efficacy and safety of rivaroxaban in patients with heart
TRANSCRIPT
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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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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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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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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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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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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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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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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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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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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at Bayer HealthCare / Bayer Schering Pharma on February 3, 2014http://circheartfailure.ahajournals.org/Downloaded from
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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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at Bayer HealthCare / Bayer Schering Pharma on February 3, 2014http://circheartfailure.ahajournals.org/Downloaded from
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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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at Bayer HealthCare / Bayer Schering Pharma on February 3, 2014http://circheartfailure.ahajournals.org/Downloaded from
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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.
References
1. Tsang TSM, Petty GW, Barnes ME, O’Fallon WM, Bailey KR, Wiebers DO, Sicks JD, Christianson TJH, Seward JB, Gersh BJ. The prevalence of atrial fibrillation in incident stroke cases and matched population controls in rochester, minnesota: Changes over three decades. J Am Coll Cardiol. 2003; 42:93-100.
2. Ezekowitz JA, Kaul P, Bakal JA, Quan H, McAlister FA. Trends in heart failure care: Has the incident diagnosis of heart failure shifted from the hospital to the emergency department and outpatient clinics? Eur J Heart Fail. 2011; 13:142-147.
3. Maisel WH, Stevenson LW. Atrial fibrillation in heart failure: Epidemiology, pathophysiology, and rationale for therapy. Am J Cardiol. 2003; 91:2-8.
4. van Diepen S, Majumdar SR, Bakal JA, McAlister FA, Ezekowitz JA. Heart failure is a risk factor for orthopedic fracture. Circulation. 2008; 118:1946-1952.
5. Adams Jr KF, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT, Berkowitz RL, Galvao M, Horton DP. Characteristics and outcomes of patients hospitalized for heart failure in the united states: Rationale, design, and preliminary
(formerly Johnhnhnhnhnhnns
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r s
u A
mmmmm,,, ,, Bristotototol-l-l-l MyMyMyMyMyererererersss s SqSqSqSqSquiuiuiuiuibbbbbbbbbb,,, DaDaDDD iichcchi SaSaSaSaSanknknknknkyoyoyoyyo,, JoJoJoJoJohnhnnsososososon n n nn &&&&& JoJoJoJoJohnhnhnhnhnso
resssseaeaeaeaearcrcrcrcr h hhhh suuuuuppppppppppororororort ttt cooooontntntnntrarararar cttttt wiwiwiwiwiththththth JJJJJohohohoho nsnsnsnsn ononononon &&&&& JJJJJohohohohohnnsnnn ononononon; ;;;; sssess rvrvrvrr ededededed aaaaasss
utututiviviveee cococommmmmmitititteteteeee mememembmbmbererer. SSSDBDBDB iiisss aaannn emememplplplpp oyoyoyyeeeeee ooofff BaBaBayeyeyey rrr. KAKAKA
at Bayer HealthCare / Bayer Schering Pharma on February 3, 2014http://circheartfailure.ahajournals.org/Downloaded from
14
observations from the first 100,000 cases in the acute decompensated heart failure national registry (AHDERE). Am Heart J. 2005; 149:209-216.
6. Nieminen MS, Brutsaert D, Dickstein K, Drexler H, Follath F, Harjola V-P, Hochadel M, Komajda M, Lassus J, Lopez-Sendon JL, Ponikowski P, Tavazzi L. Euroheart failure survey II (EHFS II): A survey on hospitalized acute heart failure patients: Description of population. Eur Heart J. 2006; 27:2725-2736
7. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006; 355:251-259.
8. The Stroke Prevention in Atrial Fibrillation Investigators. Predictors of thromboembolism in atrial fibrillation: I. Clinical features of patients at risk. Ann Intern Med. 1992; 116:1-5.
9. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke. JAMA. 2001; 285:2864-2870.
10. Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le Heuzey J-Y, Kay GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S, Smith SC, Jacobs AK, Adams CD, Anderson JL, Antman EM, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, Blanc J-J, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Zamorano JL. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation—executive summary. Circulation. 2006; 114:700-752.
