efficacy and safety of rivaroxaban in patients with heart

Berkowitz, Robert M. Califf, Keith A.A. Fox and Kenneth W. MahaffeyHacke, Jonathan L. Halperin, Graeme J. Hankey, Christopher C. Nessel, Daniel E. Singer, Scott D.

Sean van Diepen, Anne S. Hellkamp, Manesh R. Patel, Richard C. Becker, Günter Breithardt, WernerFibrillation: Insights from ROCKET AF

Efficacy and Safety of Rivaroxaban in Patients with Heart Failure and Non-Valvular Atrial

Print ISSN: 1941-3289. Online ISSN: 1941-3297 Copyright © 2013 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation: Heart Failure published online May 30, 2013;Circ Heart Fail.

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1

Efficacy and Safety of Rivaroxaban in Patients with Heart Failure and Non-

Valvular Atrial Fibrillation: Insights from ROCKET AF

van Diepen et al: Rivaroxaban in Atrial Fibrillation and Heart Failure

Sean van Diepen, MD MSc;* Anne S. Hellkamp, MS;† Manesh R. Patel, MD;†

Richard C. Becker, MD;† Günter Breithardt, MD;‡ Werner Hacke, MD;§

Jonathan L. Halperin, MD;|| Graeme J. Hankey, MD;¶ Christopher C. Nessel, MD;#

Daniel E. Singer, MD;** Scott D. Berkowitz, MD;†† Robert M. Califf, MD;‡‡

Keith A.A. Fox, MD;§§ Kenneth W. Mahaffey, MD†

*Divisions of Critical Care and Cardiology, University of Alberta, Edmonton, Alberta, Canada; †Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA; ‡Department of Cardiology and Angiology, Hospital of the University of Münster, Münster,

Germany; §Ruprecht-Karls-University, Heidelberg, Germany; ||Mount Sinai Medical Center,

New York, NY, USA; ¶Royal Perth Hospital, Perth, WA, Australia; #Johnson & Johnson

Pharmaceutical Research and Development, Raritan, NJ, USA; **Massachusetts General Hospital

and Harvard Medical School, Boston, MA, USA; ††Bayer HealthCare Pharmaceuticals,

Montville, NJ, USA; ‡‡Duke Translational Medicine Institute, Duke University Medical Center,

Durham, NC, USA; §§University of Edinburgh, Scotland, UK

Correspondence to Dr. Sean van Diepen 2C2 Cardiology WMC, University of Alberta Hospital 8440-112St, Edmonton, Alberta, T6G 2B7 Tel: 780-407-6507 Fax: 780-407-7485 Email: [email protected]

DOI: 10.1161/CIRCHEARTFAILURE.113.000212

Journal Subject Codes: [5] Arrhythmias, clinical electrophysiology, drugs [110] Congestive

Heart Failure [184] Coumarins [185] Other Anticogulants

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2

Abstract

Background—In ROCKET AF, rivaroxaban was non-inferior to warfarin for the prevention of

stroke and systemic embolic events and significantly reduced intracranial bleeding in patients

with non-valvular atrial fibrillation (AF). We explore the safety and efficacy of rivaroxaban in

patients with heart failure (HF).

Methods and Results—A total of 9033 (63.7%) patients had HF. The primary efficacy analysis

was rates of stroke or systemic embolism (per 100 patient years) by intention to treat. The safety

outcomes were major or non-major clinically relevant (NMCR) bleeding and hemorrhagic stroke

during treatment. Patients with HF were younger (72 vs. 74 years), more likely to have

persistent AF (83.0% vs. 77.6%), and had higher mean CHADS2 scores (3.7 vs. 3.1). The

efficacy of rivaroxaban compared with warfarin was similar in patients with HF (1.90 vs. 2.09)

and without HF (2.10 vs. 2.54; p-interaction=0.62). The risk of major or NMCR bleeding with

rivaroxaban was similar to warfarin in patients with HF (14.22 vs. 14.02) and without HF (16.12

vs. 15.35; p-interaction=0.99). A reduction in hemorrhagic stroke was observed with

rivaroxaban in HF patients as in the overall trial (adjusted hazard ratio 0.38: 95% CI 0.19-0.76,

p-interaction=0.067). Among patients with HF, the efficacy of rivaroxaban was similar

irrespective of ejection fraction <40 or 40% (p-interaction=0.38), New York Heart Association

class I-II vs. III-IV (p-interaction=0.68), HF preserved or reduced EF (p-interaction=0.35), or

CHADS2 score 2 vs. 3 (p-interaction=0.48).

Conclusions—Treatment related outcomes were similar in patients with and without HF and

across HF subgroups. These findings support the use of rivaroxaban as an alternative to warfarin

in patients with AF and HF.

Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier:

NCT00403767.

Key Words: heart failure, arrhythmia, anticoagulant

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3

The prevalence of both heart failure (HF) and atrial fibrillation (AF) are increasing in the general

population.1, 2 AF occurs in 12-41% of HF patients and its prevalence correlates with HF

severity.3-7 Multiple studies and thromboembolic risk prediction scores, such as CHADS2, have

reported that a clinical history of HF is an independent risk factor for thromboembolic events in

patients with non-valvular AF.8-12 Vitamin K antagonists (VKAs) are recommended by both AF

and HF guidelines to reduce thromboembolic risk in patients with both conditions.10, 13, 14

Among AF patients who are anticoagulated with VKAs, time in the therapeutic range

