Web appendix: Supplementary material

A. Flow diagram

B. Randomized clinical trial populations

C. Details on PS estimation and trimming.

D. Codes for outcomes and covariates used to create cohort of patients identified from routine care

E. Standard Randomized Clinical Trial Bleeding Definitions applied to ARISTOTLE participants

F. Results using a thromboembolism outcome including only ischemic or ill-defined stroke and

systemic embolism

Appendix A: Flow Diagram

The inclusion/exclusion applied to the routine care cohort of patients with atrial fibrillation who were

observed to initiate treatment with dabigatran or warfarin can be compared to the inclusion/exclusion

criteria for participation in the RE-LY trial1 , excerpted below:

Inclusion: Patients meeting any of the criteria a-f:

a. Ischemic or ill-defined stroke

b. TIA

c. Systemic embolism

d. Heart failure diagnosis within 6 months

e. Age ≥75 y

f. Age ≥65 y AND

i. Diabetes mellitus on treatment

ii. Myocardial infarction

iii. CABG or PCI surgery

iv. Hypertension on treatment

Exclusion: Patients meeting any of the criteria 1-7

1. Valvular heart disease

2. Stroke within the previous 14 days

3. History of intracranial, gastrointestinal, urogenital or other bleeds

4. Peptic ulcer disease within 30 days

5. Joint replacement

6. Renal dysfunction, dialysis or kidney transplant

7. Liver disease

Appendix B: Randomized clinical trial populations

RCT based predictions for rates of thromboembolism and major bleeding events within strata of risk

scores were obtained from publications of the Randomized Evaluation of Long-Term Anticoagulation

Therapy (RE-LY) trial comparing dabigatran to warfarin and the Apixaban for Reduction in Stroke and

Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial comparing apixaban and

warfarin.2 The inclusion and exclusion criteria for these trials were different from the population

initiating treatment as part of routine care. The RE-LY and ARISTOTLE trials included participants who

had been on long term warfarin therapy prior to study entry and randomization. Patients for both trials

were required to have electrocardiography documented non-valvular atrial fibrillation and have at least

one known risk factor for stroke. The RE-LY trial excluded patients with recent (<14 days) or severe

strokes within 6 months of screening. 3 The ARISTOTLE trial also excluded patients with recent stroke

(<7 days). Both trials excluded patients with conditions putting them at higher risk of bleed, e.g. patients

with severe renal insufficiency, anemia, active liver disease or alcohol use disorders. Additional details on

other trial inclusion/exclusion criteria are available in the original articles.1-4

Randomization into the dabigatran and warfarin arms of the RE-LY trial resulted in well balanced

treatment arms in terms of risk factors for stroke. Observed differences between the RCT and routine

care populations for non-demographic baseline characteristics may be in part attributable to differences in

criteria used to define presence/absence of these characteristics.

The RE-LY trial publication reported aspirin use as a baseline characteristic, where the prevalence was

higher than that for medications predisposing to bleed (including aspirin) observed in the initiators

identified in routine care. This may be partially explained by the poor capture of aspirin use in healthcare

claims data.

The relative measure of effect comparing apixaban to warfarin on major bleeding did not differ across the

three HAS-BLED strata in the ARISTOTLE trial regardless of which major bleeding criteria were used

(e.g. ISTH, TIMI, GUSTO); however the effect of apixaban was stronger than observed for dabigatran

versus warfarin in the RE-LY trial (ARISTOTLE: 0.60-0.69, RE-LY: 0.93).2,3

Appendix C. Details on propensity score estimation and trimming

Propensity scores (PS) were calculated using logistic regression predicting initiation of dabigatran as

opposed to warfarin as the dependent variable. All predictors were assessed in the year prior to and

including the index date for initiation. Detailed code lists for predictors of exposure are available in

additional appendices and include:

1. Gender (Female/Male)

2. Age (under 65, 65-74, 75+)

3. Acute renal disease

4. Chronic renal disease

5. Renal (abnormal)

6. Miscellaneous renal disease

7. Alcohol use disorder

8. Atherosclerosis

9. Bleeding history

10. Coronary artery disease

11. Cerebral ischemia

12. Diabetes

13. Drugs predisposing to bleed (NSAID, aspirin, prasugrel, clopidogrel, ticagrelor)

14. Deep vein thrombosis

15. Heart failure

16. Hemorrhagic stroke

17. Hypertension

18. Hyperlipidemia

19. Ischemic stroke

20. Liver disease

21. Pulmonary embolism

22. Prior myocardial infarction

23. Peripheral vascular disease

24. Statin

25. Stroke/TIA/TE

26. Systemic embolism

27. Ulcer

28. Valvular heart disease

29. Vascular disease

30. Hospitalized within 30 days

31. Number of hospitalizations

32. Number of generics

33. Region

We restricted the sample of initiators to patients with observed “empirical equipoise”5 by trimming the

patients who fell within non-overlapping regions of PS. Patients with propensity scores falling in the

region of overlap for dabigatran and warfarin initiators, that is, between the maximum PS for warfarin and

minimum PS for dabigatran patients were included. Initiators falling outside of this region of overlap

were excluded because patients outside of the overlap region were observed to be treated deterministically

with dabigatran at the higher tail and warfarin at the lower tail.

Stabilized inverse probability of treatment weights were calculated for each individual by using the

marginal probability of observed treatment as the numerator and the predicted probability of observed

treatment (based on the propensity score) as the denominator.

Appendix D. Codes for outcomes and covariates used to create cohort of patients identified from

routine care

Outcome Definitions

Definition (ICD-9 diagnosis unless otherwise noted)

Thromboembolic Event Any of the codes below occurring as a primary discharge diagnosis

Systemic embolism 444.x Arterial embolism

Ischemic stroke6,7

433.x1 Occlusion and stenosis of precerebral arteries with cerebral

infarction

434.x1 Occlusion and stenosis of cerebral arteries with cerebral infarction

Stroke uncertain classification 436.x (acute, but ill-defined cerebrovascular disease)

Transient Ischemic Attack (TIA) 8,9 435.xx (transient cerebral ischemia)

Deep vein thrombosis (DVT) 10,11 451.1x (Phlebitis and thrombophlebitis of deep vessels of lower

extremities)

451.2x (of lower extremities, unspecified)

451.81 (of Iliac vein)

451.9x (of unspecified site)

453.1x (thrombophlebitis migrans)

453.2x ( venous embolism and thrombosis of vena cava)

453.8x (venous embolism and thrombosis of other specified veins)

453.9x (venous embolism and thrombosis of unspecified site)

Not in the validated algorithm but will be included following Mini-Sentinel

recommendation for VTE outcome:

453.40 (Venous embolism and thrombosis of unspecified deep vessels of

lower extremity (includes DVT)

453.41 (Venous embolism and thrombosis of deep vessels of proximal

lower extremity (includes femoral, iliac, popliteal, thigh, and upper leg)

453.42 (Venous embolism and thrombosis of deep vessels of distal lower

extremity (includes calf, lower leg, peroneal, and tibia)

453.0 (Hepatic vein thrombosis)

Pulmonary Embolism (PE) 11 415.1x (pulmonary embolism and infarction)

Major bleed Any of the codes below occurring within an inpatient encounter

Hemorrhagic stroke12,13

Hospitalization with primary diagnosis of:

431.x

Major upper GI bleed7 Hospitalization with any diagnosis of:

531.0x, 531.2x, 531.4x, 531.6x, 532.0x, 532.2x, 532.4x, 532.6x, 533.0x,

533.2x, 533.4x, 533.6x, 534.0x, 534.2x, 534.4x, 534.6x, 578.0

- OR -

ICD-9 procedure code of: 44.43

- OR -

CPT code 43255

Major lower and unspecified GI

bleed14

Hospitalization with any diagnosis of:

562.02, 562.03, 562.12, 562.13, 569.3x, 569.85, 578.1x, 578.9

Major urogenital bleed14

Hospitalization with any diagnosis of:

599.7

OR

626.2x and secondary diagnosis indicating acute bleeding: anemia (280.0,

285.1, 285.9)

Major other bleed14

Hospitalization with any diagnosis of:

719.1x, 423.0x, 786.3x, 784.7x, 459.0x, 285.1x

Covariate Definitions

Definition

Female gender

Age 65-74 years

Age ≥ 75 years

Congestive heart

failure/LV

dysfunction

1 inpatient or 2 outpatient claims with any of ICD-9 codes : 428.x (heart

failure), 398.91 (rheumatic heart failure (congestive)),

402.x1 ( hypertensive heart disease with heart failure: 402.01 malignant,

402.11 benign, 402.91 unspecified)

