Effectiveness And Safety Of Oral Anticoagulants Among Obese Patients With Non-Valvular A-Fib In VA Patients With Medicare

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04681482
• Collaborator: (none)
• Enrollment: 107,383
• Location: 1
• Actual Duration (Days): 1
• Patients Per Site Per Month: 3268470.1

Study Details

Study Description

Brief Summary

The overall objective of this analysis is to understand patient characteristics, the use of treatment, and clinical outcomes among obese (overweight) and severely obese patients with non-valvular atrial fibrillation (NVAF) who initiate therapy with OACs (oral anti-coagulants). The aim of this study is to compare all DOACs (direct oral anti-coagulants) to warfarin.

However, the primary analysis will be conducted among apixaban vs warfarin patients only. If sample size permits, we will also conduct other DOAC vs warfarin and DOAC vs DOAC analysis.

Condition or Disease	Intervention/Treatment	Phase
Atrial Fibrillation; Obesity; Anticoagulants	Drug: Apixaban

Study Design

• Study Type: Observational
• Actual Enrollment: 107383 participants
• Observational Model: Cohort
• Time Perspective: Retrospective
• Official Title: Effectiveness and Safety of Oral Anticoagulants Among Obese Patients With Non-Valvular Atrial Fibrillation in the Veterans Affairs Population With Medicare
• Actual Study Start Date: Nov 2, 2020
• Actual Primary Completion Date: Nov 3, 2020
• Actual Study Completion Date: Nov 3, 2020

Arms and Interventions

Arm	Intervention/Treatment
Apixaban Group The cohort prescribed apixaban and diagnosed with Atrial Fibrillation	Drug: Apixaban; Anticoagulant medication used to treat and prevent blood clots and to prevent stroke in people with nonvalvular atrial fibrillation.; Other Names: Eliquis
Warfarin Group patients prescribed warfarin only diagnosed with Atrial Fibrillation.

Outcome Measures

Primary Outcome Measures

1. Event Rate Per 100 Participant-Years For First Occurrence of Major Bleeding Events After Index Date in Obese Participants [From first dose of study drug to follow-up period or within 30 days from last prescription date (data collected and observed retrospectively for 3.5 years)]

   Event rate per 100 participant-years for first occurrence of major bleeding (MB) event after index date in obese participants was reported. MB after index date was identified using hospital claims and occurred anytime during the follow-up period of drug use or within 30 days from the last day of treatment prescription. Index date was defined as date of first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017 [3.5 years]). The first warfarin prescription date was designated as the index date for participants without any DOAC claim. MB events included the composite of gastrointestinal (GI), intracranial hemorrhage (ICH), and other sites. MB was equal to 1 if bleeding event was greater than equal to (>=) 1.

2. Event Rate Per 100 Participant-Years For First Occurrence of Major Bleeding Events After Index Date in Morbidly Obese Participants [From first dose of study drug to follow-up period or within 30 days from last prescription date (data collected and observed retrospectively for 3.5 years)]

   Event rate per 100 participant-years for first occurrence of MB event after index date in morbidly obese participants was reported. MB after index date was identified using hospital claims and occurred anytime during the follow-up period of drug use or within 30 days from the last day of treatment prescription. Index date was defined as date of first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017). The first warfarin prescription date was designated as the index date for participants without any DOAC claim. MB events included the composite of GI, ICH, and other sites. MB was equal to 1 if bleeding event was >=1.

3. Event Rate Per 100 Participant-Years For First Occurrence of Stroke or Systemic Embolism (SE) Events After Index Date in Obese Participants [From first dose of study drug to follow-up period or within 30 days from last prescription date (data collected and observed retrospectively for 3.5 years)]

   Event rate per 100 participant-years for first occurrence of stroke or SE events after index date in obese participants was reported. Stroke/SE were identified using hospital claims and occurred anytime during the period of drug use or within 30 days from the last day of treatment prescription. Index date was defined as date of first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017). The first warfarin prescription date was designated as the index date for participants without any DOAC claim. Stroke events included the composite of any ischemic, any hemorrhagic and SE stroke events. Stroke/SE was equal to 1 if stroke event was >=1.