(TTR) is an important determinant of stroke prevention and bleeding risk.15-17 HF is a

recognized risk for reduced TTR and patients receiving VKAs may be predisposed to reduced

efficacy and increased bleeding.18-22 Rivaroxaban, an oral factor Xa inhibitor, has a predictable

pharmacokinetic profile and dual clearance pathways, renal and hepatic. 23, 24 Rivaroxaban

therefore represents a theoretically attractive alternative to VKAs in patients with HF and AF. In

the ROCKET AF (Rivaroxaban Once daily, oral, direct factor Xa inhibition Compared with

vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial,

rivaroxaban was non-inferior to warfarin for the prevention of embolic events in moderate to

high risk AF patients with non-valvular AF, and it significantly reduced the risk of intracranial

hemorrhage (ICH).25 A total of 62.5% of randomized patients in this trial had a history of HF or

a low ejection fraction (EF); whereas 32.0% of RE-LY and 35.4% in the ARISTOTLE trial

participants had HF.26, 27 This provided a unique opportunity to explore the efficacy and safety

of rivaroxaban in a large cohort of AF patients with HF and examine whether treatment effects

were consistent across important HF subgroups such as functional class, ejection fraction, and

CHADS2 score.

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4

Methods

The methods and results of the ROCKET AF trial (ClinicalTrials.gov number NCT00403767)

have been described.25, 28 Briefly, it was an international, multi-center, double blind, double-

dummy randomized non-inferiority trial that compared rivaroxaban 20 mg daily (or 15 mg daily

in patients with creatinine clearance 30-49 mL/min) with adjusted-dose warfarin (target

international normalized ratio [INR] 2.5, range 2.0-3.0) in patients with non-valvular AF.

Patients with electrocardiographic documentation of AF with a moderate to high risk of stroke

were eligible for enrollment. Moderate to high stroke risk was defined as a history of stroke,

transient ischemic attack, or systemic embolism, or at least 2 CHADS2 risk factors: clinical HF or

a left ventricular EF of 35%, hypertension, age 75 years, or diabetes mellitus.9 The number

of patients with only 2 CHADS2 risk factors was capped at 10% for each region. Key exclusion

criteria included patients with prosthetic heart valves, hemodynamically significant mitral

stenosis, creatinine clearance <30mL/min, a recent embolic event, and those at increased risk of

bleeding.28 The institutional review boards at each participating site approved the protocol and

all patients provided written consent.

Definition of Heart Failure and Subgroups

Patients with HF, and important covariates, were identified from individual case report forms

which were completed by local site investigators. HF was defined a priori as a history of HF or

a left ventricular EF < 40% (measured by any imaging modality). Although the original

ROCKET AF manuscript classified patients with an EF <35 % as having HF, in this analysis the

EF was changed to <40% so the results would be in line with the EF definition of systolic HF

used in many randomized trials. The primary analysis compared patients assigned to the

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5

rivaroxaban and warfarin therapy. Pre-specified secondary subgroup analyses examined the

comparative efficacy in patients classified by EF ( or < 40%), New York Heart Association

(NHYA) class, HF with preserved and reduced EF, CHADS2 score, CHA2DS2-VASc Score and

device (implantable cardioverter defibrillator [ICD] or biventricular-ICD [BiV-ICD]).

Outcomes

The primary efficacy outcome was stroke (ischemic or hemorrhagic) or non-central nervous

system embolism. The secondary efficacy outcomes included all-cause death, myocardial

infarction, and the composite (and individual components) of stroke, systemic embolism, or

vascular death. The intention-to-treat (ITT) study population was used for all efficacy outcomes.

However, all 93 patients were excluded from 1 study site with violations in Good Clinical

Practice guidelines.25 Efficacy endpoints were measured until the time of site notification of

study termination. The primary safety endpoint was major or non-major clinically relevant

(NMCR) bleeding. The secondary safety endpoints were ICH and hemorrhagic stroke. Safety

endpoints were analyzed using the safety population (patients who were randomized and

received at least 1 dose of the study drug). A per-protocol sensitivity analysis used the subset of

patients from the safety population who had no protocol violations. For safety and per-protocol

analyses, endpoints were measured during treatment with study drug (first dose until 2 days after

the last dose). All events were adjudicated by an independent clinical events committee blinded

to treatment assignment and using predefined endpoint definitions .28

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6

Statistical Analysis

Categorical data are summarized as counts (percentages) and differences were tested with the

Pearson 2 test; continuous variables are summarized as medians (25th percentile, 75th percentile)

and differences were tested with the Wilcoxon rank sum test. Outcomes are presented as events

per 100 patient-years. Cox proportional hazards models were used to assess the association with

risk of outcomes for (1) patients with vs. patients without HF; (2) rivaroxaban vs. warfarin

within subgroups defined by HF; and (3) rivaroxaban vs. warfarin within subgroups of HF

patients defined by EF, NYHA class, and CHADS2 score. Models for (2) and (3) included terms

for the interaction between randomized treatment and the subgroup of interest. All models

included covariates identified as predictive of outcomes by modeling in the full ROCKET AF

cohort. For efficacy endpoints, these included: age, sex, body mass index, region (Latin

America), prior stroke or transient ischemic attack, prior myocardial infarction, peripheral

arterial disease, carotid occlusive vascular disease, hypertension, chronic obstructive pulmonary

disease, diabetes, paroxysmal atrial fibrillation, left ventricular EF, heart rate, diastolic blood

pressure, creatinine clearance at baseline (calculated using the Cockroft-Gault formula), and

abstinence from alcohol use. In the safety analysis, the following variables were entered into the

model: age, sex, region (Eastern Europe), prior stroke or transient ischemic attack,

gastrointestinal bleed, chronic obstructive pulmonary disease, diastolic blood pressure,

creatinine clearance at baseline (calculated using the Cockroft-Gault formula), anemia, platelets,

albumin, prior aspirin use, and prior use of a VKA or thienopyridine. An additional per-protocol

sensitivity analysis examined the primary efficacy endpoint, major or NMCR bleeding, and

hemorrhagic stroke in the per-protocol population; these models were performed in the same

manner as above. Risk relationships are presented as adjusted hazard ratios (HR) with 95%

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7

confidence intervals (CI) derived from the adjusted Cox models. The TTR in patients treated

with warfarin was calculated using the Rosendaal method.29 A level of significance of p<0.05

was pre-specified. All analyses were performed with SAS version 9.2 (SAS Institute, Inc, Cary,

NC).

