supplementary online content - jama · procedure codes (sks code) pacemakr/icd fpg fpe percutaneous...

Supplementary Online Content

Melgaard L, Gorst-Rasmussen A, Lane DA, Rasmussen LH, Larsen TB, Lip GYH. Assessment of the CHA2DS2-VASc score in predicting ischemic stroke, thromboembolism, and death in patients with heart failure with and without atrial fibrillation. JAMA. doi:10.1001/jama.2015.10725

eTable 1. ICD10-Codes and ATC-Codes Used in the Study eTable 2. Crude Incidence Rates at 5-Year Follow-up in the Heart Failure Study Population, Stratified According to Prior Diagnosis of Atrial Fibrillation

eTable 3. Crude Relative Risks at 1-Year Follow-up in the Heart Failure Population, When Comparing Patients With and Without Atrial Fibrillation

eTable 4. Association Between Each Individual Component of the CHA2DS2-VASc Score and Ischemic Stroke Risk

eFigure 1. Absolute Risks and Relative Risks by CHA2DS2-VASc Score Components During 5-Year of Follow-up, Stratified According to Prior Diagnosis of Atrial Fibrillation

eFigure 2. Sensitivity Analysis (Extending the Definition of Concomitant AF at Baseline): Absolute Risks and Relative Risks by CHA2DS2-VASc Score Components During the First Year of Follow-up, Stratified According to Prior Diagnosis of Atrial Fibrillation

eFigure 3. Sensitivity Analysis (Censoring Patients Who Get a Diagnosis of AF During Follow-up): Absolute Risks and Relative Risks by CHA2DS2-VASc Score Components During the First Year of Follow-up, Stratified According to Prior Diagnosis of Atrial Fibrillation

eFigure 4. Sensitivity Analysis (Split Sample Analysis – Early Study Period): Absolute Risks and Relative Risks by CHA2DS2-VASc Score Components During the First Year of Follow-up, Stratified According to Prior Diagnosis of Atrial Fibrillation

eFigure 5. Sensitivity Analysis (Split Sample Analysis – Late Study Period): Absolute Risks and Relative Risks by CHA2DS2-VASc Score Components During the First Year of Follow-up, Stratified According to Prior Diagnosis of Atrial Fibrillation

eFigure 6. Sensitivity Analysis (Including Patients With COPD): Absolute Risks and Relative Risks by CHA2DS2-VASc Score Components During the First Year of Follow-up, Stratified According to Prior Diagnosis of Atrial Fibrillation

This supplementary material has been provided by the authors to give readers additional information about their work.

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eTable 1. ICD-10 Codes and ATC-Codes Used in the Study

ICD 10-Codes and ATC-Codes used in the Study Main diagnosis ICD 10-codes Congestive heart failure I50.0-I50.9, I11.0, I13.0, I13.2 Atrial fibrillation I48.0-I48.9 Endpoints Stroke (ischemic) I63.0-I63.9, I64.9 Ischemic stroke (Thromboembolic event) I63.0-I63.9, I64.9

Transient ischemic attack (Thromboembolic event) G45.0-G45.9*

Systemic embolism (Thromboembolic event) I74.0-I74.9

Pulmonary embolism (Thromboembolic event) I26.0-I26.9

Acute myocardial infarction (Thromboembolic event) I21.0-I21.9, I23.0-I23.9

Comorbidities ICD 10-codes Prior stroke (ischemic or hemorrhagic) I60.0-I60.9, I61.0-I61.9, I62.0-I62.9, I63.0-I63.9, I64.9

Acute myocardial infarction I21.0-I21.9, I23.0-I23.9 Peripheral ischemic disease† I70.2-I70.9, I71.0-I71.9, I73.9 Vascular disease I21.0-I21.9, I23.0-I23.9, I70.0, I70.2-I70.9, I71.0-I71.9, I73.9 Diabetes mellitus E10.0-E10.9, E11.0-E11.9 Hypertension I10.0-I10.9, I11.0-I11.9, I12.0-I12.9, I13.0-I13.9, I15.0–I15.9