4. Event Rate Per 100 Participant-Years For First Occurrence of Stroke or Systemic Embolism (SE) Events After Index Date in Morbidly Obese Participants [From first dose of study drug to follow-up period or within 30 days from last prescription date (data collected and observed retrospectively for 3.5 years)]

   Event rate per 100 participant-years for first occurrence of stroke or SE events after index date in morbidly obese participants was reported. Stroke/SE were identified using hospital claims and occurred anytime during the period of drug use or within 30 days from the last day of treatment prescription. Index date was defined as date of first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017). The first warfarin prescription date was designated as the index date for participants without any DOAC claim. Stroke events included the composite of any ischemic, any hemorrhagic and SE stroke events. Stroke/SE was equal to 1 if stroke event was >=1.

5. Event Rate Per 100 Participant-Years For First Occurrence of Net Clinical Benefit After Index Date in Obese Participants [From first dose of study drug to follow-up period or within 30 days from last prescription date (data collected and observed retrospectively for 3.5 years)]

   Event rate per 100 participant-years for first occurrence of net clinical benefit after index date in obese participants was reported. For participants with stroke/SE or MB event, net clinical benefit was assessed by evaluating the first hospital claim for a stroke/SE or MB event. The hospital claim occurred anytime during the period of drug use or within 30 days from the last day of supply of treatment prescription. Index date was defined as date of first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017). The first warfarin prescription date was designated as the index date for participants without any DOAC claim.

6. Event Rate Per 100 Participant-Years For First Occurrence of Net Clinical Benefit After Index Date in Morbidly Obese Participants [From first dose of study drug to follow-up period or within 30 days from last prescription date (data collected and observed retrospectively for 3.5 years)]

   Event rate per 100 participant-years for first occurrence of net clinical benefit after index date in morbidly obese participants was reported. For participants with stroke/SE or MB event, net clinical benefit was assessed by evaluating the first hospital claim for a stroke/SE or MB event. The hospital claim occurred anytime during the period of drug use or within 30 days from the last day of supply of treatment prescription. Index date was defined as date of first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017). The first warfarin prescription date was designated as the index date for participants without any DOAC claim.

7. Charlson Comorbidity Index (CCI) [Baseline (6 months prior to index date)]

   CCI based on various comorbid conditions such as myocardial infarction, CHF, peripheral vascular disease, cerebrovascular disease, dementia, chronic obstructive pulmonary disease, rheumatologic disease, peptic ulcer disease, mild liver disease, diabetes (mild to moderate), diabetes + complications, hemiplegia or paraplegia, renal disease, any malignancy (lymphoma and leukemia), moderate/severe liver disease, metastatic solid tumor, and acquired immune deficiency syndrome (AIDS) were reported. CCI score range was from 0 to 14, where "0"= low comorbid condition and "14"= high comorbid condition, higher scores indicated more comorbidity.

Secondary Outcome Measures

1. Time in Therapeutic Range (TTR) During Follow-up Period [From first dose of study drug to follow-up period or within 30 days from last prescription date (data collected and observed retrospectively for 3.5 years)]

   TTR was computed using INR values among warfarin participants during the follow-up. TTR was calculated based on the percentage of time a participant remained in therapeutic range evaluated during the entire follow-up period. TTR >=65 percent (%) was observed as good and TTR less than (<) 65% was observed as poor.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Obese or severely obese.

• Initiated an OAC from July 1, 2013 - December 31, 2017; the first DOAC pharmacy claim date during the identification period will be designated as the index date. The first warfarin prescription date will be designated as the index date for patients without any DOAC claim.

• Individuals ≥18 years old as of the index date.

• Had 6 months continuous health plan enrollment with medical benefits (Parts A & B) for at least 6 months pre-index date (baseline period).

• At least 1 diagnosis of AF prior to or on index date, identified by any medical claim associated with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code of 427.31 or International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) code of I480-I482, and I4891.

• Had body weight or BMI value reported within ±6 months of the index date.