Results

In the ROCKET AF trial, 9033 (63.7%) of participants were classified as having HF at the time

of randomization, based on a history of clinical HF or a left ventricular EF < 40%. Table 1

presents baseline characteristics according to treatment randomization and history of HF.

Among participants with HF, 4530 (50.1%) were randomized to rivaroxaban and 4503 (49.9%)

to warfarin. Rivaroxaban and warfarin treated participants with HF had similar persistent AF

rates (83.6% vs 82.3%), ejection fraction <40% (33.3% vs 34.5%), previous VKA use (58.7% vs

58.2%), concurrent aspirin use (30.3 vs 31.7%), and mean CHADS2 scores (both 3.7).

Differences in baseline clinical variables among patients with and without HF are presented in

Appendix 1. Among participants randomized to warfarin therapy, the mean TTR was 53% in

participants with HF and 59% in those without HF (Appendix 2).

Outcomes in patients with and without heart failure

Overall rates of stroke or systemic embolization per 100 patient-years were similar in patients

with and without HF (1.99 vs 2.32; adjusted HR 0.94: 95% CI 0.78-1.13, p=0.51) (Table 2). HF

patients had a higher risk of the composite of stroke, systemic embolization, or vascular death

(5.00 vs 3.50; adjusted HR 1.28: 95% CI 1.11-1.47, p=0.0006), all-cause death (5.26 vs 3.37;

adjusted HR 1.34: 95% CI 1.17-1.55, p<0.0001) and vascular death (3.53 vs 1.75; adjusted HR

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8

1.65: 95% CI 1.37 -1.98, p<0.0001). Safety endpoints were similar between patients with and

without HF. Results were similar in the per-protocol treatment population (Appendix 3).

Outcomes by heart failure and treatment assignment

Table 3 and Figure 1 show the efficacy and safety outcomes in patients with and without HF by

treatment assignment. The primary efficacy outcomes in rivaroxaban and warfarin treated

patients were similar in patients with HF (1.90 vs. 2.09; adjusted HR 0.91: 95 % CI, 0.74-1.13)

and without HF (2.10 vs. 2.54; adjusted HR 0.84: 95% CI, 0.65-1.09, p =0.62 for

interaction)(Figure 2). No differences in treatment effect were detected between patients with

and without HF for any of the secondary efficacy outcomes (p>0.5 for interaction for all).

Additionally, no differences in treatment effect were observed in the primary safety outcome of

major or NMCR bleeding. A lower risk of hemorrhagic stroke was observed with rivaroxaban

therapy in HF patients (0.16 vs 0.43; adjusted HR 0.38: 95% CI 0.19-0.76) but not in patients

without HF (0.43 vs 0.47; adjusted HR 0.91: 95% CI 0.48-1.73), although the interaction

between HF and treatment was not significant (p=0.067). In the per-protocol sensitivity

analysis, similar results were observed compared with the ITT analyses for primary efficacy

outcome, major or NMCR bleeding, or hemorrhagic stroke (Appendix 4).

Heart Failure Subgroups

The primary efficacy and safety outcomes in the HF subgroups are presented in Table 4. Point

estimates for efficacy favored rivaroxaban therapy in most subgroups, and no difference was

detected in the efficacy of rivaroxaban in patients classified by left ventricular EF < 40 % or

40% (p=0.38 for interaction), HNYHA class I-II vs III-IV (p=0.68 for interaction), HF with

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9

preserved or reduced EF (p=0.35 for interaction), device therapy (p=0.11 for interaction),

CHADS2 score 2 vs. 3 (p=0.48 for interaction), or CHA2DS2-VASc Score (p=0.19 for

interaction). No differences in treatment effect for major or NMCR bleeding were detected

between NYHA class (p=0.19 for interaction), HF with preserved or reduced EF (p=0.23 for

interaction ), CHADS2 score (p=0.15 for interaction), or CHA2DS2-VASc Score (p=0.19 for

interaction) subgroups, and a borderline p value for interaction was observed in the left

ventricular EF subgroups (EF 40% HR 1.00: 95% CI, 0.88-1.13; EF <40% HR 1.15: 95% CI,

0.96-1.36, p=0.051 for interaction). Rivaroxaban was associated with a higher risk of major or

NMCR bleeding among 297 study participants with an ICD or BiV-ICD (HR 2.00: 95% CI,

1.31-3.05, p=0.0015 for interaction). The median times in therapeutic range for warfarin treated

participants across all HF subgroups are presented in Appendix 2.

Discussion

In this study, which represents a large cohort of AF patients with HF, 3 important findings

emerge. First, adjusted rates of stroke or systemic embolism and bleeding were similar between

patients with and without HF. Second, the treatment effect of rivaroxaban was similar in patients

with and without HF, suggesting the efficacy and safety of rivaroxaban extend to the HF patient

population with AF. Third, comparable treatment effects of rivaroxaban were observed across

important HF subgroups such as systolic function, functional class, and CHADS2 score.

