Beruflich Dokumente
Kultur Dokumente
11, 2017
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
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 Echouffo-Tcheugui et al. 1327
SEPTEMBER 12, 2017:132535 Diabetes and Outcomes of AF
OUTCOMES. Patients were followed at 6-month in- models for adjustment and is listed in the Online
tervals for up to 3 years. Outcomes assessed at follow- Appendix. Adjusted associations for outcomes are
up were all-cause mortality, CV death, non-CV death, displayed as hazard ratio (HR) or OR with corre-
hospitalization (all-cause, CV-related, bleeding- sponding 95% condence interval (CI). We assessed
related, and non-CV and nonbleeding-related), stroke the inuence of age, race (white vs. nonwhite), use of
or non-central nervous system systemic embolism or anticoagulants, renal function (as dened by esti-
transient ischemic attack (TIA), incident new-onset mated glomerular ltration rate), type of AF (parox-
HF, AF progression, bleeding events, AF symptoms, ysmal vs. nonparoxysmal), history of ablation
health status, and use of targeted therapies. AF pro- procedure, and pulse pressure on the relationship
gression was dened as either: 1) progression from between diabetes and outcomes, by testing the
paroxysmal AF at baseline to either persistent or interaction of each of these factors with diabetes. In
permanent AF reported at any subsequent follow-up models, all continuous variables were tested for
visit; or 2) progression from persistent AF at base- linearity with each outcome, and any nonlinear
line to permanent AF reported at any subsequent associations are accounted for using linear splines.
follow-up visit (15,16). Paroxysmal AF was dened as Missing covariate data in the regression analysis were
recurrent AF episodes that terminate spontaneously handled by multiple imputation using Markov Chain
within 7 days; persistent AF as recurrent AF that is Monte Carlo and regression methods. Final estimates
sustained for more than 7 days; and permanent AF as and associated standard errors reect the combined
AF in which the presence of the AF is accepted. The analysis over 5 imputed datasets.
assessment of the use of targeted therapies included Analyses were performed using SAS version 9.3
the management strategy (rate control, rhythm (SAS Institute Inc., Cary, North Carolina). All p values
control), medication use (warfarin, non-vitamin were based on 2-sided tests and were considered
K oral anticoagulants [OACs], aspirin, clopidogrel, statistically signicant at p < 0.05.
beta-blockers, calcium-channel blockers, digoxin,
amiodarone, sotalol, dofetilide, propafenone, ecai- RESULTS
nide), and procedures (catheter ablation for AF or
atrial utter, atrioventricular node ablation The nal study sample from ORBIT-AF contained
cardioversion). 9,749 patients from 174 practices, among whom 2,874
STATISTICAL ANALYSIS. We compared patient (de- (29.5%) had diabetes, with median follow-up of 2.78
mographic and clinical) and hospital characteristics, years (IQR: 1.95 to 3.00 years) and mean follow-up of
as well as proportional use of different AF manage- 2.41 0.75 years. The proportion of surviving
ment strategies between patients with and without patients by period of follow-up are 6.8% with <1 year
diabetes. Categorical variables are presented as count of follow-up, 12.5% with <1.5 years of follow-up,
and proportion, and differences were tested using the 17.6% with <1.8 years of follow-up, and 28.9%
Pearson chi-square test. Continuous variables are with <2.0 years of follow-up.
presented as median (interquartile range [IQR]), and Baseline clinical and demographic characteristics
differences between groups were tested using the of the study participants by diabetes status are given
Wilcoxon rank sum test. in Table 1. Patients with diabetes were more likely to
The event rate for each outcome was estimated be younger, male, from an ethnic minority (Hispanic
both overall and by diabetes status, with rates pre- and black), a smoker, and have a higher body mass
sented as the number of events per 100 patient-years index and a history of comorbidities, with the largest
of follow-up. We used Cox proportional hazards differences from nondiabetic patients observed for
survival models to test the association between dia- hypertension, obesity, hyperlipidemia, chronic kid-
betes and each clinical outcome. For AF progression, ney disease or dialysis, chronic pulmonary obstruc-
we estimated the frequency and percentage of AF tive disease, obstructive sleep apnea, coronary artery
progression, and a logistic regression model was used disease, cerebrovascular disease, and HF. Patients
to estimate the odds ratio (OR) for the association with diabetes had a higher stroke risk compared to
between diabetes and AF progression. All models those without diabetes as estimated by media
used a robust variance estimate to account for CHADS2 (3 vs. 2; p < 0.001) and CHA2DS2 -VASc scores
correlation within sites. Covariates for the multivari- (5 vs. 4; p < 0.001). Only 0.7% of patients with
able modeling were chosen based on their clinical diabetes had a CHA2DS 2-VASc score of 1 compared to
relevance or known association with diabetes and 12.4% of patients without diabetes (p < 0.001).
