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Original Article Sex-Specific Comparative Effectiveness of Oral Anticoagulants in Elderly Patients With Newly Diagnosed Atrial Fibrillation Ghanshyam Palamaner Subash Shantha, MBBS, MPH; Prashant D. Bhave, MD; Saket Girotra, MBBS, SM; Denice Hodgson-Zingman, MD, PhD; Alexander Mazur, MD; Michael Giudici, MD; Elizabeth Chrischilles, PhD; Mary S. Vaughan Sarrazin, PhD

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Background—Sex-specific comparative effectiveness of direct oral anticoagulants among patients with nonvalvular atrial fibrillation is not known. Via this retrospective cohort study, we assessed the sex-specific, comparative effectiveness of direct oral anticoagulants (rivaroxaban and dabigatran), compared to each other and to warfarin among patients with atrial fibrillation. Methods and Results—Elderly (aged ≥66 years) Medicare beneficiaries enrolled in Medicare Part D benefit plan from November 2011 to October 2013 with newly diagnosed atrial fibrillation formed the study cohort (65 734 [44.8%] men and 81 137 [55.2%] women). Primary outcomes of inpatient admissions for ischemic strokes and major bleeding were compared across the 3 drugs (rivaroxaban: 20 mg QD, dabigatran: 150 mg BID, or warfarin) using 3-way propensitymatched samples. In men, rivaroxaban use decreased stroke risk when compared with warfarin use (hazard ratio, 0.69; 95% confidence interval, 0.48–0.99; P=0.048) and dabigatran use (hazard ratio, 0.66; 95% confidence interval, 0.45–0.96; P=0.029) and was associated with a similar risk of any major bleeding when compared with warfarin and dabigatran. In women, although ischemic stroke risk was similar in the 3 anticoagulant groups, rivaroxaban use significantly increased the risk for any major bleeding when compared with warfarin (hazard ratio, 1.20; 95% confidence interval, 1.03–1.42; P=0.021) and dabigatran (hazard ratio, 1.27; 95% confidence interval, 1.09–1.48; P=0.011). Conclusions—The reduced risk of ischemic stroke in patients taking rivaroxaban, compared with dabigatran and warfarin, seems to be limited to men, whereas the higher risk of bleeding seems to be limited to women. (Circ Cardiovasc Qual Outcomes. 2017;10:e003418. DOI: 10.1161/CIRCOUTCOMES.116.003418.) Key Words: anticoagulants ◼ atrial fibrillation ◼ stroke ◼ United States ◼ women

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compared with that in men even after initiating and sustaining similar quality warfarin therapy.16 Hence, there is a need to understand the effectiveness of DOACs in women with AF. One shortcoming of directly extrapolating randomized controlled trial data on DOACs into clinical management of women with AF is that women constituted much smaller numbers in both the dabigatran and rivaroxaban trials7–9 compared with contemporary clinical practice. Also, variability in treatment adherence and patient follow-up are some of the challenges in the clinical management of patients that are not reflected in randomized trials.17,18 Finally, previous clinical trials for DOACs do not allow for head-to-head comparisons of rivaroxaban to dabigatran, and sex-specific effectiveness of rivaroxaban to dabigatran is not known. In order to bridge this literature gap, we used a nationally representative cohort of elderly Medicare beneficiaries with

onvalvular atrial fibrillation (AF) affects 3 million adults in the United States.1,2 By 2050, ≈8 million US adults will have AF.1 AF confers a 3- to 5-fold increase in the risk of stroke.3,4 For decades, warfarin was the only oral anticoagulant available for stroke prophylaxis in patients with AF. In recent years, direct oral anticoagulants (DOAC) dabigatran and rivaroxaban have been approved for stroke prophylaxis in this population.5,6 Randomized controlled trial data support the efficacy of these DOACs,7–11 and they are commonly used in clinical practice. Women with AF have significantly higher stroke risk compared with their male counterparts, irrespective of their age and comorbid disease profile.12,13 As a result, female sex has been incorporated into the most widely accepted risk scoring algorithms to identify AF patients who will benefit from anticoagulation.14,15 However, stroke risk remains elevated in women

Received November 9, 2016; accepted February 27, 2017. From the Department of Cardiovascular Medicine (G.P.S.S., P.D.B., S.G., D.H.-Z., A.M., M.G.) and Department of Internal Medicine (M.S.V.S.), Roy and Lucille J. Carver College of Medicine and Department of Epidemiology, College of Public Health (E.C.), University of Iowa, Iowa City; and Comprehensive Access and Delivery Research and Evaluation Center, Iowa City VA Medical Center, IA (M.S.V.S.). The views expressed in this paper are those of the authors and do not represent the Department of Veterans Affairs. The Data Supplement is available at http://circoutcomes.ahajournals.org/lookup/suppl/doi:10.1161/CIRCOUTCOMES.116.003418/-/DC1. Correspondence to Mary S. Vaughan Sarrazin, PhD, University of Iowa Institute for Clinical and Translational Sciences, 200 Hawkins Dr, C44-GH, Iowa City, IA 52242. E-mail [email protected] © 2017 American Heart Association, Inc. Circ Cardiovasc Qual Outcomes is available at http://circoutcomes.ahajournals.org