In patients with AF, guidelines define HF (moderate to severe left ventricular systolic

dysfunction or recent decompensated HF requiring hospitalization irrespective of EF) as an

independent risk factor for thromboembolism.8-11, 14, 30, 31 After adjusting for baseline

differences, but not treatment randomization, we observed that HF patients had a similar risk of

iV ICD (HR 2222222.0......

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10

stroke or systemic embolism, myocardial infarction, and bleeding but a higher observed risk of

all-cause death and vascular death than patients without HF. Although HF was not

independently associated with an increased risk of stroke or systemic embolism, we hypothesize

that the lack of an observed difference may be due to the high thromboembolic risk of the

ROCKET AF study participants; wherein the mean CHAD S2 in this trial was 3.5 (compared to

the RE-LY and ARISTOTLE trials which had a mean CHAD S2 scores of 2.1) and a large

proportion of the study population could be categorized as having HF at the time of

randomization.

With the rising prevalence of both HF and AF, it is likely that an increasing number of

patients will require thromboembolic prophylaxis.1, 2 VKAs are recommended in patients with

AF and HF, however the narrow therapeutic range, need for monitoring, and multiple food and

drug interactions make their use challenging for physicians and patients.10, 14 Warfarin therapy

has been reported to decrease thromboembolic events in HF patients and increase the risk of

bleeding.32 A recent meta-analysis reported that warfarin-treated patients have mean TTRs of

only 55%.33 In anti-coagulated AF patients, TTR is an important determinant of both the clinical

benefit and bleeding risk of warfarin.15-17 Our results are consistent with studies by Rose and

colleagues which reported that HF is an independent risk factor for lower TTR and with

SPORTIF and AFFIRM trial analyses have shown HF is an independent predictor of bleeding in

patients anti-coagulated for AF.18-20 In this analysis, the primary efficacy and safety treatment

effects were similar between patients with and without HF. Although it is not clear if optimal

warfarin management would change these results, the effect of rivaroxaban did not differ across

quartiles of TTR in the overall trial population.25 Additionally, a previous meta-analysis of all

novel oral anticoagulants versus warfarin trials reported no significant difference the primary

that an increasasasasasasasi

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11

trial endpoints in patients with HF, though detailed in all efficacy and safety endpoints were

lacking.34 These findings suggest that the reported efficacy of rivaroxaban therapy extends to

patients with HF and AF and that rivaroxaban is a reasonable therapeutic alternative to warfarin

in this growing clinical population.

Most studies that have evaluated thromboembolic risk factors in AF have defined HF

based on clinical history or symptoms and have not accounted for differences in left ventricular

function or clinical symptoms. The association between HF and thromboembolic risk has not

been consistent across all studies and it is unclear whether differences between HF subgroups

could potentially account for these reported discrepancies in all studies.9, 11, 35-37 Analyses by two

groups reported that the severity of left ventricular systolic dysfunction was associated with an

increased risk of stroke, though an analysis of over 2400 patients from AFFIRM found no

significant association.12, 38, 39 Given that it remains unclear how EF and severity of HF

symptoms modify thromboembolic risk, we explored treatment effects across important HF and

thromboembolic risk subgroups. The lack of an observed interaction between the primary

efficacy outcome and EF, HF with preserved versus reduced systolic function, functional class,

or CHADS2 score suggests that the benefit of rivaroxaban over warfarin extends to HF patients

with AF irrespective of the definition of HF, severity of symptoms, or thromboembolic risk. A

higher bleeding risk on rivaroxaban was observed among a small group of patients with ICDs or

BiV-ICDs at the time of randomization. The clinical significance of this finding is unclear.

Limitations

This analysis has several limitations that merit consideration. First, the TTR was lower than

reported in some studies, but similar to that of large-scale registry and observational programs.33,

tudies. A

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12

40, 41 The efficacy of rivaroxaban was favorable across INR control groups in the overall trial

population.25 Second, ROCKET AF predominantly enrolled patients at moderate to high

embolic risk, consequently >93% of patients in this analysis had a CHADS2 score 3. Thus it is

unclear how well these results can be extended to patients with HF and an otherwise low embolic

risk.

Conclusions

In a large international population of patients with HF and AF, the adjusted rates of stroke or

systemic embolization and bleeding were similar between patients with and without HF and no

treatment-related differences were detected. Moreover, no difference in the efficacy of

rivaroxaban was observed across important clinical or thromboembolic risk HF subgroups. In a

clinical environment where the prevalence of both HF and AF are increasing, these data suggest

that rivaroxaban is an efficacious and safe alternative to VKAs in the HF population with AF.

Acknowledgements

We would like to gratefully acknowledge the editorial support provided by Ms. Elizabeth Cook.

Sources of Funding

Sponsored by Johnson & Johnson Pharmaceutical Research & Development, Raritan, NJ and

Bayer HealthCare AG, Leverkusen, Germany.

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13

Disclosures

SVD, ASH: None. Disclosures for MRP, RCB, RMC, and KWM are publically listed at

https://www.dcri.org/about-us/conflict-of-interest. GB has received honoraria from Johnson &

Johnson and Bayer; and advisory board fees from Boehringer Ingelheim, Bristol-Myers Squibb,

Pfizer, and Sanofi-Aventis. SDB is employed by Bayer HealthCare Pharmaceuticals. WH has

received honoraria for serving on an executive committee for Johnson & Johnson and Bayer.