Exclusion Criteria:

• Had medical claims indicating a diagnosis or procedure of rheumatic mitral valvular heart disease, heart valve replacement/transplant, venous thromboembolism, or transient AF 6 months prior to or on the index date.

• Had hip/knee replacement surgery within 6 weeks prior to or on the index date.

• Were pregnant during the study period.

• Had an OAC prescription during the 6 months pre-index date.

• Had follow-up time equal to 0 days.

• Had more than one OAC on the index date.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pfizer	New York	New York	United States	10012

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 14, 2020

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT04681482
• Other Study ID Numbers: B0661162
• First Posted: Dec 23, 2020
• Last Update Posted: Dec 6, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by Pfizer: Medicare; Veterans Affairs; Major Bleeding; Stroke
• Additional relevant MeSH terms: Atrial Fibrillation; Apixaban

Study Results

Participant Flow

Recruitment Details

This was a retrospective population-based registry study. Data for participants diagnosed with non-valvular atrial fibrillation (NVAF) and treated with either oral anticoagulants (OAC [Warfarin]) or direct oral anticoagulants (DOAC [Apixaban, Dabigatran and Rivaroxaban]) retrieved from the Veterans Affairs (VA) Population and Centre for Medicare and Medicare Services (CMS) database from January 2013 to December 2017.

Pre-assignment Detail

In this study, inverse probability of treatment weighted (IPTW) method was used in analysis of outcome measures to balance participant's characteristics among reporting groups. Baseline for this study was 6 months prior to the index date. The index date was the date of first prescription for an OAC (Warfarin) or DOAC (Apixaban, Dabigatran, and Rivaroxaban) pharmacy claim during the identification period from July 1, 2013 -December 31, 2017.