404.x1 (hypertensive heart and chronic kidney disease, with heart failure

and with chronic kidney disease stage I-IV or unspecified: 404.01

malignant, 404.11 benign, 404.91 unspecified)

404.x3 (hypertensive heart and chronic kidney disease, with heart

failure and with chronic kidney disease stage V or end stage renal

disease: 404.03 malignant, 404.13 benign, 404.93 unspecified)

Hypertension At least 1 Dx of ICD-9 codes

401.x (essential hypertension)

402.x (hypertensive heart disease)

403.x (hypertensive chronic kidney disease)

404.x (hypertensive heart and chronic kidney disease)

405.x (secondary hypertension)

OR

At least 1 dispensing of a CCB, ACEI, ARB, BB, a thiazide diuretic or a

direct antihypertensive agent

Diabetes At least 2 outpatient diagnoses of DM (ICD-9 250.X (diabetes)) OR 1

hospital discharge Dx of DM OR 1 diagnosis of DM plus an insulin or

oral antidiabetic dispensing

Stroke/TIA/thromboe

mbolism

ICD-9 codes for stroke/TIA: 433.xx (occlusion and stenosis of

precerebral arteries), 434.x (occlusion of cerebral arteries), 435.x

(transient cerebral ischemia), 436.x (acute but ill-defined

cerebrovascular disease), 437.x (other and ill-defined cerebrovascular

disease)

ICD-9 codes for thromboembolism:

VTE: 451.x (phlebitis and thrombophlebitis), 453.x (other venous

embolism and thrombosis)

PE: 415.11 (iatrogenic pulmonary embolism and infarction), 415.12

(septic pulmonary embolism), 415.19 (other pulmonary embolism)

Vascular disease

(prior MI, PAD, or

aortic plaque)

ICD-9 codes for MI: 412.x (old myocardial infarction) 410.x (acute

myocardial infarction)

Peripheral vascular disease:

ICD9 diagnosis: 440.20 - 440.24 (atherosclerosis of native arteries of the

extremities—with intermittent claudication, with rest pain, with

ulceration, with gangrene), 440.29 (other atherosclerosis of native

arteries of the extremities), 440.30-440.32 (atherosclerosis of bypass

graft of the extremities: of unspecified graft, of autologous vein bypass

graft, of nonautologous biological bypass graft), 443.9x (peripheral

vascular disease unspecified)

Arterial peripheral thromboembolism: 444.x (arterial embolism and

thrombosis), 445.x (atheroembolism),

Atherosclerosis: 440.x

Abnormal renal and ICD-9 diagnosis codes:

Definition

liver function (1 point

each)

580.xx (acute glomerulonephritis), 581.xx (nephrotic syndrome), 582.xx

(chronic glomerulonephritis), 583.xx (nephritis and nephropathy not

specified as acute or chronic), 584.xx ((acute kidney failure), 585.xx

(chronic kidney disease), 586.xx (renal failure unspecified)

or ICD-9 procedure codes: 39.95 (hemodialysis), 54.98 (peritoneal

dialysis), V56.0 (aftercare involving extracorporeal dialysis), V56.8

(aftercare involving other dialysis)

or CPT-4 codes: 90935-90993 (hemodialysis, miscellaneous dialysis

procedures), 99512 (home visit for hemodialysis), 99559 (home

infusion, peritoneal dialysis, per visit)

Abnormal liver

function

ICD-9 diagnosis codes: 070.x (viral hepatitis), 571.x (chronic liver

disease and cirrhosis), 572.x (alcoholic cirrhosis of liver), 573.x (other

disorders of liver), 576.8x (other specified disorders of biliary tract),

456.0x -456.2x (esophageal varices with bleeding, without bleeding, in

diseases classified elsewhere), 155.0x (malignant neoplasm of liver

primary), 155.1x (malignant neoplasm of intrahepatic bile ducts), 155.2x

(malignant neoplasm of liver not specified as primary or secondary) or

ICD-9 procedure codes: 39.1x (intra-abdominal venous shunt), 42.91

(ligation of esophageal varices)

Stroke ICD-9 codes for stroke/TIA 433.xx (occlusion and stenosis of precerbral

arteries), 434.x (occlusion of cerebral arteries), 435.xx (transient cerebral

ischemia), 436.x (acute but ill-defined cerebrovascular disease), 437.x

(other and ill-defined cerebrovascular disease)

Bleeding history or

predisposition

(anemia)