JLH has received honoraria and served as a consultant and on an advisory board for Bayer and

Johnson & Johnson. GJH has received honoraria for serving on executive committees for

Johnson & Johnson and Bayer. CCN is an employee for Janssen (formerly Johnson & Johnson

PRD). DES has served as a consultant and/or member of a scientific advisory board for Bayer,

Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, and Pfizer;

has an institutional research support contract with Johnson & Johnson; served as an unpaid

ROCKET AF executive committee member. SDB is an employee of Bayer. KAAF received

grant funding and honoraria from Bayer and Johnson& Johnson.

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OlOlOlOllsesesesesen nnnn AMAMAMAMAM, GiGiGiGiGislslslsslasonononoo GGGGGH,HHHH TTTTTorororororp-pp-pp PePePePePededededederrrrrsesesesesen nnnn C.CCCC VVVVValalllalidididididatatatatatioioiii n nnnn ofofoffof rrrrrisiipredicting strokeee ananannand d d d d thththththrororororombmbmbm oeoeembmbmbmbmbooooolilismssmsmm iiiiin nnn n papppp tients with atriacccohohohorororttt stststudududy.y.y.y BMBMJJ. 202020111111;3;3;3424242:d:d:d121212444 JJJlatatioioionn InInvevesttstttigigigi atatttororss EEEEEchchchhhococarardididididiogograraphphphhhicicicii ppreredidididdicttcttororss oofffff ststrorokekeke iiinn




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17

Table 1. Baseline characteristics for all patients in the intention to treat population classified by history of history of HF and treatment randomization

Variable

Heart Failure No Heart Failure Rivaroxaban

(N=4530) Warfarin (N=4503)

Rivaroxaban (N=2551)

Warfarin (N=2587)

Age, median (25th, 75th), years 72 (65, 78) 72 (64, 78) 74 (66, 79) 74 (67, 78) Female, n (%) 1773 (39.1%) 1760 (39.1%) 1029 (40.3%) 1043 (40.3%) Body Mass Index, median (25th, 75th), kg/m2 28.7 (25.4, 32.8) 28.6 (25.5, 32.4) 27.6 (24.7, 31.0) 27.2 (24.5, 30.7) Atrial Fibrillation Variables Atrial Fibrillation type, n (%) Persistent 3789 (83.6%) 3708 (82.3%) 1965 (77.0%) 2023 (78.2%) Paroxysmal 698 (15.4%) 733 (16.3%) 533 (20.9%) 526 (20.3%) New Onset 43 (0.9%) 62 (1.4%) 53 (2.1%) 38 (1.5%) Previous Stroke or TIA, n (%) 1954 (42.9%) 1914 (42.2%) 1800 (70.0%) 1800 (69.2%) Previous Non-CNS Embolism, n (%) 169 (3.7%) 178 (4.0%) 105 (4.1%) 99 (3.8%) Carotid Occlusive Disease, n (%) 180 (4.0%) 176 (3.9%) 110 (4.3%) 123 (4.8%) CHADS2 Score, mean (SD) 3.7 (0.9) 3.7 (0.9) 3.2 (0.9) 3.1 (0.8) CHA2DS2-VASc score, mean (SD) 5.1 (1.3) 5.1 (1.4) 4.5 (1.2) 4.5 (1.2) Heart Failure Variables Ejection Fraction <40%, n (%) 1043 (33.3%) 1102 (34.5%) 0 (0.0%) 0 (0.0%) NYHA Class, n (%) I 606 (13.7%) 586 (13.3%) II 2502 (56.4%) 2511 (56.9%) III 1255 (28.3%) 1256 (28.5%) IV 74 (1.7%) 60 (1.4%) ICD or BiV-ICD, n(%) 148 (3.6%) 150 (3.7%) 10 (0.4%) 6 (0.3%) Other Baseline Comorbidities, n (%) Hypertension 4202 (92.8%) 4200 (93.3%) 2187 (85.7%) 2235 (86.4%) Diabetes Mellitus 1916 (42.3%) 1912 (42.5%) 935 (36.7%) 884 (34.2%) Myocardial Infarction 942 (20.8%) 1011 (22.5%) 231 (9.1%) 262 (10.1%) Coronary Artery Bypass 350 (7.7%) 382 (8.5%) 153 (6.0%) 144 (5.6%) Peripheral Vascular Disease 292 (6.4%) 313 (7.0%) 106 (4.2%) 121 (4.7%) Chronic Obstructive Pulmonary Disease 557 (12.3%) 565 (12.5%) 190 (7.4%) 169 (6.5%) Presenting Characteristics, median (25th, 75th) Heart Rate, beats/min 77 (68, 86) 77 (68, 87) 74 (65, 84) 75 (65, 84) Systolic Blood Pressure, mmHg 130 (120, 140) 130 (120, 140) 130 (120, 140) 130 (120, 140) Creatinine Clearance*, ml/min 68 (52, 89) 68 (52, 88) 67 (53, 86) 67 (53, 84)

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18

Previous and Concurrent medications, n (%) Prior VKA Use 2658 (58.7%) 2621 (58.2%) 1755 (68.8%) 1819 (70.3%) Prior ASA Use 1864 (41.1%) 1901 (42.2%) 850 (33.3%) 846 (32.7%) Concurrent ASA Use 1373 (30.3%) 1428 (31.7%) 657 (25.8%) 640 (24.7%) Beta-Blocker 3113 (68.7%) 3174 (70.5%) 1448 (56.8%) 1449 (56.0%) Digitalis 2023 (44.7%) 2037 (45.2%) 699 (27.4%) 701 (27.1%) Angiotensin Converting Enzyme Inhibitors 2792 (61.6%) 2707 (60.1%) 1059 (41.5%) 1100 (42.5%) Diuretics 3235 (71.4%) 3169 (70.4%) 1006 (39.4%) 1031 (39.9%)