Arm/Group Title	Warfarin	Apixaban	Dabigatran	Rivaroxaban
Arm/Group Description	Participants diagnosed with NVAF, who initiated warfarin on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first warfarin prescription for participants without any DOAC claim.	Participants diagnosed with NVAF, who initiated apixaban on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017).	Participants diagnosed with NVAF, who initiated dabigatran on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017).	Participants diagnosed with NVAF, who initiated rivaroxaban on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017).
Period Title: Overall Study
STARTED	35051	38756	12148	21428
COMPLETED	35051	38756	12148	21428
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Warfarin	Apixaban	Dabigatran	Rivaroxaban	Total
Arm/Group Description	Participants diagnosed with NVAF, who initiated warfarin on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first warfarin prescription for participants without any DOAC claim.	Participants diagnosed with NVAF, who initiated apixaban on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017).	Participants diagnosed with NVAF, who initiated dabigatran on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017).	Participants diagnosed with NVAF, who initiated rivaroxaban on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017).	Total of all reporting groups
Overall Participants	35051	38756	12148	21428	107383
Age, Customized (Count of Participants)
18-54 years	182 0.5%	94 0.2%	88 0.7%	105 0.5%	469 0.4%
55-64 years	1380 3.9%	833 2.1%	580 4.8%	827 3.9%	3620 3.4%
65-74 years	12410 35.4%	13037 33.6%	6873 56.6%	10070 47%	42390 39.5%
75-79 years	5817 16.6%	6504 16.8%	1741 14.3%	3472 16.2%	17534 16.3%
>=80 years	15262 43.5%	18288 47.2%	2866 23.6%	6954 32.5%	43370 40.4%
Sex: Female, Male (Count of Participants)
Female	456 1.3%	576 1.5%	139 1.1%	299 1.4%	1470 1.4%
Male	34595 98.7%	38180 98.5%	12009 98.9%	21129 98.6%	105913 98.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	2086 6%	2024 5.2%	621 5.1%	1172 5.5%	5903 5.5%
White	32246 92%	35847 92.5%	11184 92.1%	19732 92.1%	99009 92.2%
More than one race	529 1.5%	654 1.7%	220 1.8%	343 1.6%	1746 1.6%
Unknown or Not Reported	190 0.5%	231 0.6%	123 1%	181 0.8%	725 0.7%
Number of Participants From Different Regions of United States (Count of Participants)
Northeast	7016 20%	6821 17.6%	1887 15.5%	3718 17.4%	19442 18.1%
Midwest	10498 30%	10046 25.9%	3008 24.8%	5858 27.3%	29410 27.4%
South	11809 33.7%	15311 39.5%	5080 41.8%	8398 39.2%	40598 37.8%
West	5576 15.9%	6392 16.5%	2134 17.6%	3361 15.7%	17463 16.3%
Other/Unknown	152 0.4%	186 0.5%	39 0.3%	93 0.4%	470 0.4%
Number of Participants Classified According to OAC Index Year (Count of Participants)
2013	5090 14.5%	395 1%	974 8%	1135 5.3%	7594 7.1%
2014	9024 25.7%	2548 6.6%	2462 20.3%	3996 18.6%	18030 16.8%
2015	7770 22.2%	6792 17.5%	2178 17.9%	4370 20.4%	21110 19.7%
2016	7289 20.8%	12705 32.8%	3336 27.5%	5600 26.1%	28930 26.9%
2017	5878 16.8%	16316 42.1%	3198 26.3%	6327 29.5%	31719 29.5%
Dose of the Index DOAC (Count of Participants)
Standard Dose (5 mg Apixaban, 150 mg Dabigatran, 20 mg Rivaroxaban)	0 0%	30494 78.7%	11411 93.9%	16108 75.2%	58013 54%
Lower Dose (2.5 mg Apixaban, 75 mg Dabigatran, 15 mg Rivaroxaban)	0 0%	8262 21.3%	726 6%	4550 21.2%	13538 12.6%
Other Dose (10 mg Rivaroxaban , 110 mg Dabigatran)	0 0%	0 0%	11 0.1%	770 3.6%	781 0.7%
Body Weight (Count of Participants)
<=60 Kg	871 2.5%	1009 2.6%	149 1.2%	359 1.7%	2388 2.2%