ICD-9 codes: 430.x (subarachnoid hemorrhage), 431.x (intracerebral

hemorrhage), 432.x (other and unspecified intracranial hemorrhage)

531.0x (acute gastric ulcer with hemorrhage), 531.2x (acute gastric ulcer

with hemorrhage and perforation), 531.4x (chronic or unspecified gastric

ulcer with hemorrhage), 531.6x (chronic or unspecified gastric ulcer with

hemorrhage and perforation), 532.0x (acute duodenal ulcer with

hemorrhage), 532.2x (acute duodenal ulcer with hemorrhage and

perforation), 532.4x (chronic or unspecified duodenal ulcer with

hemorrhage), 532.6x (chronic or unspecified duodenal ulcer with

hemorrage and perforation), 533.0x (acute peptic ulcer of unspecified

site with hemorrhage), 533.2x (acute peptic ulcer of unspecified site with

hemorrhage and perforation), 533.4x (chronic or unspecified peptic ulcer

of unspecified site with hemorrhage), 533.6x (chronic or unspecified

peptic ulcer of unspecified site with hemorrhage and perforation), 534.0x

(acute gastrojejunal ulver with hemorrhage), 534.2x (acute gastrojejunal

ulcer with hemorrhage and perforation), 534.4x (chronic or unspecified

gastrojejunal ulcer with hemorrhage), 534.6x (chronic or unspecified

gastrojejunal ulcer with hemorrhage and perforation), 578.0

(gastrointestinal hemorrhage); 455.2x (internal hemorrhoids with other

complication), 455.5x (external hemorrhoids with other complication),

455.8x (unspecified hemorrhoids with other complication), 562.02

(diverticulosis of small intestine with hemorrhage), 562.03 (diverticulitis

of small intestine with hemorrhage), 562.12 (diverticulosis of colon with

hemorrhage), 562.13 (diverticulitis of colon with hemorrhage), 568.81

(hemoperitoneum nontraumatic), 569.3 (hemorrhage of rectum and

anus), 569.83 (perforation of intestine), 569.85 (angiodysplasia of

intestine with hemorrhage), 569.86 (dieulafoy lesion (hemorrhagic) of

intestine), 578.1x (blood in stool), 578.9 (hemorrhage of gastrointestinal

tract unspecified); 599.7x (hematuria), 719.1x (hemathrosis), 423.0x

(hemopericardium), 786.3x (hemoptysis), 784.7x (epistaxis), 459.0x

(hemorrhage unspecified)

Definition

ICD-9 procedure code: 44.43 (endoscopic control of gastric or duodenal

bleeding)

CPT code 43255 (upper gastrointestinal endoscopy including esophagus,

stomach, and either the duodenum and/or jejunum as appropriate) with

control of bleeding, any method)

Anemia ICD-9 codes: 285.0x (sideroblastic anemia), 285.1x (acute

posthemorrhagic anemia), 285.9x (anemia unspecified)

Labile INR Is not calculated

Drugs predisposing to

bleed

NSAIDs, Aspirin, clopidogrel, prasugrel, ticagrelor

Alcohol Alcohol abuse ICD-9 codes:

94.61 – 94.63 – alcohol rehabilitation and detoxification

94.67-94.69 – combined alcohol/drug rehabilitaion and detoxification

303.0x – 303.9x – alcoholism

291.xx – alcohol-induced mental disorders

357.5x – alcoholic polyneuropathy

425.5x – alcoholic cardiomyopathy

571.1x – acute alcoholic hepatitis

571.2x – alcoholic cirrhosis of liver

571.3x – alcoholic liver damage, unspecified

305.0x -alcohol abuse

Appendix E. Standard Randomized Clinical Trial Bleeding Definitions applied to ARISTOTLE participants

1. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus

report from the Bleeding Academic Research Consortium. Circulation. Jun 14 2011;123(23):2736-2747.

2. An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction. New

England Journal of Medicine. 1993;329(10):673-682.

3. Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the S, Standardization Committee of the

International Society on T, Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic

medicinal products in non-surgical patients. Journal of thrombosis and haemostasis : JTH. Apr 2005;3(4):692-694.

4. Rao AK, Pratt C, Berke A, et al. Thrombolysis in myocardial infarction (TIMI) trial—Phase I: Hemorrhagic

manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue

plasminogen activator and streptokinase. Journal of the American College of Cardiology. 1988;11(1):1-11.