*Creatinine Clearance was calculated using the Cockcroft–Gault formula

Abbreviations: BiV-ICD, Biventricular Implantable Cardioverter Defibrillator; NYHA, New York Heart Association; ICD, Implantable Cardioverter Defibrillator; VKA, vitamin K antagonist




19

Table 2. Efficacy and safety endpoints in patients with and without heart failure

Outcomes Heart Failure*

No Heart Failure*

Heart Failure vs No Heart Failure

HR (95% CI) p value

Efficacy Outcomes Stroke or Systemic Embolization 1.99 (343) 2.32 (232) 0.94 (0.78, 1.13) 0.51

Stroke, Systemic Embolization, or Vascular Death

5.00 (835) 3.50 (346) 1.28 (1.11, 1.47) 0.0006

Stroke 1.84 (317) 2.16 (217) 0.95 (0.78, 1.15) 0.57 Systemic Embolization 0.17 (30) 0.17 (17) 0.93 (0.48, 1.82) 0.84

All-Cause Death 5.26 (879) 3.37 (335) 1.34 (1.17, 1.55) <0.0001 Vascular Death 3.53 (600) 1.75 (176) 1.65 (1.37, 1.98) <0.0001

Myocardial infarction 1.15 (200) 0.71 (72) 1.20 (0.89, 1.63) 0.23 Safety Outcomes

Major OR NMCR Bleeding 14.12 (1766) 15.73 (1158) 1.00 (0.92, 1.08) 0.99 Hemorrhagic Stroke 0.29 (41) 0.45 (38) 0.73 (0.45, 1.20) 0.22

Intracranial Hemorrhage 0.53 (74) 0.77 (65) 0.84 (0.58, 1.22) 0.36 Abbreviations: NMCR, Non-major clinically relevant bleeding

*Reported as events per 100 patient-years (total events); Adjusted efficacy outcomes

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20

Table 3. Efficacy and safety endpoints by treatment and heart failure

Outcomes

Heart Failure No Heart Failure p-value

for interaction‡ Rivaroxaban*

Warfarin*

Rivaroxaban vs.

Warfarin HR (95% CI)

Rivaroxaban*

Warfarin*

Rivaroxaban vs.

Warfarin HR (95% CI)

Efficacy Outcomes (n=4530) (n=4503) (n=2551) (n=2587)

Stroke or Systemic Embolization 1.90 (164) 2.09 (179) 0.91 (0.74, 1.13) 2.10 (105) 2.54 (127) 0.84 (0.65, 1.09) 0.62 Stroke, Systemic Embolization, or

Vascular Death 4.88 (409) 5.11 (426) 0.97 (0.85, 1.11) 3.29 (163) 3.71 (183) 0.89 (0.72, 1.10) 0.52

Stroke 1.78 (154) 1.89 (163) 0.94 (0.76, 1.17) 1.97 (99) 2.35 (118) 0.85 (0.65, 1.11) 0.57 Systemic Embolization 0.15 (13) 0.19 (17) 0.78 (0.38, 1.61) 0.14 (7) 0.19 (10) 0.72 (0.27, 1.88) 0.88

All-cause Death 5.05 (423) 5.46 (456) 0.93 (0.82, 1.07) 3.20 (159) 3.54 (176) 0.89 (0.71, 1.10) 0.68 Vascular Death 3.44 (292) 3.63 (308) 0.96 (0.82, 1.13) 1.65 (83) 1.84 (93) 0.89 (0.66, 1.20) 0.64

Myocardial Infarction 1.09 (95) 1.21 (105) 0.94 (0.71, 1.24) 0.69 (35) 0.72 (37) 0.94 (0.59, 1.49) 0.99 Safety Outcomes (n=4550) (n=4527) (n=2561) (n=2598)

Major OR NMCR Bleeding 14.22 (888) 14.02 (878) 1.05 (0.95, 1.15) 16.12 (587) 15.35 (571) 1.05 (0.93, 1.18) 0.99 Hemorrhagic Stroke 0.16 (11) 0.43 (30) 0.38 (0.19, 0.76) 0.43 (18) 0.47 (20) 0.91 (0.48, 1.73) 0.067

Intracranial Hemorrhage 0.40 (28) 0.65 (46) 0.63 (0.40, 1.02) 0.64 (27) 0.89 (38) 0.72 (0.44, 1.19) 0.71

Abbreviations: NMCR, Non-major clinically relevant bleeding

*Reported as events per 100 patient-years (total events); Adjusted efficacy outcomes ‡p value for interaction of heart failure and treatment

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21

Table 4. Treatment comparisons for efficacy and safety endpoints among heart failure subgroups

Heart Failure Subgroup

Stroke or non-CNS embolism Major or Non-Major Clinically Relevant Bleeding

ITT n

Rivaroxaban*

Warfarin*

Rivaroxaban vs. Warfarin

HR (95% CI)

p-value for interaction‡

Safety n

Rivaroxaban

Warfarin


HR (95% CI)

p-value for interaction‡

Ejection Fraction 40% 4893 2.00 (93) 2.06 (95) 0.98 (0.74, 1.31) 0.38 4914 14.18 (487) 14.81 (504) 1.00 (0.88, 1.13) 0.051

< 40% 2497 1.34 (33) 1.87 (46) 0.72 (0.46, 1.12) 2521 15.34 (265) 14.10 (246) 1.15 (0.96, 1.36) NYHA Class

I or II 6205 1.90 (111) 2.02 (118) 0.94 (0.73, 1.22) 0.68 6217 14.83 (631) 14.15 (610) 1.08 (0.97, 1.21) 0.19 III or IV 2645 1.88 (49) 2.10 (54) 0.90 (0.61, 1.32) 2676 12.45 (232) 13.54 (249) 0.96 (0.80, 1.15)

