.48 (1,693) 1.33 (1.251.41) <0.001 1.15 (1.091.22) <0.001
CV hospitalization 15.14 (1,992) 20.08 (1,015) 1.31 (1.211.42) <0.001 1.13 (1.051.22) 0.001
Bleeding hospitalization 2.95 (453) 4.00 (245) 1.35 (1.161.57) <0.001 1.04 (0.891.21) 0.630
Non-CV, nonbleeding hospitalization 15.01 (2,010) 21.02 (1,073) 1.39 (1.281.52) <0.001 1.19 (1.101.30) <0.001
New-onset heart failure 1.49 (168) 1.85 (68) 1.15 (0.861.54) 0.346 1.08 (0.801.47) 0.615

% (No. of Events) Unadjusted Adjusted

No Diabetes Diabetes
(n 4,626) (n 1,850) OR (95% CI) p Value OR* (95% CI) p Value

AF progression 28.02 (1,296) 28.3 (510) 1.05 (0.931.17) 0.443 0.96 (0.851.08) 0.462

*Adjusted for demographic and clinical factors.

CI condence interval; CNS central nervous system; CV cardiovascular, HR hazard ratio; OR odds ratio; other abbreviations as in Table 1.

explained by a greater prevalence of persistent and
permanent AF, whereas ablation is more likely to be
performed in the setting of paroxysmal AF and
would typically occur in relatively young subjects
without CV risk factors. Conversely, we observed a
greater use of rate-control medications in patients
with diabetes, which may parallel the use of
anticoagulants.
To our knowledge, our study was the rst of its
kind to report on the inuence of diabetes on the
occurrence of SCD among patients with AF. The
increase in the risk of SCD may be related to the fact
that diabetes and AF potentiate their respective
individual effects. It is well known that AF and dia-
betes independently increase the risk of SCD in the
general population (26,27).
The lack of association between diabetes and AF
progression contrasted somewhat with previous
studies suggesting that elevated glucose levels may
contribute to the persistence of AF in general (28) or
to the recurrence of AF after ablation (29). The
HATCH score (which is based on hypertension,
age $75 years, TIA or stroke, chronic obstructive
pulmonary disease, and HF) for predicting progres-
sion from paroxysmal to permanent AF did not
include diabetes (16). Furthermore, there is no
direct evidence showing that maintenance of well
controlled blood glucose, in accordance with guide-
lines, would be benecial. However, the ARREST-AF
(Aggressive Risk Factor Reduction Study for Atrial
Fibrillation and Implications for the Outcome of
Ablation) trial suggested that this may be the case, as
it showed that a strategy of aggressive modication
of several risk factors, including weight loss and
improved glycemic control, was associated with an
almost 5-fold increased odds of arrhythmia-free
survival after ablation (30). It is possible that the
degree of blood glucose control and the duration of
diabetes matter, as these would inuence left atrial
remodeling. Unfortunately, we did not have data on
these aspects of diabetes. Diabetes may confer a
specic pathophysiological substrate that would
theoretically aggravate AF and predispose to worse
thromboembolic outcomes. This substrate includes
structural (nonenzymatic glycation and connexin-
mediated brosis), electrical (intra-atrial conduc-
tion), and autonomic changes to the left atrium
(8,31). However, we did not observe an increase in
the risk of AF progression or poor thromboembolic
outcomes with diabetes. It is possible that the risk
of thromboembolic events was mitigated by the use
of OAC therapy, as diabetes is systematically
included in thromboembolic events risk prediction
tools.
1332 Echouffo-Tcheugui et al. JACC VOL. 70, NO. 11, 2017

Diabetes and Outcomes of AF SEPTEMBER 12, 2017:132535

C E N T R A L IL L U ST R A T I O N Comparative Outcomes of AF Between Patients With and

Without Diabetes

Mortality: Age <70 Years

Mortality: Age 70 Years
CV Death: Age <70 Years
CV Death: Age 70 Years
Non-CV Death
Outcomes

Sudden Cardiac Death

Stroke, Non-CNS Embolism or TIA
All-cause Hospitalization
CV Hospitalization
Bleeding Hospitalization
Non-CV Non-Bleeding Hospitalization
New-Onset Heart Failure
AF Progression
0 .5 1 1.5 2 2.5 3 3.5 4 4.5
Relative Risk
Better Worse
Echouffo-Tcheugui, J.B. et al. J Am Coll Cardiol. 2017;70(11):132535.

Although diabetes is a risk factor for thromboembolism in patients with atrial brillation (AF), its inuence on outcomes in such patients
requires study. We evaluated data from a national prospective registry of patients with AF and found that in nearly all outcomes studied,
including mortality, hospitalization, new-onset heart failure, and AF progression, diabetes was associated with higher risk for the
clinical outcomes compared to those patients without diabetes. Diabetes also was associated with worse AF symptoms and lower quality of
life but not thromboembolic or bleeding events. CNS central nervous system; CV cardiovascular; TIA transient ischemic attack.