Renal disease I12.0-I12.9, I13.0-I13.9, N00-N07, N11.0-N11.9, N14.0-N14.4, N17.0-N17.9, N18.0-N18.9, N19, Q61.0-Q61.9

Liver disease B15.0-B15.9, B16.0-B16.9, B17.0-B17.9, B18.0-B18.9, B19.0-B19.9, K70.4, K72.0-K72.9, K76.6 Hyperthyroidisme E05.0-E05.9, E06.0-E06.9 Chronic obstructive pulmonary disease (COPD) J44.0-J44.9

Valvular disease (exclusion criteria) I05.0-I05.9, I06.0-I06.9, I34.0-I34.9, I35.0-I35.9 Mechanical cardiac valve (exclusion criteria) Z95.2, Z95.3, Z95.4

Cancer any type (exclusion criteria) C00-C97 Concomitant medication ATC-codes Warfarin (exclusion criteria) B01AA03 Phenprocoumon (exclusion criteria) B01AA04 ACE-inhibitors C09AA Angiotensin receptor blockers C09CA Beta-blockers C07

Non-loop diuretics C02DA, C02L, C03A, C03B, C03D, C03E, C03X, C07C, C07D, C08G,C09BA, C09DA, C09XA52 Aldosterone antagonists C03DA Loop diuretics C03C Statins C10



Concomitant medication ATC-codes Non steroidal anti-inflammatory drugs (NSAIDs) M01A

Aspirin B01AC06 Thienopyridines B01AC04, B01AC22, B01AC24 Antidiabetics A10 Calcium chanel antagonists C07F C08 C09BB C09DB Digoxin C01AA05 Vasodilators C02DB C02DD C02DG C04 C05 Interventions Procedure codes (SKS code) Pacemakr/ICD FPG FPE Percutaneous coronary intervention(PCI) FNG

Coronary artery bypass graft (CABG) FNA FNC FND FNE

* Not inclusive G45.3 (Amaurosis fugax) † Peripheral arterial disease, refers to the obstruction of large arteries not within the coronary, aortic arch vasculature, or brain



eTable 2. Crude Incidence Rates at 5-Year Follow-up in the Heart Failure Study Population, Stratified According to Prior Diagnosis of Atrial Fibrillation

Endpoint CHA2DS2-VASc score - Additional risk factor

Overall 1 (HF only) 2 3 4 5 6+

Non-AF

Patients in each score, No. (%)

33,592 2,366

(7.0)

4,503 (13.4) 7,462

(22.2)

9,183

(27.3)

5,958

(17.7)

4,120

(12.3)

Ischemic stroke

Events, No. 2,080 64 151 395 548 455 467

Person-years 3.14e+07 2.723.598 5.204.536 7.478.778 8.172.942 4.930.078 2.058.004

Incidence rate (95% CI) 0.7

(0.6-0.7)

0.2

(0.2-0.3)

0.3

(0.2-0.3)

0.5

(0.5-0.6)

0.7

(0.6-0.7)

0.9

(0.8-1.0)

1.6

(1.5-1.8)

Thromboembolism†

Events, No. 5,572 202 506 1,073 1,501 1,224 1,066

Person-years 2.93e+07 2.632.036 4.941.719 7.057.264 7.607.543 4.532.796 1.824.215


(1.8-1.9)

0.7

(0.7-0.9)

1.0

(0.9-1.1)

1.5

(1.4-1.6)

2.0

(1.9-2.1)

2.7

(2.6-2.9)

4.1

(3.9-4.4)

Death

Events, No. 13,836 354 818 2,633 4,444 3,144 2,443

Person-years 3.25e+07 2.765.491 5.305.327 7.686.298 8.450.027 5.161.519 2.206.065


(4.3-4.3)

1.3

(1.2-1.4)

1.5

(1.4-1.7)

3.4

(3.3-3.6)

5.3

(5.1-5.4)

6.1

(5.9-6.3)