HF Classification

HFpEF§ 4893 2.00 (93) 2.06 (95) 0.98 (0.74, 1.31) 0.35 4914 14.18 (487) 14.81 (504) 1.00 (0.88, 1.13) 0.23

HFrEF¶ 2315 1.27 (29) 1.70 (39) 0.75 (0.46, 1.22) 2338 15.05 (241) 13.89 (227) 1.14 (0.95, 1.37) Device Therapy

No Device 7899 1.96 (147) 2.08 (156) 0.94 (0.75, 1.18) 0.11 7937 13.08 (722) 13.72 (753) 0.99 (0.89, 1.09) 0.0015 ICD or BiV-ICD 298 0.33 (1) 1.96 (6) 0.17 (0.02, 1.39) 297 32.43 (56) 16.37 (35) 2.00 (1.31, 3.05)

CHADS2 Score 2 610 1.30 (10) 1.16 (9) 1.09 (0.44, 2.69) 0.48 610 15.96 (83) 10.02 (56) 1.54 (1.10, 2.16) 0.15 3 8423 1.96 (154) 2.18 (170) 0.90 (0.72, 1.12) 8467 14.06 (805) 14.42 (822) 1.02 (0.92, 1.12)

CHA2DS2-VASc Score

4 3150 1.27 (40) 1.53 (48) 0.82 (0.54, 1.25) 0.19 3160 13.34 (309) 11.62 (278 1.15 (0.98, 1.35) 0.82 5 5883 2.26 (124) 2.40 (131) 0.95 (0.74, 1.21) 5917 14.74 (579) 15.52 (600) 1.01 (0.90, 1.13)

Abbreviations: BiV-ICD, biventricular- implantable cardioverter defibrillator; ICD, implantable cardioverter defibrillator; HF, heart failure; ITT, intention to treat; NYHA, New York Heart Association; HFpEF, heart failure preserved ejection fraction; HFrEF, heart failure reduced ejection fraction.

*Reported as events per 100 patient-years (total events); Adjusted efficacy outcomes ‡p value for interaction of subgroup and treatment

§ Defined as a history of heart failure at randomization with an EF 40%

¶ Defined as a history of heart failure at randomization with an EF < 40%

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22

Figure Legend

Figure 1. Efficacy and safety endpoints by treatment and heart failure

Figure shows relative efficacy and safety of rivaroxaban versus warfarin across all endpoints among patients with heart failure

Figure 2. Cumulative rate of stroke or systemic embolism in patients by heart failure and treatment

Figure shows no difference in the primary efficacy outcome among rivaroxaban and warfarin treated patients with and without heart failure (p =0.62 for interaction)




SUPPLEMENTAL MATERIAL

Appendix 1: Baseline characteristics for all patients in the intention to treat population classified by

history of heart failure

Variable All Patients (n=14171)

Patients with Heart Failure

(n=9033)

Patients without Heart Failure

(n=5138)

p value

Age, median (25th, 75th), years 73 (65, 78) 72 (65, 78) 74 (66, 79) <0.0001

Female, n (%) 5605 (39.6%) 3533 (39.1%) 2072 (40.3%) 0.15

Body Mass Index, median (25th, 75th), kg/m2 28.2 (25.1, 32.0) 28.7 (25.5, 32.5) 27.4 (24.6, 30.9) <0.0001

Geographic region, n (%) <0.0001

Asia/Pacific 2109 ( 14.8%) 966 (10.6%) 1143 (22.1%)

Eastern Europe 5500 (38.6%) 4453 (49.0%) 1047 (20.2%)

Western Europe 2096 (14.7%) 1058 (11.6%) 1038 (20.1%)

North America 2681 (18.8%) 1447 (15.9%) 1234 (23.9%)

Latin America 1878 (13.2%) 1167 (12.8%) 711 (13.7%)

Atrial Fibrillation Variables

Atrial Fibrillation type, n (%) <0.0001

Persistent 11485 (81.0%) 7497 (83.0%) 3988 (77.6%)

Paroxysmal 2490 (17.6%) 1431 (15.8%) 1059 (20.6%)

New Onset 196 (1.4%) 105 (1.2%) 91 (1.8%)

Previous Stroke or TIA, n(%) 7468 (52.4%) 3868 (42.6%) 3600 (69.6%) <0.0001

Previous Non-CNS Embolism, n (%) 551 (3.9%) 347 (3.8%) 204 (4.0%) 0.70

Carotid Occlusive Disease, n (%) 589 (4.2%) 356 (3.9%) 233 (4.5%) 0.089

CHADS2 Score, n (%) <.0001

1 3 (<0.1%) 0 (0.0%) 3 (0.1%)

2 1859 (13.0%) 610 (6.7%) 1249 (24.1%)

3 6216 (43.6%) 3966 (43.6%) 2250 (43.5%)

4 4091 (28.7%) 2719 (29.9%) 1372 (26.5%)

5 1813 (12.7%) 1514 (16.7%) 299 (5.8%)

6 282 (2.0%) 282 (3.1%) 0 (0.0%)

CHADS2 Score, mean (SD) 3.5 (0.9) 3.7 (0.9) 3.1 (0.8)

CHA2DS2-VASc score, mean (SD) 4.9 (1.3) 4.5 (1.2) 5.1 (1.3) <0.0001

Heart Failure Variables Excluded

Ejection Fraction <40%, n (%) 2145 (23.6%) 2145 (33.9%)

NYHA Class, n (%)

I 1192 (13.5%)