Our study provided signicant complementary
information on the association of diabetes with AF
symptoms, health status, and clinical outcomes of AF.
In addition to information on the mortality risk
among patients with AF, we also provided informa-
tion on hospitalization, bleeding, and AF progression
as well as onset of HF rates. Previous outcome studies
of patient with diabetes and AF were limited by
incomplete adjustment for confounding factors,
relatively small sample sizes, and a shorter follow-up
period (1 year) (19,20). These studies have also lacked
the depth and diversity of our study population with
respect to race, age, or sex; in addition, the other
studies did not always characterize outcomes other
than death and stroke risk (19,20). Our ndings
highlighted the importance of diabetes management
in patients with AF and emphasized the importance
of using proven therapies that can reduce CV events
and mortality in patients with diabetes, such as
statins and certain diabetes medications.
management of comorbid diabetes and AF presents
unique challenges, especially in the context of the
emergence of new diabetes and AF therapies, with a
potential impact on the outcomes of AF or diabetes.
However, opportunities to improve outcomes in pa-
tients with diabetes have emerged, with recently
tested therapies (sodium-glucose cotransporter-2
inhibitors) having shown clear and important bene-
ts in terms of CV events (including HF) and CV
mortality (32). Diabetes among patients with AF may
be associated with higher expenditures, so inte-
grating management of AF and diabetes might
improve functional outcomes and reduce costs.
STUDY LIMITATIONS. The strengths of our study
include a large nationwide cohort, a standardized
methodology for data collection, and the examina-
tion of AF subtypes, regular follow-up, detailed in-
formation on comorbid illness, and several clinically
The relevant outcomes. However, there were limitations
JACC VOL. 70, NO. 11, 2017 Echouffo-Tcheugui et al. 1333
SEPTEMBER 12, 2017:132535 Diabetes and Outcomes of AF

to our study. First, reliance on clinical practice

F I G U R E 1 All-Cause Mortality
data for diabetes ascertainment might have missed
patients without a pre-hospitalization history of
1.00
diabetes and who were not screened during their
hospitalization for diabetes, especially as up to one-
fourth of all persons with diabetes in the United
States are undiagnosed (33). Diabetes might have

Probability of Survival
been underreported by using clinically diagnosed 0.95

and documented diabetes rather than using

strict laboratory criteria. Likewise, we did not
ascertain cases of diabetes that developed during
study follow-up. The consequence of underestima- 0.90
tion of diabetes frequency would be to bias the in-
uence of diabetes on the outcomes of AF toward
the null.
Second, the main endpoint for this analysis was
0.85
all-cause mortality; the causes of death are not
0.0 0.5 1.0 1.5 2.0
known because we did not have access to this in-
Time, Years
formation (especially the CV causes). However, dif-
#At risk 6875 6579 6195 5722 4562
ferences in overall and CV-related hospitalization 2874 2722 2515 2276 1830
rates pointed to a potentially high contribution of CV Mortality risk
diseases to deaths. Third, we did not have informa- No Diabetes (N = 6875) Diabetes (N = 2874)
tion on the degree of glycemic control (as repre-
sented by HbA 1c) or duration of diabetes, which Patients with diabetes had a higher rate of all-cause mortality than those without
might inuence outcomes. The levels of HbA1c are diabetes.
associated with stroke risk among those with AF and
improve the predictive accuracy for stroke in dia-
betic patients with AF (24). The duration of diabetes
might also be important for assessing the risk of confounders in our models, residual confounding
ischemic stroke among patients who have diabetes may have persisted, potentially affecting our
and AF (10,11). We did not have information on the ndings.
medications used for glycemic control (insulin or
noninsulin-based therapies), which may inuence
CONCLUSIONS
AF outcomes, especially given that some medication
classes (the thiazolidinediones) may be related to
Among patients with AF in this nationwide cohort,
better AF outcomes (34).
the prevalence of diabetes mellitus was 30%,
Fourth, the ORBIT-AF registry relied on voluntary
emphasizing the importance of diabetes screening in
participation from sites and patients. Thus, the re-
patients diagnosed with AF. Patients with AF and
sults might not be generalizable to all U.S. patients,
diabetes had more symptoms and worse health status
particularly those who are managed in different
along with higher mortality and higher frequency of
clinical settings compared with that of the ORBIT-AF
hospitalization than patients without diabetes.
participants. Fifth, the follow-up duration in our
Future studies are warranted to explore ways to
study (2 years) might not reveal the longer-terms
mitigate this mounting problem, which could expo-
effects of diabetes. Furthermore, given the average
nentially worsen in the years to come given the
age of our participants (>70 years) and that younger
growing diabetes epidemic.
people with diabetes might be at greater risk for
developing AF (35), there may have been a selection
bias related to the enrollment process. However, it is ADDRESS FOR CORRESPONDENCE: Dr. Gregg C.
important to bear in mind that age is a signicant Fonarow, Ahmanson-UCLA Cardiomyopathy Center,
risk factor for AF. Finally, we may have had a Ronald Reagan-UCLA Medical Center, 10833 LeConte
limited power to detect a difference in some of the Avenue, Room 47123 CHS, Los Angeles, California
outcomes, and, despite appropriate adjustment for 90095. E-mail: GFonarow@mednet.ucla.edu.
1334 Echouffo-Tcheugui et al. JACC VOL. 70, NO. 11, 2017

Diabetes and Outcomes of AF SEPTEMBER 12, 2017:132535

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE: In pa- TRANSLATIONAL OUTLOOK: Future efforts to

tients with AF, concurrent diabetes inuences the burden
of AF-related symptoms, risk of hospitalization, and
cardiovascular outcomes.
improve clinical outcomes for patients with AF should
recognize that diabetes contributes to adverse outcomes
beyond thromboembolic events, but more research is
needed to understand the mechanisms by which diabetes
effects these outcomes.

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Echouffo-Tcheugui et al. 1335
Diabetes and Outcomes of AF
KEY WORDS anticoagulation, heart failure,
hospitalization, mortality, thromboembolic
events
A PP END IX For a list of covariates for
multivariable modeling as well as supplemental
tables and gures, please see the online version
of this article.