7.7

(7.4-8.0)



AF

Patients in each score, No. (%)

9,395 606

(6.5)

931

(9.9)

1,752

(18.7)

2,571

(27.4)

1,937

(20.6)

1,598

(17.0)

Ischemic stroke

Events, No. 590 14 19 69 159 158 171

Person-years 4.092.929 145.003 305.795 789.468 1.265.106 918.162 423.061


(1.3-1.6)

1.0

(0.6-1.6)

0.6

(0.4-1.0)

0.9

(0.7-1.1)

1.3

(1.1-1.5)

1.7

(1.5-2.0)

2.6

(2.2-3.0)

Thromboembolism†

Events, No. 1,124 31 49 152 294 296 302

Person-years 3.897.488 139.425 291.140 756.390 1.225.451 877.400 386.309


(2.7-3.1)

2.2

(1.6-3.2)

1.7

(1.3-2.2)

2.0

(1.7-2.4)

2.4

(2.1-2.7)

3.4

(3.0-3.8)

5.0

(4.4-5.6)

Death

Events, No. 3,766 26 90 561 1,190 963 936

Person-years 4.301.442 147.071 310.708 809.780 1.332.492 975.518 453.103


(8.5-9.0)

1.8

(1.2-2.6)

2.9

(2.4-3.6)

6.9

(6.4-7.5)

8.9

(8.4-9.5)

9.9

(9.3-10.5)

12.9

(12.1-13.7)

All study patients had heart failure at baseline

Incidence rates are reported as % per year over 5 years of follow-up

Abbreviations: HF=heart failure; CHA2DS2-VASc score=congestive heart failure, hypertension, age ≥75 years (doubled), diabetes, stroke/TIA/thromboembolism (doubled), vascular disease (prior myocardial infarction, peripheral artery disease, or aortic plaque), age 65–75 years, sex category (female); CI=confidence interval

†Composite endpoint of ischemic stroke, transient ischemic attack, systemic embolism, pulmonary embolism, acute myocardial infarction



eTable 3. Crude Relative Risks at 1-Year Follow-up in the Heart Failure Population, When Comparing Patients With and Without Atrial Fibrillation

Non-AF patients vs AF patients (reference: AF patients)

ENDPOINT Risk score RR after 1 year (95% CI)

Test for interaction, overall

ISCHEMIC STROKE

CHA2DS2-VASc score P=0.001

1 (HF only) Ref.

2 additional risk factor 2.21 (1.53-3.19)

3 additional risk factors 1.60 (1.20-2.15)



6+ additional risk factors 1.05 (0.85-1.30)

THROMBO-EMBOLISM†

CHA2DS2-VASc score P=0.000

1 (HF only) Ref.






DEATH CHA2DS2-VASc score P=0.000

1 (HF only) Ref.







Abbreviations: AF=atrial fibrillation; CHA2DS2-VASc score=congestive heart failure, hypertension, age ≥75 years (doubled), diabetes, stroke/TIA/thromboembolism (doubled), vascular disease (prior myocardial infarction, peripheral artery disease, or aortic plaque), age 65–75 years, sex category (female)

†Composite endpoint of ischemic stroke, transient ischemic attack, systemic embolism, pulmonary embolism, acute myocardial infarction



eTable 4. Association Between Each Individual Component of the CHA2DS2-VASc Score and Ischemic Stroke Risk

Individual components of the CHA2DS2-VASc score Non-AF

Crude RR (95% CI)

AF

Crude RR (95% CI)

Hypertension 1.30 (1.13-1.51) 1.24 (1.09-1.40)

Age ≥75 years 1.33 (1.17-1.51) 1.34 (1.20-1.49)

Diabetes 1.50 (1.29-1.73) 1.42 (1.25-1.62)

Stroke/TIA/thromboembolism 4.92 (4.34-5.58) 4.40 (3.94-4.90)

Vascular disease 1.32 (1.16-1.51) 1.24 (1.10-1.40)