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DOI: 10.1161/CIRCOUTCOMES.116.003418

2 Shantha et al Sex-Specific Outcomes and Oral Anticoagulants

WHAT IS KNOWN • DOACs have similar efficacy to warfarin for stroke prevention among patients with AF. • DOACS are associated with similar overall bleeding rates when compared with warfarin, although some studies suggest higher rates of gastrointestinal hemorrhage and lower rates of intracranial hemorrhage with DOACs.

WHAT THE STUDY ADDS


• Women tended to bleed more with DOACs compared with warfarin, whereas the risk of bleeding in men was similar for DOACs and warfarin. • Rivaroxaban may be more effective for stroke prevention compared with dabigatran and warfarin in men, but all 3 drugs seem to provide similar stroke prevention in women.

newly diagnosed AF to assess the sex-specific comparative effectiveness of rivaroxaban and dabigatran to each other and to warfarin.

Methods Using the Centers for Medicare and Medicaid Services patient records, we linked data sources including (1) Beneficiary Summary File Base and Chronic Conditions segments; (2) Inpatient (part A) and Carrier (part B) Standard Analytic Files for 2011 through 2013; and (3) Pharmacy Drug Event (part D) files for 2011 to 2013. The institutional review board of University of Iowa approved the study. This being a retrospective cohort analysis of claims data, informed consent was not required. We identified 213 705 Medicare beneficiaries who were enrolled in Centers for Medicare and Medicaid Services part D prescription drug coverage plan, were newly diagnosed with AF between November 1, 2011, and October 31, 2013, and initiated dabigatran 150 mg BID, rivaroxaban 20 mg QD, or warfarin within 90 days after AF diagnosis. Patient selection and study cohort formation algorithms are detailed in Figure I in the Data Supplement. New AF was defined based on previously published algorithms (ie, one inpatient claim or 2 outpatient claims within 90 days with International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 427.31 as primary or first secondary diagnosis).19,20

Outcomes The primary outcomes were inpatient admissions for acute ischemic stroke or major bleeding, as defined by Rothendler et al21 and Suh et al22 based on the primary ICD-9-CM diagnosis on inpatient standard analytical files claims for acute care stays. The secondary outcomes were subdivisions of major bleeding, defined as intracranial hemorrhage (ICH; including hemorrhagic stroke), gastrointestinal hemorrhage (GIH), and other major non-GIH, based on previously published algorithms.23

Patient Characteristics Patient characteristics were derived from Medicare enrollment data and inpatient and carrier claims. Age, sex, and race were identified from Medicare enrollment data. Comorbid diseases19,20 defined by Elixhauser et al24 were identified by ICD-9-CM diagnoses in inpatient and outpatient claims during the 12 months preceding AF diagnosis. Previous cerebrovascular events and previous bleeding episodes were also identified using previously published algorithms.21,22 We also identified

additional comorbidities of importance to AF outcomes, including other dysrhythmias (ICD-9-CM codes 427.X, excluding 427.3), cardiomyopathy (ICD-9 codes 425.X), cardiac conduction disorder (eg, bundle branch block; ICD-9 codes 426.X), and previous implantable cardiac device (eg, pacemaker; ICD-9 codes V45.0 and V53.3). Stroke risk was assessed using the standard CHA2DS2-VASc (1 point each for congestive heart failure diagnosis, female sex, hypertension diagnosis, diabetes diagnosis, age 65-75 years, and vascular disease diagnosis; 2 points each for age >75 years and prior stroke or transient ischemic attack) scoring system.25 The HAS-BLED (1 point each for hypertension diagnosis, renal disease, liver disease, stroke history, prior major bleeding, labile INR, age >65 years, medication usage predisposing to bleeding and alcohol or drug use history) algorithm was used to assess bleeding risk.26 Finally, the comorbidity score defined by Gagne et al27 was calculated to assess disease burden. This score is of proven value to improve death prediction in hospitalized patients.27