11. Olesen JB, Lip GY, Hansen ML, Hansen PR, Tolstrup JS, Lindhardsen J, Selmer C, Ahlehoff O, Olsen AM, Gislason GH, Torp-Pedersen C. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: Nationwide cohort study. BMJ. 2011;342:d124
12. Atrial Fibrillation Investigators. Echocardiographic predictors of stroke in patients with atrial fibrillation: A prospective study of 1066 patients from 3 clinical trials. Arch Intern Med. 1998; 158:1316-1320.
13. Singer DE, Albers GW, Dalen JE, Go AS, Halperin JL, Manning WJ. Antithrombotic therapy in atrial fibrillation. Chest. 2004; 126:429S-456S
14. Dries D, Exner D, Gersh B, Domanski M, Waclawiw M, Stevenson L. Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: A retrospective analysis of the solvd trials. J Am Coll Cardiol. 1998; 32:695-703.
15. Veeger NJGM, Piersma-Wichers M, Tijssen JGP, Hillege HL, van der Meer J. Individual time within target range in patients treated with vitamin k antagonists: Main determinant of quality of anticoagulation and predictor of clinical outcome. A retrospective study of 2300 consecutive patients with venous thromboembolism. Brit J Haematol. 2005; 128:513-519.
16. White HD, Gruber M, Feyzi J, Kaatz S, Tse HF, Husted S, Albers GW,. Comparison of outcomes among patients randomized to warfarin therapy according to anticoagulant control: Results from sportif iii and v. Arch Interen Med. 2007; 167:239-245.
17. Connolly SJ, Pogue J, Eikelboom J, Flaker G, Commerford P, Franzosi MG, Healey JS, Yusuf S, Investigators obotAW. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved
n EM, Hunt SASAAAAAA, ,ajajajajajajaj AAAAAAA, ,,,, ,, CaCaCaCaCaCaCammmmmmmmmmmmmm AAAAAAAJ,J,J,J,J,J,J,or K,K,K,K,K,K,K, MMMMMMMetetetetetetetrarararararara MMMMMMM,
, Zamorano JL. ACC/AHA/ESC 2006 guidelines for the mah 1L
sp aclation Investigators Echocardiographic predictors of stroke in
, ZZZZZamamamamamorororororanaaaa o o oo o JL. ACC/AHA/ESSSSCCCCC 2006 guideeeeelillll nes for the mah atatatatatrial fibibibibibrrrrrilililllaaaaatititititiononononon—e—e—e—e—exexexexexecucucucc tiiiivevevvv sumumummamamamamaryryryryry.. CiCiCiC rcrcrcrcrculu atatatattioioioioionnnnn. 20202020200606060606; ;;;; 1Lipipipipip GY, Hanaanseeenn MLMLMLMLML, Hansnn enn PRRR, ToToToToTolslslslslstttrupupp JS,SS, LLLLLiiinii dhhhhhaaaraa dsdd enn J
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
at Bayer HealthCare / Bayer Schering Pharma on February 3, 2014http://circheartfailure.ahajournals.org/Downloaded from
15
by centers and countries as measured by time in therapeutic range. Circulation. 2008; 118:2029-2037.
18. Rose AJ, Hylek EM, Ozonoff A, Ash AS, Reisman JI, Berlowitz DR. Patient characteristics associated with oral anticoagulation control: Results of the veterans affairs study to improve anticoagulation (VARIA). J Thromb Haemost. 2010; 8:2182-2191.
19. Lip GYH, Frison L, Halperin JL, Lane DA. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: The HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile inr, elderly, drugs/alcohol concomitantly) score. J Am Coll Cardiol. 2011; 57:173-180.
20. DiMarco JP, Flaker G, Waldo AL, Corley SD, Greene HL, Safford RE, Rosenfeld LE, Mitrani G, Nemeth M. Factors affecting bleeding risk during anticoagulant therapy in patients with atrial fibrillation: Observations from the atrial fibrillation follow-up investigation of rhythm management (AFFIRM) study. Am Heart J. 2005; 149:650-656.
21. Witt DM, Delate T, Clark NP, Martell C, Tran T, Crowther MA, Garcia DA, Ageno W, Hylek EM. Outcomes and predictors of very stable inr control during chronic anticoagulation therapy. Blood. 2009; 114:952-956.