61-99 Kg	22449 64%	25698 66.3%	6924 57%	13225 61.7%	68296 63.6%
100-119 Kg	7102 20.3%	7830 20.2%	3094 25.5%	4776 22.3%	22802 21.2%
>=120 Kg	3714 10.6%	3261 8.4%	1614 13.3%	2478 11.6%	11067 10.3%
Missing	915 2.6%	958 2.5%	367 3%	590 2.8%	2830 2.6%
Body Mass Index (BMI) (Count of Participants)
<18.5 kg/m^2	285 0.8%	296 0.8%	47 0.4%	121 0.6%	749 0.7%
(18.5-24.9) kg/m^2	5921 16.9%	6890 17.8%	1586 13.1%	3158 14.7%	17555 16.3%
(25-29) kg/m^2	8803 25.1%	10490 27.1%	3041 25%	5563 26%	27897 26%
(30-39) kg/m^2	10293 29.4%	11425 29.5%	4357 35.9%	6923 32.3%	32998 30.7%
>40 kg/m^2	2176 6.2%	1746 4.5%	896 7.4%	1294 6%	6112 5.7%
Missing	7573 21.6%	7909 20.4%	2221 18.3%	4369 20.4%	22072 20.6%
International Normalized Ratio (INR) (Count of Participants)
Yes	15304 43.7%	9133 23.6%	3561 29.3%	3977 18.6%	31975 29.8%
No	19747 56.3%	29623 76.4%	8587 70.7%	17451 81.4%	75408 70.2%
CHADS2 Score (Count of Participants)
0	1424 4.1%	1506 3.9%	944 7.8%	1352 6.3%	5226 4.9%
1	6829 19.5%	7280 18.8%	3640 30%	5413 25.3%	23162 21.6%
2	11372 32.4%	12318 31.8%	3985 32.8%	6935 32.4%	34610 32.2%
>=3	15426 44%	17652 45.5%	3579 29.5%	7728 36.1%	44385 41.3%
CHA2DS2-VASc Score (Count of Participants)
0	79 0.2%	70 0.2%	71 0.6%	87 0.4%	307 0.3%
1	1280 3.7%	1405 3.6%	886 7.3%	1227 5.7%	4798 4.5%
2	4703 13.4%	5764 14.9%	2709 22.3%	4007 18.7%	17183 16%
3	8196 23.4%	9734 25.1%	3520 29%	5718 26.7%	27168 25.3%
>=4	20793 59.3%	21783 56.2%	4962 40.8%	10389 48.5%	57927 53.9%
HAS-BLED Score (Count of Participants)
0	135 0.4%	109 0.3%	83 0.7%	130 0.6%	457 0.4%
1	3859 11%	4522 11.7%	1733 14.3%	2770 12.9%	12884 12%
2	11444 32.6%	13675 35.3%	5457 44.9%	8533 39.8%	39109 36.4%
>=3	19613 56%	20450 52.8%	4875 40.1%	9995 46.6%	54933 51.2%
Baseline Medication Use (Count of Participants)
ACE/ARB	13562 38.7%	14295 36.9%	4777 39.3%	8049 37.6%	40683 37.9%
Beta blockers	18486 52.7%	20198 52.1%	6177 50.8%	11211 52.3%	56072 52.2%
H2-receptor antagonist	2268 6.5%	2584 6.7%	695 5.7%	1288 6%	6835 6.4%
Proton pump inhibitor	12227 34.9%	13793 35.6%	3896 32.1%	7178 33.5%	37094 34.5%
Statins	23095 65.9%	25830 66.6%	7959 65.5%	13901 64.9%	70785 65.9%
Anti-platelets	8686 24.8%	10515 27.1%	2980 24.5%	5141 24%	27322 25.4%
NSAIDS	3819 10.9%	5319 13.7%	1904 15.7%	3388 15.8%	14430 13.4%
Bariatric Surgery (Count of Participants)
Count of Participants [Participants]	130 0.4%	125 0.3%	43 0.4%	93 0.4%	391 0.4%
Comorbid Conditions (Count of Participants)
Bleeding History	6021 17.2%	5564 14.4%	1367 11.3%	2886 13.5%	15838 14.7%
CHF	13188 37.6%	12385 32%	3025 24.9%	6062 28.3%	34660 32.3%
Diabetes Mellitus	15527 44.3%	15225 39.3%	4714 38.8%	8453 39.4%	43919 40.9%
Hypertension	29689 84.7%	32639 84.2%	10117 83.3%	17961 83.8%	90406 84.2%
Renal Disease	4540 13%	8022 20.7%	929 7.6%	2367 11%	15858 14.8%
Liver Disease	1430 4.1%	1388 3.6%	418 3.4%	814 3.8%	4050 3.8%
Myocardial Infarction	5344 15.2%	5628 14.5%	1200 9.9%	2841 13.3%	15013 14%
Dyspepsia or Stomach Discomfort	4322 12.3%	4201 10.8%	1110 9.1%	2438 11.4%	12071 11.2%
Non-stroke/SE Peripheral Vascular Disease	8994 25.7%	9560 24.7%	2276 18.7%	4836 22.6%	25666 23.9%
Stroke/SE	4468 12.7%	4731 12.2%	1062 8.7%	2186 10.2%	12447 11.6%
TIA	2750 7.8%	4508 11.6%	840 6.9%	1807 8.4%	9905 9.2%
Anemia and Coagulation Defects	10572 30.2%	9987 25.8%	2129 17.5%	4640 21.7%	27328 25.4%
Alcoholism	11323 32.3%	14181 36.6%	4241 34.9%	7567 35.3%	37312 34.7%
Peripheral Artery Disease	8817 25.2%	8927 23%	2156 17.7%	4610 21.5%	24510 22.8%
Coronary Artery Disease	19283 55%	21041 54.3%	5664 46.6%	10903 50.9%	56891 53%