II 5013 (56.6%)

III 2511 (28.4%)

IV 134 (1.5%)

ICD or BiV-ICD, n(%) 314 (2.5%) 298 (3.6%) 16 (0.3%) <0.0001

Other Baseline Comorbidities, n (%)

Hypertension 12824 (90.5%) 8402 (93.0%) 4422 (86.1%) <0.0001

Diabetes Mellitus 5647 (39.8%) 3828 (42.4%) 1819 (35.4%) <0.0001

Myocardial Infarction 2446 (17.3%) 1953 (21.6%) 493 (9.6%) <0.0001

Coronary Artery Bypass 1029 (7.3%) 732 (8.1%) 297 (5.8%) <0.0001

Peripheral Vascular Disease 832 (5.9%) 605 (6.7%) 227 (4.4%) <0.0001

Chronic Obstructive Pulmonary Disease 1481 (10.5%) 1122 (12.4%) 359 (7.0%) <0.0001

Presenting Characteristics, median (25th,

75th)

Heart Rate, beats/min 76 (67, 86) 77 (68, 86) 74 (65, 84) <0.0001

Systolic Blood Pressure, mmHg 130 (120, 140) 130 (120, 140) 130 (120, 140) 0.014

Diastolic Blood Pressure, mmHg 80 (70, 85) 80 (70, 86) 80 (70, 85) 0.012

Creatinine Clearance*, ml/min 67 (52, 87) 68 (52, 89) 67 (53, 85) <0.0001

Previous and Concurrent medications, n (%)

Prior VKA Use 8853 (62.5%) 5279 (58.4%) 3574 (69.6%) <0.0001

Prior ASA Use 5461 (38.5%) 3765 (41.7%) 1696 (33.0%) <0.0001

Concurrent ASA Use 4098 (28.9%) 2801 (31.0%) 1297 (25.2%) <0.0001

Beta-Blocker 9184 (64.8%) 6287 (69.6%) 2897 (56.4%) <0.0001

Digitalis 5460 (38.5%) 4060 (44.9%) 1400 (27.2%) <0.0001

Angiotensin Converting Enzyme Inhibitors 7658 (54.0%) 5499 (60.9%) 2159 (42.0%) <0.0001

Diuretics 8441 (59.6%) 6404 (70.9%) 2037 (39.6%) <0.0001 *Creatinine Clearance was calculated using the Cockcroft–Gault formula

Abbreviations: BiV-ICD, Biventricular Implantable Cardioverter Defibrillator; NYHA, New York Heart

Association; ICD, Implantable Cardioverter Defibrillator; VKA, vitamin K antagonist

Appendix 2: Time in therapeutic range among warfarin treated patients.

Subgroup N Time in Therapeutic Range mean (SD)

All patients without heart failure on warfarin

2554 59.1 (20.6)

All heart failure patients on warfarin

4429 52.9 (21.3)

HF subgroups: Ejection Fraction

≥ 40% 2396 53.7 (20.8) < 40% 1244 52.7 (22.2)

NYHA Class I or II 3045 54.4 (21.1)

III or IV 1295 49.3 (21.2) Device Therapy

No Device 3872 52.0 (21.5) ICD or BiV-ICD 146 61.1 (16.9)

CHADS2 Score 2 300 53.8 (19.9)

≥3 4129 52.9 (21.4)

Abbreviations: BiV-ICD, biventricular- implantable cardioverter defibrillator; ICD, implantable

cardioverter defibrillator; SD, standard deviation

Appendix 3: Efficacy and safety endpoints in patients with and without heart failure (per-protocol

study population)

Outcomes Heart Failure*

No Heart Failure*

Heart Failure vs No Heart failure

HR (95% CI)Ɨ p value

Efficacy Outcomes (n=8966) (n=5088) Stroke or Systemic Embolization 1.81 (251) 2.14 (178) 0.89 (0.72, 1.11) 0.31

Safety Outcomes (n=8908) (n=5054) Major or NMCR bleeding 14.13 (1740) 15.80 (1142) 0.99 (0.92, 1.08) 0.90

Hemorrhagic Stroke 0.29 (40) 0.46 (38) 0.72 (0.44, 1.18) 0.19 *Reported as events per 100 patient-years (total events); Ɨ Adjusted efficacy outcomes

Appendix 4: Treatment comparisons for efficacy and safety endpoints in patients with and without

heart failure (per-protocol study population)

Outcomes

Heart Failure No Heart Failure p-value for interactionƗ Rivaroxaban*

Warfarin*


HR (95% CI)Ɨ

Rivaroxaban*

Warfarin*


HR (95% CI) Ɨ

Efficacy Outcomes (n=4487) (n=4479) (n=2521) (n=2567)

Stroke or Systemic Embolization 1.56 (107) 2.07 (144) 0.75 (0.58, 0.96) 1.98 (81) 2.31 (97) 0.87 (0.64, 1.16) 0.47

Safety Outcomes (n=4457) (n=4451) (n=2501) (n=2553)

Major or NMCR bleeding 14.28 (876) 13.99 (864) 1.06 (0.96, 1.16) 16.21 (578) 15.41 (564) 1.05 (0.93, 1.18) 0.92

Hemorrhagic Stroke 0.16 (11) 0.42 (29) 0.40 (0.20, 0.80) 0.44 (18) 0.47 (20) 0.91 (0.48, 1.73) 0.084 *Reported as events per 100 patient-years (total events); Ɨ Adjusted efficacy outcomes ‡p value for interaction of heart failure and treatment Abbreviations: NMCR, Non-major clinically relevant bleeding

efficacy and safety of rivaroxaban in patients with heart

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