International Society

on Thrombosis and

Haemostasis (ISTH)

Major bleeding in non-surgical patients

Fatal bleeding.

Symptomatic bleeding in a critical area or organ, such as intracranial,

intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or

intramuscular with compartment syndrome.

Bleeding causing a fall in hemoglobin level of 2 g/dL (1.24 mmol/L) or

more, or leading to transfusion of two or more units of whole blood or red

cells.

Thrombolysis in

Myocardial Infarction

(TIMI)

Major (non CABG related)

Any intracranial bleeding (excluding microhemorrhages <10 mm evident

only on gradient-echo MRI)

Clinically overt signs of hemorrhage associated with a drop in hemoglobin

of ≥5 g/dL

Fatal bleeding (bleeding that directly results in death within 7 d)

Minor (non CABG related)

Clinically overt (including imaging), resulting in hemoglobin drop of 3 to

<5 g/dL

Requiring medical attention

Any overt sign of hemorrhage that meets one of the following criteria and

does not meet criteria for a major or minor bleeding event, as defined

above

Requiring intervention (medical practitioner-guided medical or surgical

treatment to stop or treat bleeding, including temporarily or permanently

discontinuing or changing the dose of a medication or study drug)

Leading to or prolonging hospitalization

Prompting evaluation (leading to an unscheduled visit to a healthcare

professional and diagnostic testing, either laboratory or imaging)

Global Use of

Strategies to Open

Occluded Arteries

(GUSTO)

Severe or life-threatening

Intracerebral hemorrhage

Resulting in substantial hemodynamic compromise requiring treatment

Moderate

Requiring blood transfusion but not resulting in hemodynamic compromise

Trial Bleeding Criteria Citations:

Appendix F. Results using a reduced thromboembolism outcome including only ischemic or ill-defined stroke and systemic

embolism

Discrimination and Calibration

Dabigatran Initiators Warfarin Initiators

Thromboembolism (reduced) N events = 23 N events = 40

Discrimination Calibration Discrimination Calibration

C-Index GoF Test Statistic p-value C-Index GoF Test Statistic p-value

CHADS - RCT 0.69 20.82 0.00 0.65 255.73 0.00

CHADS - Model 0.51 6.79 0.03 0.65 10.30 0.01

CHADS - Score 0.71 624.07 0.00 0.65 3566.93 0.00

CHADSVASC - Model 0.55 7.35 0.03 0.67 10.72 0.00

CHADSVASC - Score 0.68 181.83 0.00 0.63 1683.66 0.00

RCT: Estimated rate of outcomes in trial participants randomized to warfarin or dabigatran.

Model: Estimated rate of outcomes from models fit separately in initiators of warfarin and dabigatran in routine care, using risk factors in relevant risk score.

Performance evaluated for average estimate from repeated 10 fold cross validation.

Score: Estimated baseline rate of outcome from relevant external risk score developed in patients not on oral anticoagulation therapy

(or mix of treated and untreated)

Risk score factors:

CHADS2 includes age ≥75, stroke/TIA/TE, CHF, hypertension, diabetes

CHA2DS2-VASc includes female, age 65-74, age ≥75, stroke/TIA/TE, CHF, hypertension, diabetes, vascular disease

Calibration plots –thromboembolism (reduced)

Predicted annual rates of thromboembolism (reduced) in initiators of dabigatran or warfarin as part of routine care

D: dabigatran

W: warfarin

RCT: Estimated rate of outcomes in trial participants randomized to warfarin or dabigatran.

Model: Estimated rate of outcomes from models fit separately in initiators of warfarin and dabigatran in routine care, using risk factors in relevant risk score.

Performance evaluated for average estimate from repeated 10 fold cross validation.

Risk Score: Estimated baseline rate of outcome from relevant external risk score developed in patients not on oral anticoagulation therapy

(or mix of treated and untreated)

Thromboembolism

CHADS CHADSVASC

RCT Model Risk Score Model Risk Score

D W D W D W D W D W

All 1.1 1.6 0.9 0.5 5.2 5.0 0.9 0.5 3.4 3.3

Low 0.7 1.1 0.5 0.3 2.0 2.0 0.5 0.3 1.6 1.6

Medium 0.8 1.4 0.7 0.4 4.5 4.5 0.7 0.4 3.2 3.3

High 1.9 2.7 1.6 0.9 10.0 9.9 1.7 0.9 5.8 5.7

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