Age 65-75 years 1.57 (1.34-1.85) 1.64 (1.41-1.90)

Female sex 0.84 (0.74-0.95) 0.96 (0.86-1.07)


Abbreviations: AF: atrial fibrillation; CHA2DS2-VASc score=congestive heart failure, hypertension, age ≥75 years (doubled),

diabetes, stroke/TIA/thromboembolism (doubled), vascular disease (prior myocardial infarction, peripheral artery disease, or aortic

plaque), age 65–75 years, sex category (female); CI: confidence interval; RR: relative risk; TIA: transient ischemic attack



eFigure 1. Absolute Risks and Relative Risks by CHA2DS2-VASc Score Components During 5-Year of Follow-up, Stratified According to Prior Diagnosis of Atrial Fibrillation

A) Absolute risk of ischemic stroke; B) Relative risk of ischemic stroke; C) Absolute risk of thromboembolism; D) Relative risk of thromboembolism; E) Absolute risk of death; F) Relative risk of death. Number of patients contributing data in each group for each CHA2DS2-VASc score (non-AF: 2,366, 4,503, 7,462, 9,183, 5,958, and 2,733; AF: 606, 931, 1,752, 2,571, 1,937, and 980, for score 1-6).



eFigure 2. Sensitivity Analysis (Extending the Definition of Concomitant AF at Baseline): Absolute Risks and Relative Risks by CHA2DS2-VASc Score Components During the First Year of Follow-up, Stratified According to Prior Diagnosis of Atrial Fibrillation

A) Absolute risk of ischemic stroke; B) Relative risk of ischemic stroke; C) Absolute risk of thromboembolism; D) Relative risk of thromboembolism; E) Absolute risk of death; F) Relative risk of death. Number of patients contributing data in each group for each CHA2DS2-VASc score (non-AF: 2,277, 4,377, 7,267, 8,941, 5,817, and 2,671; AF: 695, 1,057, 1,947, 2,813, 2,078, and 1,042, for score 1-6).



eFigure 3. Sensitivity Analysis (Censoring Patients Who Get a Diagnosis of AF During Follow-up): Absolute Risks and Relative Risks by CHA2DS2-VASc Score Components During the First Year of Follow-up, Stratified According to Prior Diagnosis of Atrial Fibrillation




eFigure 4. Sensitivity Analysis (Split Sample Analysis – Early Study Period (2000-2005)): Absolute Risks and Relative Risks by CHA2DS2-VASc Score Components During the First Year of Follow-up, Stratified According to Prior Diagnosis of Atrial Fibrillation




eFigure 5. Sensitivity Analysis (Split Sample Analysis – Late Study Period (2006-2012)): Absolute Risks and Relative Risks by CHA2DS2-VASc Score Components During the First Year of Follow-up, Stratified According to Prior Diagnosis of Atrial Fibrillation

A) Absolute risk of ischemic stroke; B) Relative risk of ischemic stroke; C) Absolute risk of thromboembolism; D) Relative risk of thromboembolism; E) Absolute risk of death; F) Relative risk of death. Number of patients contributing data in each group for each CHA2DS2-VASc score (non-AF: 1,096, 2,124, 3,175, 3,710, 2,726, and 1,322; AF: 349, 550, 878, 1,211, 1,046, and 596, for score 1-6).



eFigure 6. Sensitivity Analysis (Including Patients With COPD): Absolute Risks and Relative Risks by CHA2DS2-VASc Score Components During the First Year of Follow-up, Stratified According to Prior Diagnosis of Atrial Fibrillation

A) Absolute risk of ischemic stroke; B) Relative risk of ischemic stroke; C) Absolute risk of thromboembolism; D) Relative risk of thromboembolism; E) Absolute risk of death; F) Relative risk of death. Number of patients contributing data in each group for each CHA2DS2-VASc score (non-AF: 2,605, 5,269, 8,784, 10,670, 6,935, and 4,816; AF: 664, 1,095, 2,238, 3,204, 2,474, and 2,076, for score 1-6).



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