Outcome Measures

1. Primary Outcome

Title	Event Rate Per 100 Participant-Years For First Occurrence of Major Bleeding Events After Index Date in Obese Participants
Description	Event rate per 100 participant-years for first occurrence of major bleeding (MB) event after index date in obese participants was reported. MB after index date was identified using hospital claims and occurred anytime during the follow-up period of drug use or within 30 days from the last day of treatment prescription. Index date was defined as date of first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017 [3.5 years]). The first warfarin prescription date was designated as the index date for participants without any DOAC claim. MB events included the composite of gastrointestinal (GI), intracranial hemorrhage (ICH), and other sites. MB was equal to 1 if bleeding event was greater than equal to (>=) 1.
Time Frame	From first dose of study drug to follow-up period or within 30 days from last prescription date (data collected and observed retrospectively for 3.5 years)

Outcome Measure Data

Analysis Population Description

Obese participants with or without DOAC treatment diagnosed with NVAF were included in the outcome measure. Analysis performed using IPTW method to balance participant characteristics among reporting groups.

Arm/Group Title	Warfarin	Apixaban
Arm/Group Description	Participants diagnosed with NVAF, who initiated warfarin on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first warfarin prescription for participants without any DOAC claim.	Participants diagnosed with NVAF, who initiated apixaban on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017).
Measure Participants	12918	13604
Number [Events Per 100 Participant-Years]	7.27	4.06

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Warfarin, Apixaban
	Comments	Cox Proportional Hazards Model was used to compare the risk of MB between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cox Proportional Hazards Model
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95%; 0.54 to 0.70
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Event Rate Per 100 Participant-Years For First Occurrence of Major Bleeding Events After Index Date in Morbidly Obese Participants
Description	Event rate per 100 participant-years for first occurrence of MB event after index date in morbidly obese participants was reported. MB after index date was identified using hospital claims and occurred anytime during the follow-up period of drug use or within 30 days from the last day of treatment prescription. Index date was defined as date of first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017). The first warfarin prescription date was designated as the index date for participants without any DOAC claim. MB events included the composite of GI, ICH, and other sites. MB was equal to 1 if bleeding event was >=1.
Time Frame	From first dose of study drug to follow-up period or within 30 days from last prescription date (data collected and observed retrospectively for 3.5 years)

Outcome Measure Data

Analysis Population Description

Morbidly obese participants with or without DOAC treatment diagnosed with NVAF were included in the outcome measure. Analysis performed using IPTW method to balance participant characteristics among reporting groups.

Arm/Group Title	Warfarin	Apixaban
Arm/Group Description	Participants diagnosed with NVAF, who initiated warfarin on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first warfarin prescription for participants without any DOAC claim.	Participants diagnosed with NVAF, who initiated apixaban on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017).
Measure Participants	2176	1746
Number [Events Per 100 Participant-Years]	5.52	3.94

3. Primary Outcome

Title	Event Rate Per 100 Participant-Years For First Occurrence of Stroke or Systemic Embolism (SE) Events After Index Date in Obese Participants
Description	Event rate per 100 participant-years for first occurrence of stroke or SE events after index date in obese participants was reported. Stroke/SE were identified using hospital claims and occurred anytime during the period of drug use or within 30 days from the last day of treatment prescription. Index date was defined as date of first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017). The first warfarin prescription date was designated as the index date for participants without any DOAC claim. Stroke events included the composite of any ischemic, any hemorrhagic and SE stroke events. Stroke/SE was equal to 1 if stroke event was >=1.
Time Frame	From first dose of study drug to follow-up period or within 30 days from last prescription date (data collected and observed retrospectively for 3.5 years)

Outcome Measure Data

Analysis Population Description

Obese participants with or without DOAC treatment diagnosed with NVAF were included in this outcome measure. Analysis performed using IPTW method to balance participant characteristics among reporting groups.