outcome(s). A common set of variables was used in Patients with diabetes also had a signicantly
1328 Echouffo-Tcheugui et al. JACC VOL. 70, NO. 11, 2017
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
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 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
explained by a greater prevalence of persistent and controlled blood glucose, in accordance with guide-
permanent AF, whereas ablation is more likely to be lines, would be benecial. However, the ARREST-AF
performed in the setting of paroxysmal AF and (Aggressive Risk Factor Reduction Study for Atrial
would typically occur in relatively young subjects Fibrillation and Implications for the Outcome of
without CV risk factors. Conversely, we observed a Ablation) trial suggested that this may be the case, as
greater use of rate-control medications in patients it showed that a strategy of aggressive modication
with diabetes, which may parallel the use of of several risk factors, including weight loss and
anticoagulants. improved glycemic control, was associated with an
To our knowledge, our study was the rst of its almost 5-fold increased odds of arrhythmia-free
kind to report on the inuence of diabetes on the survival after ablation (30). It is possible that the
occurrence of SCD among patients with AF. The degree of blood glucose control and the duration of
increase in the risk of SCD may be related to the fact diabetes matter, as these would inuence left atrial
that diabetes and AF potentiate their respective remodeling. Unfortunately, we did not have data on
individual effects. It is well known that AF and dia- these aspects of diabetes. Diabetes may confer a
betes independently increase the risk of SCD in the specic pathophysiological substrate that would
general population (26,27). theoretically aggravate AF and predispose to worse
The lack of association between diabetes and AF thromboembolic outcomes. This substrate includes
progression contrasted somewhat with previous structural (nonenzymatic glycation and connexin-
studies suggesting that elevated glucose levels may mediated brosis), electrical (intra-atrial conduc-
contribute to the persistence of AF in general (28) or tion), and autonomic changes to the left atrium
to the recurrence of AF after ablation (29). The (8,31). However, we did not observe an increase in
HATCH score (which is based on hypertension, the risk of AF progression or poor thromboembolic
age $75 years, TIA or stroke, chronic obstructive outcomes with diabetes. It is possible that the risk
pulmonary disease, and HF) for predicting progres- of thromboembolic events was mitigated by the use
sion from paroxysmal to permanent AF did not of OAC therapy, as diabetes is systematically
include diabetes (16). Furthermore, there is no included in thromboembolic events risk prediction
direct evidence showing that maintenance of well tools.
1332 Echouffo-Tcheugui et al. JACC VOL. 70, NO. 11, 2017
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 management of comorbid diabetes and AF presents
information on the association of diabetes with AF unique challenges, especially in the context of the
symptoms, health status, and clinical outcomes of AF. emergence of new diabetes and AF therapies, with a
In addition to information on the mortality risk potential impact on the outcomes of AF or diabetes.
among patients with AF, we also provided informa- However, opportunities to improve outcomes in pa-
tion on hospitalization, bleeding, and AF progression tients with diabetes have emerged, with recently
as well as onset of HF rates. Previous outcome studies tested therapies (sodium-glucose cotransporter-2
of patient with diabetes and AF were limited by inhibitors) having shown clear and important bene-
incomplete adjustment for confounding factors, ts in terms of CV events (including HF) and CV
relatively small sample sizes, and a shorter follow-up mortality (32). Diabetes among patients with AF may
period (1 year) (19,20). These studies have also lacked be associated with higher expenditures, so inte-
the depth and diversity of our study population with grating management of AF and diabetes might
respect to race, age, or sex; in addition, the other improve functional outcomes and reduce costs.
studies did not always characterize outcomes other
than death and stroke risk (19,20). Our ndings STUDY LIMITATIONS. The strengths of our study
highlighted the importance of diabetes management include a large nationwide cohort, a standardized
in patients with AF and emphasized the importance methodology for data collection, and the examina-
of using proven therapies that can reduce CV events tion of AF subtypes, regular follow-up, detailed in-
and mortality in patients with diabetes, such as formation on comorbid illness, and several clinically
statins and certain diabetes medications. 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
Probability of Survival
been underreported by using clinically diagnosed 0.95
PERSPECTIVES
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