Author's Accepted Manuscript
Glycated Hemoglobin and Risk of First Episode Stroke in Diabetic Patients with Atrial Fibrillation: A Cohort Study W. Saliba M.D., MPH, O. Barnett-Griness Ph.D., M. Elias M.D., G. Rennert M.D., Ph.D.
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PII: DOI: Reference:
S1547-5271(15)00075-2 http://dx.doi.org/10.1016/j.hrthm.2015.01.025 HRTHM6096
To appear in:
Heart Rhythm
Cite this article as: W. Saliba M.D., MPH, O. Barnett-Griness Ph.D., M. Elias M.D., G. Rennert M.D., Ph.D., Glycated Hemoglobin and Risk of First Episode Stroke in Diabetic Patients with Atrial Fibrillation: A Cohort Study, Heart Rhythm, http://dx.doi.org/ 10.1016/j.hrthm.2015.01.025 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Glycated Hemoglobin and Risk of First Episode Stroke in Diabetic Patients with Atrial Fibrillation: A Cohort Study Short title: Glycated hemoglobin and stroke in atrial fibrillation
W. Saliba, M.D., MPHa,b, O. Barnett-Griness, Ph.Da, M. Elias, M.D.b, G. Rennert, M.D., Ph.D. a,c From the aDepartment of Community Medicine and Epidemiology, Carmel Medical Center, Clalit Health Services, and Bruce Rappaport Faculty of Medicine, Technion– Israel Institute of Technology, Haifa, Israel. bInternal Medicine C, Ha'emek Medical Center, Afula, Israel, and cDepartment of Epidemiology and Disease Prevention, Office of the Chief Physician, Clalit Health Services Headquarters, Tel Aviv, Israel.
Word count: 4,717 No conflict of interest or financial disclosures were reported by the authors of this paper
Address of corresponding author: Walid Saliba, M.D., MPH Department of Internal Medicine C, Ha'emek Medical Center, 18101 Afula, Israel Tel: 972-4-6495132 Fax:972-4-6495243 e-mail: [email protected]
2
Abstract Background: Diabetes is associated with increased risk of stroke in patients with atrial fibrillation. Whether glycemic control, evaluated by glycated hemoglobin, affects the risk of stroke in diabetic patients with atrial fibrillation remains unknown. Methods: Using the computerized database of the largest HMO in Israel, we identified a cohort of adults 20 years old or older with atrial fibrillation diagnosed before 1st January 2012. Eligible subjects had no prior stroke or TIA and were not on anticoagulants at baseline. The cohort (37,358 subjects) was followed for the first event of stroke or TIA until 31st December 2012. Results: Overall 1,052 subjects developed stroke during 35,278 person-years follow up, (stroke rate, 2.98 per 100 person-years). Cox proportional hazard regression analysis adjusting for CHA2DS2-VASc score risk factors showed that, compared to subjects without diabetes, the HR for stroke was 1.04 (95% CI, 0.83-1.30) for the lowest glycated hemoglobin quartile (values 7.70%) (P for trend 7.70%] n = 2,662 (7.1%)
72.0 (14.5) 75.0 (63.083.0)
71.0 (15.7) 74.0 (61.083.0)
10,445 (28.0%) 8,160 (21.8%) 18,753 (50.2%) 18,762 (50.2%) 26,809 (71.8%) 6,605 (17.7%) 17,640 (47.2%)
8,195 (31.3%) 5,199 (19.9%) 12,788 (48.8%) 13,225 (50.5%) 17.071 (65.2%) 3,566 (13.6%) 10.863 (41.5%)
75.3 (10.8) 75.0 (10.4) 74.7 (10.6 71.6 77.0 (68.0- 76.0 (68.0- 76.0 (67.0- (11.6) 83.0) 83.0) 82.0) 72.0 (63.7507 503 471 80.0) (17.4%) (16.9%) (17.9%) 704 804 713 769 (24.2%) (27.0%) (27.1%) (28.9%) 1,702 1,667 1,443 740 (58.4%) (56.1%) (54.9%) (27.8%) 1,153 (43.3%) 1,457 1,515 1,287 1,278 (50.0%) (50.9%) (49.0%) (48.0%) 2,522 2,565 2,338 2,313 (86.6%) (86.2%) (89.0%) (86.9%) 733 708 721 877 (25.2%) (23.8%) (27.4%) (32.9%) 1,646 1,735 1,657 1,739 (56.5%) (58.3%) (63.1%) (65.3%)
3.39 (1.77) 4 (2-5)
2.88 (1.66) 3 (2-4)
4.59 (1.42) 4.58 (1.40) 4.65 (1.38) 4.48 5 (4-6) 5 (4-6) 5 (4-6) (1.46) 5 (3-6)
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Table 2: Incidence density of first episode stroke in patients with atrial fibrillation presented by CHADS2 and CHA2DS2-VASc scores Number of points* 0 – points 1 – point 2 – points 3 – points 4 – points 5 – points 6 – points 7 – points HR (95% CI)for each point increase
CHADS2 score Number (%) Incidence density rate (Per 100 person-years) 6,563(17.6%) 0.82 9,086 (24.3%) 2.06 12,751 (34.1%) 3.54 7,077 (18.9%) 4.82 1,881 (5.0%) 5.41 1.53 (1.45-1.62)
CHA2DS2-VASc score Number (%) Incidence density rate (Per 100 person-years) 2,616 (7.0%) 0.42 3,976 (10.6%) 0.82 4,862 (13.0%) 1.81 6,556 (17.5%) 2.57 8,385 (22.4%) 3.71 8,850 (18.3%) 4.52 3,291 (8.8%) 5.10 822 (2.2%) 5.60 1.36 (1.31-1.41)
*; because we have excluded patients with prior stroke or TIA which confers 2 points for CHADS2 and CHA2DS2-VASc score, the maximum score in our cohort is 4 and 7 points respectively.