Arm/Group Title	Warfarin	Apixaban
Arm/Group Description	Participants diagnosed with NVAF, who initiated warfarin on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first warfarin prescription for participants without any DOAC claim.	Participants diagnosed with NVAF, who initiated apixaban on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017).
Measure Participants	12918	13604
Number [Events Per 100 Participant-Years]	2.09	1.51

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Warfarin, Apixaban
	Comments	Cox Proportional Hazards Model was used to compare the risk of stroke/SE between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.088
	Comments
	Method	Cox Proportional Hazards Model
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Event Rate Per 100 Participant-Years For First Occurrence of Stroke or Systemic Embolism (SE) Events After Index Date in Morbidly Obese Participants
Description	Event rate per 100 participant-years for first occurrence of stroke or SE events after index date in morbidly obese participants was reported. Stroke/SE were identified using hospital claims and occurred anytime during the period of drug use or within 30 days from the last day of treatment prescription. Index date was defined as date of first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017). The first warfarin prescription date was designated as the index date for participants without any DOAC claim. Stroke events included the composite of any ischemic, any hemorrhagic and SE stroke events. Stroke/SE was equal to 1 if stroke event was >=1.
Time Frame	From first dose of study drug to follow-up period or within 30 days from last prescription date (data collected and observed retrospectively for 3.5 years)

Outcome Measure Data

Analysis Population Description

Morbidly obese participants with or without DOAC treatment diagnosed with NVAF were included in this outcome measure. Analysis performed using IPTW method to balance participant characteristics among reporting groups.

Arm/Group Title	Warfarin	Apixaban
Arm/Group Description	Participants diagnosed with NVAF, who initiated warfarin on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first warfarin prescription for participants without any DOAC claim.	Participants diagnosed with NVAF, who initiated apixaban on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017).
Measure Participants	2176	1746
Number [Events Per 100 Participant-Years]	1.51	0.92

5. Primary Outcome

Title	Event Rate Per 100 Participant-Years For First Occurrence of Net Clinical Benefit After Index Date in Obese Participants
Description	Event rate per 100 participant-years for first occurrence of net clinical benefit after index date in obese participants was reported. For participants with stroke/SE or MB event, net clinical benefit was assessed by evaluating the first hospital claim for a stroke/SE or MB event. The hospital claim occurred anytime during the period of drug use or within 30 days from the last day of supply of treatment prescription. Index date was defined as date of first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017). The first warfarin prescription date was designated as the index date for participants without any DOAC claim.
Time Frame	From first dose of study drug to follow-up period or within 30 days from last prescription date (data collected and observed retrospectively for 3.5 years)

Outcome Measure Data

Analysis Population Description

Obese participants with or without DOAC treatment diagnosed with NVAF were included in this outcome measure. Analysis performed using IPTW method to balance participant characteristics among reporting groups.

Arm/Group Title	Warfarin	Apixaban
Arm/Group Description	Participants diagnosed with NVAF, who initiated warfarin on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first warfarin prescription for participants without any DOAC claim.	Participants diagnosed with NVAF, who initiated apixaban on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017).
Measure Participants	12918	13604
Number [Event Rate Per 100 Participant-Years]	8.44	5.12

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Warfarin, Apixaban
	Comments	Cox Proportional Hazards Model was used to compare the risk of net clinical benefit between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cox Proportional Hazards Model
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.60 to 0.76
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Primary Outcome

Title	Event Rate Per 100 Participant-Years For First Occurrence of Net Clinical Benefit After Index Date in Morbidly Obese Participants
Description	Event rate per 100 participant-years for first occurrence of net clinical benefit after index date in morbidly obese participants was reported. For participants with stroke/SE or MB event, net clinical benefit was assessed by evaluating the first hospital claim for a stroke/SE or MB event. The hospital claim occurred anytime during the period of drug use or within 30 days from the last day of supply of treatment prescription. Index date was defined as date of first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017). The first warfarin prescription date was designated as the index date for participants without any DOAC claim.
Time Frame	From first dose of study drug to follow-up period or within 30 days from last prescription date (data collected and observed retrospectively for 3.5 years)

Outcome Measure Data

Analysis Population Description

Morbidly obese participants with or without DOAC treatment diagnosed with NVAF were included in this outcome measure. Analysis performed using IPTW method to balance participant characteristics among reporting groups.