Statistical Analysis Separate male and female cohorts were constructed. Comparisons were made between 3 treatment groups: participants initiated on dabigatran 150 mg BID (dabigatran group), participants initiated on rivaroxaban 20 mg QD (rivaroxaban group), and participants who were initiated on warfarin (warfarin group). Demographic variables, comorbid diseases, medication use, CHA2DS2-VASc score, HASBLED score, and Gagne score were compared between the 3 treatment groups separately in men and women, using a χ2 test or 1-way ANOVA as applicable. We then used the 3-way propensity-matching method described by Rassen et al28 to create groups of patients receiving dabigatran, rivaroxaban, or warfarin that were balanced with respect to patient covariates and also had clinical equipoise—that is, patients included in the matched samples were plausible candidates for all 3 anticoagulants under study. Propensity matching was conducted separately for men and women. Success of the matching algorithm was evaluated by comparing standardized differences in demographic variables, comorbid diseases, medication use, CHA2DS2-VASc score, HAS-BLED score, and the Gagne score between each drug in the matched samples. In accordance with Austin,29 we evaluated the success of the matching algorithm using standardized differences rather than P values because P values depend on sample sizes and may, therefore, not adequately reflect meaningful differences. Standardized differences 65 years, medication usage predisposing to bleeding and alcohol or drug use history; NSAID, nonsteroidal anti-inflammatory drugs; and TIA, transient ischemic attack.

5 Shantha et al Sex-Specific Outcomes and Oral Anticoagulants Table 2. Sex-Specific Outcomes in Propensity-Matched Samples Reported as Rates/100 Patient-Years of Follow-Up Men

Women

Dabigatran 150 mg BID

Rivaroxaban 20 mg QD

Warfarin

Dabigatran 150 mg BID

Rivaroxaban 20 mg QD

Warfarin

No. of patients

7618

7618

7618

11 031

11 031

11 031

Stroke

1.53 (1.31–1.81; 69)

0.97 (0.66–1.24; 48)

1.42 (1.29–1.77; 68)

1.44 (1.21–2.01; 107) 1.67 (1.20–2.11; 119)

1.75 (1.41–2.59; 130)

Any hemorrhage

3.16 (2.61–3.69; 142) 3.86 (3.66–4.48; 189) 4.23 (3.81–4.78; 202) 3.82 (3.10–4.27; 282) 5.18 (4.70–5.99; 327)

3.90 (3.01–4.36; 288)

GIH

2.73 (2.15–3.27; 123) 3.30 (3.09–4.01; 162) 3.24 (2.83–3.82; 155) 3.49 (2.88–3.89; 258) 4.55 (3.98–5.24; 288)

2.89 (2.13–3.61; 214)

ICH

0.13 (0.03–(0.29; 6)

0.26 (0.08–0.58; 13)

0.44 (0.33–0.91; 21)

0.21 (0.01–0.33; 16)

0.38 (0.10–0.96; 24)

0.54 (0.37–1.01; 40)

Other non-GIH 0.49 (0.10–0.77; 22)

0.55 (0.15–0.83; 27)

1.02 (0.87–1.67; 49)

0.35 (0.06–0.51; 26)

0.66 (0.53–0.81; 42)

1.07 (0.90–1.77; 80)

Values are represented as 95% CI and no. of events in parenthesis. GIH indicates gastrointestinal hemorrhage; and ICH, intracranial hemorrhage.


studies to assess if there is an association between the duration of rivaroxaban use and the effectiveness of stroke protection it confers. In contrary, this observation was not seen in women (Figure 1B). Previous studies using observational data report conflicting results30–33 with some supporting a superiority of rivaroxaban to warfarin for stroke prevention and bleeding risk,32,33 and some reporting similar efficacy of the 2 anticoagulants.31 However, no previous study using observational data has assessed sex-specific effectiveness of these 2 anticoagulants.

In a sex-specific subgroup analysis of RELY,7 dabigatran 150 mg BID was superior to warfarin for stroke prevention in both men and women, whereas sex-specific bleeding outcomes were not reported. The baseline stroke risk of RELY trail participants (CHADS2 score of 2.1±1.1) were similar to our men (2.3±0.97) and women (2.4±1.1) using dabigatran. In spite we noted similar effectiveness of dabigatran to warfarin with stroke protection in men and women whereas RELY reported superiority of dabigatran to warfarin for stroke prevention in men and women. Observational data have both

Table 3. Risk-Adjusted Relative Hazard of Each Outcome for Men and Women Taking Rivaroxaban vs Warfarin, Dabigatran vs Warfarin, and Rivaroxaban vs Dabigatran, in Separate Propensity-Matched Samples for Men and Women Men

P Value

Women

P Value

Rivaroxaban vs warfarin

0.69 (0.48–0.99)

0.048

0.98 (0.76–1.25)

0.881

Dabigatran vs warfarin

1.05 (0.75–1.47)

0.788

0.81 (0.62–1.04)

0.098

Rivaroxaban vs dabigatran

0.66 (0.45–0.96)

0.029

1.20 (0.93–1.61)

0.271


0.91 (0.75–1.11)

0.344

1.20 (1.03–1.42)

0.021

Dabigatran vs warfarin

0.73 (0.59–0.90)

0.004

0.97 (0.82–1.14)

0.716

Rivaroxaban vs dabigatran

1.24 (0.99–1.55)

0.051

1.27 (1.09–1.48)

0.011


1.02 (0.82–1.27)

0.854

1.43 (1.20–1.71)