21
Table 3: Number of events and crude incidence rate of first episode stroke in patients with atrial fibrillation presented separately for non-diabetic and diabetic patients and according to glycated hemoglobin quartiles in diabetic patients; CHS cohort, Israel 2012 (n=37,357) Category
Number
Follow up
Stroke
Incidence rate
(person-
(n)
(per 100 person-
years)
years)
All patients
37,358
35,278
1,052
2.98
Patients without Diabetes
26,182
24,893
645
2.59
Patients with Diabetes
11,176
10,385
407
3.92
Quartile-1 [< 6.35%]
2,913
2,698
87
3.22
Quartile-2 [6.35%-6.90%]
2,974
2,790
98
3.51
Quartile-3 [6.90%-7.70%]
2,627
2,442
110
4.50
Quartile-4 [>7.70%]
2,662
2,455
112
4.56
Glycated hemoglobin*
*; glycated hemoglobin quartiles in patients with diabetes
22
Table 4: Multivariate Cox proportional regression model for the association between glycated hemoglobin and first episode stroke in patients with atrial fibrillation, adjusted for CHA2DS2-Vasc score risk factors*; CHS cohort, Israel 2012 (n=37,358) CHA2DS2-Vasc risk factors
Hazard Ratio (95% CI)
P value
Diabetes mellitus Without diabetes
Reference
Quartile-1 [< 6.35%]
1.04 (0.83-1.30)
0.746
Quartile-2 [6.35%-6.90%]
1.14 (0.92-1.42)
0.218
Quartile-3 [6.90%-7.70%]
1.46 (1.19-1.79)
7.70%]
1.63 (1.33-2.00)
Glycated Hemoglobin and Risk of First Episode Stroke in Diabetic Patients with Atrial Fibrillation: A Cohort Study W. Saliba M.D., MPH, O. Barnett-Griness Ph.D., M. Elias M.D., G. Rennert M.D., Ph.D.
www.elsevier.com/locate/buildenv
PII: DOI: Reference:
S1547-5271(15)00075-2 http://dx.doi.org/10.1016/j.hrthm.2015.01.025 HRTHM6096
To appear in:
Heart Rhythm
Cite this article as: W. Saliba M.D., MPH, O. Barnett-Griness Ph.D., M. Elias M.D., G. Rennert M.D., Ph.D., Glycated Hemoglobin and Risk of First Episode Stroke in Diabetic Patients with Atrial Fibrillation: A Cohort Study, Heart Rhythm, http://dx.doi.org/ 10.1016/j.hrthm.2015.01.025 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Glycated Hemoglobin and Risk of First Episode Stroke in Diabetic Patients with Atrial Fibrillation: A Cohort Study Short title: Glycated hemoglobin and stroke in atrial fibrillation
W. Saliba, M.D., MPHa,b, O. Barnett-Griness, Ph.Da, M. Elias, M.D.b, G. Rennert, M.D., Ph.D. a,c From the aDepartment of Community Medicine and Epidemiology, Carmel Medical Center, Clalit Health Services, and Bruce Rappaport Faculty of Medicine, Technion– Israel Institute of Technology, Haifa, Israel. bInternal Medicine C, Ha'emek Medical Center, Afula, Israel, and cDepartment of Epidemiology and Disease Prevention, Office of the Chief Physician, Clalit Health Services Headquarters, Tel Aviv, Israel.