Arm/Group Title	Warfarin	Apixaban
Arm/Group Description	Participants diagnosed with NVAF, who initiated warfarin on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first warfarin prescription for participants without any DOAC claim.	Participants diagnosed with NVAF, who initiated apixaban on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017).
Measure Participants	2176	1746
Number [Event Rate Per 100 Participant-Years]	6.48	4.52

7. Primary Outcome

Title	Charlson Comorbidity Index (CCI)
Description	CCI based on various comorbid conditions such as myocardial infarction, CHF, peripheral vascular disease, cerebrovascular disease, dementia, chronic obstructive pulmonary disease, rheumatologic disease, peptic ulcer disease, mild liver disease, diabetes (mild to moderate), diabetes + complications, hemiplegia or paraplegia, renal disease, any malignancy (lymphoma and leukemia), moderate/severe liver disease, metastatic solid tumor, and acquired immune deficiency syndrome (AIDS) were reported. CCI score range was from 0 to 14, where "0"= low comorbid condition and "14"= high comorbid condition, higher scores indicated more comorbidity.
Time Frame	Baseline (6 months prior to index date)

Outcome Measure Data

Analysis Population Description

Analysis population included obese or morbidly obese AF participants in the CMS and VA databases with newly prescribed OACs or DOACs between January 1, 2013 and December 31, 2017.

Arm/Group Title	Warfarin	Apixaban	Dabigatran	Rivaroxaban
Arm/Group Description	Participants diagnosed with NVAF, who initiated warfarin on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first warfarin prescription for participants without any DOAC claim.	Participants diagnosed with NVAF, who initiated apixaban on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017).	Participants diagnosed with NVAF, who initiated dabigatran on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017).	Participants diagnosed with NVAF, who initiated rivaroxaban on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017).
Measure Participants	35051	38756	12148	21428
Mean (Standard Deviation) [Units on a scale]	3.13 (2.68)	2.55 (2.39)	2.21 (2.18)	2.49 (2.37)

8. Secondary Outcome

Title	Time in Therapeutic Range (TTR) During Follow-up Period
Description	TTR was computed using INR values among warfarin participants during the follow-up. TTR was calculated based on the percentage of time a participant remained in therapeutic range evaluated during the entire follow-up period. TTR >=65 percent (%) was observed as good and TTR less than (<) 65% was observed as poor.
Time Frame	From first dose of study drug to follow-up period or within 30 days from last prescription date (data collected and observed retrospectively for 3.5 years)

Outcome Measure Data

Analysis Population Description

TTR was calculated only for the warfarin arm, therefore data was not collected/observed for DOACs cohorts - apixaban, dabigatran, rivaroxaban.

Arm/Group Title	Warfarin
Arm/Group Description	Participants diagnosed with NVAF, who initiated warfarin on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first warfarin prescription for participants without any DOAC claim.
Measure Participants	35051
Median (Full Range) [Percentage of time]	14

Adverse Events

Adverse Event Reporting Description	Due to observational nature of study, minimum criteria for reporting adverse events did not met, hence adverse events were not collected
Arm/Group Title	Warfarin		Apixaban		Dabigatran		Rivaroxaban
Arm/Group Description	Participants diagnosed with NVAF, who initiated warfarin on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first warfarin prescription for participants without any DOAC claim.		Participants diagnosed with NVAF, who initiated apixaban on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017).		Participants diagnosed with NVAF, who initiated dabigatran on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017).		Participants diagnosed with NVAF, who initiated rivaroxaban on the index date, were included in this cohort and their data from July 2013 to December 2017, available in VA and CMS database observed retrospectively. Index date was defined as the date of the first DOAC pharmacy claim date during the identification period (July 1, 2013-December 31, 2017).
All Cause Mortality
	Warfarin		Apixaban		Dabigatran		Rivaroxaban
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Serious Adverse Events
	Warfarin		Apixaban		Dabigatran		Rivaroxaban
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Warfarin		Apixaban		Dabigatran		Rivaroxaban
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

Data for Edoxaban drug cohort was not observed due to small sample size, based on Sponsor's decision. Data for creatinine clearance was not recorded and reported due to insufficient amount of data.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.