Word count: 4,717 No conflict of interest or financial disclosures were reported by the authors of this paper
Address of corresponding author: Walid Saliba, M.D., MPH Department of Internal Medicine C, Ha'emek Medical Center, 18101 Afula, Israel Tel: 972-4-6495132 Fax:972-4-6495243 e-mail: [email protected]
2
Abstract Background: Diabetes is associated with increased risk of stroke in patients with atrial fibrillation. Whether glycemic control, evaluated by glycated hemoglobin, affects the risk of stroke in diabetic patients with atrial fibrillation remains unknown. Methods: Using the computerized database of the largest HMO in Israel, we identified a cohort of adults 20 years old or older with atrial fibrillation diagnosed before 1st January 2012. Eligible subjects had no prior stroke or TIA and were not on anticoagulants at baseline. The cohort (37,358 subjects) was followed for the first event of stroke or TIA until 31st December 2012. Results: Overall 1,052 subjects developed stroke during 35,278 person-years follow up, (stroke rate, 2.98 per 100 person-years). Cox proportional hazard regression analysis adjusting for CHA2DS2-VASc score risk factors showed that, compared to subjects without diabetes, the HR for stroke was 1.04 (95% CI, 0.83-1.30) for the lowest glycated hemoglobin quartile (values 7.70%) (P for trend 7.70%] n = 2,662 (7.1%)
72.0 (14.5) 75.0 (63.083.0)
71.0 (15.7) 74.0 (61.083.0)
10,445 (28.0%) 8,160 (21.8%) 18,753 (50.2%) 18,762 (50.2%) 26,809 (71.8%) 6,605 (17.7%) 17,640 (47.2%)
8,195 (31.3%) 5,199 (19.9%) 12,788 (48.8%) 13,225 (50.5%) 17.071 (65.2%) 3,566 (13.6%) 10.863 (41.5%)
75.3 (10.8) 75.0 (10.4) 74.7 (10.6 71.6 77.0 (68.0- 76.0 (68.0- 76.0 (67.0- (11.6) 83.0) 83.0) 82.0) 72.0 (63.7507 503 471 80.0) (17.4%) (16.9%) (17.9%) 704 804 713 769 (24.2%) (27.0%) (27.1%) (28.9%) 1,702 1,667 1,443 740 (58.4%) (56.1%) (54.9%) (27.8%) 1,153 (43.3%) 1,457 1,515 1,287 1,278 (50.0%) (50.9%) (49.0%) (48.0%) 2,522 2,565 2,338 2,313 (86.6%) (86.2%) (89.0%) (86.9%) 733 708 721 877 (25.2%) (23.8%) (27.4%) (32.9%) 1,646 1,735 1,657 1,739 (56.5%) (58.3%) (63.1%) (65.3%)
3.39 (1.77) 4 (2-5)
2.88 (1.66) 3 (2-4)
4.59 (1.42) 4.58 (1.40) 4.65 (1.38) 4.48 5 (4-6) 5 (4-6) 5 (4-6) (1.46) 5 (3-6)
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Table 2: Incidence density of first episode stroke in patients with atrial fibrillation presented by CHADS2 and CHA2DS2-VASc scores Number of points* 0 – points 1 – point 2 – points 3 – points 4 – points 5 – points 6 – points 7 – points HR (95% CI)for each point increase
CHADS2 score Number (%) Incidence density rate (Per 100 person-years) 6,563(17.6%) 0.82 9,086 (24.3%) 2.06 12,751 (34.1%) 3.54 7,077 (18.9%) 4.82 1,881 (5.0%) 5.41 1.53 (1.45-1.62)
CHA2DS2-VASc score Number (%) Incidence density rate (Per 100 person-years) 2,616 (7.0%) 0.42 3,976 (10.6%) 0.82 4,862 (13.0%) 1.81 6,556 (17.5%) 2.57 8,385 (22.4%) 3.71 8,850 (18.3%) 4.52 3,291 (8.8%) 5.10 822 (2.2%) 5.60 1.36 (1.31-1.41)
*; because we have excluded patients with prior stroke or TIA which confers 2 points for CHADS2 and CHA2DS2-VASc score, the maximum score in our cohort is 4 and 7 points respectively.
21
Table 3: Number of events and crude incidence rate of first episode stroke in patients with atrial fibrillation presented separately for non-diabetic and diabetic patients and according to glycated hemoglobin quartiles in diabetic patients; CHS cohort, Israel 2012 (n=37,357) Category
Number
Follow up
Stroke
Incidence rate
(person-
(n)
(per 100 person-
years)
years)
All patients
37,358
35,278
1,052
2.98
Patients without Diabetes
26,182
24,893
645
2.59
Patients with Diabetes
11,176
10,385
407
3.92
Quartile-1 [< 6.35%]
2,913
2,698
87
3.22
Quartile-2 [6.35%-6.90%]
2,974
2,790
98
3.51
Quartile-3 [6.90%-7.70%]
2,627
2,442
110
4.50
Quartile-4 [>7.70%]
2,662
2,455
112
4.56
Glycated hemoglobin*
*; glycated hemoglobin quartiles in patients with diabetes
22
Table 4: Multivariate Cox proportional regression model for the association between glycated hemoglobin and first episode stroke in patients with atrial fibrillation, adjusted for CHA2DS2-Vasc score risk factors*; CHS cohort, Israel 2012 (n=37,358) CHA2DS2-Vasc risk factors
Hazard Ratio (95% CI)
P value
Diabetes mellitus Without diabetes
Reference
Quartile-1 [< 6.35%]
1.04 (0.83-1.30)
0.746
Quartile-2 [6.35%-6.90%]
1.14 (0.92-1.42)
0.218
Quartile-3 [6.90%-7.70%]
1.46 (1.19-1.79)
7.70%]
1.63 (1.33-2.00)