22. Witt DM, Delate T, Clark NP, Martell C, Tran T, Crowther MA, Garcia DA, Ageno W, Hylek EM, On Behalf Of The Warped C. Twelve-month outcomes and predictors of very stable inr control in prevalent warfarin users. J Thromb Haemost. 2010; 8:744-749.
23. Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of bay 59-7939, an oral, direct factor xa inhibitor. Clin Pharmacol Ther. 2005; 78:412-421.
24. Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. Safety, pharmacodynamics, and pharmacokinetics of bay 59-7939—an oral, direct factor xa inhibitor—after multiple dosing in healthy male subjects. Eur J Clin Pharm. 2005; 61:873-880.
25. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KAA, Califf RM. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011; 365:883-891.
26. Connolly SJ, Eikelboom J, Joyner C, Diener H-C, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim K-H, Lewis BS, Van Mieghem W, Lip GYH, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O'Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S. Apixaban in patients with atrial fibrillation. NEngl J Med. 2011; 364:806-817.
27. Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FWA, Zhu J, Wallentin L. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011; 365:981-992.
28. The Executive Steering Committee, on behalf of the ROCKET AF Study Investigators. The Rivaroxaban—once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation: Rationale and design of the ROCKET AF study. Am Heart J. 2010;159:340-347.
hhhhererererererer MMMMMMMA,A,A,A,A,A,A, GGGGGGGarararararararciciciciciciciaaaa aaa DDDDDDDouttcococococococomemememememem s s ss s s s ananananananand d dd d d d pp
ntrol in prevalent warfarin users. J Th b H t. 2010; 8Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, armc oaBecka M, Wensin G, Voith B, Zuehlsdorf M. Safe , armc —althy male subjects Eur J Clin Pharm 2005; 61:873 880
ntrrrrrololololol iiiin n nn n prpppp evevevevevalent warfarin usersrsrsrsrs.. J Thromb HHHHHaeaaaa most. 2010; 8Becececececka MMMMM, VoVoVoVoVoititittith hhhh B,BBBB ZZZZZueueueueuehlhlhlhlhlsdsdssdororooo f M,MM WWWWWenenenenensiiiiingngngnn GGGGG.. Saaaaafefefefefetytytytyty, phphphphpharararararmmmmcoooookkikkk netics oooff siiinngleeeee dosess of f bbayyy 599999-----79797979793399, annn oorararalll,ll diririririreccctt faaccctoacololololol TTTTTheheheheerrr. 20202020200500500 ; ;;; 788888:4:4:4441212121212-4-4-4442121212121.Becka M, Wensinnng ggg G,G,G,G,G, VVVVVoioioioioiththththt B,, ZuZuZuZuZuehehehehehlslsssdodododorfrfrfrfrf MMMMM. Safety, pharmcococokikikinenenetititicscscs ooofff bababayyy 595959-7-7-79393939—9—9—ananan ooorararal,l,l, dddiiirererectctct fffacacactototorrr xaxaxa iiinhnhnhibibibitititororor———alalalthththyy mamalelelell ssubububbbjejejejj cttcttss EuEEuEE rr JJJJJ CCCCClililillinn PhPhPhPhP ararmm 202020020050505005;; 6161616161:8:8:8887373737373-8-8-8808080
at Bayer HealthCare / Bayer Schering Pharma on February 3, 2014http://circheartfailure.ahajournals.org/Downloaded from
16
29. Rosendaal FR, Cannegieter SC, van der Meer FJ, Briët E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb haemostasis. 1993; 69:236-239.
30. Banerjee A, Taillandier S, Olesen JB, Lane DA, Lallemand B, Lip GYH, Fauchier L. Ejection fraction and outcomes in patients with atrial fibrillation and heart failure: The loire valley atrial fibrillation project. Eur J Heart Fail. 2012;14:295-301.
31. Camm AJ, Lip GYH, Raffaele DC, Irene S, Dan A, Hohnloser SH, Gerhard H, Paulus K. 2012 focused update of the esc guidelines for the management of atrial fibrillation. EurHeart J. 2012;33:2719-2747.
32. Go AS, Hylek EM, Chang Y, Phillips KA, Henault LE, Capra AM, Jensvold NG, Selby JV, Singer DE. Anticoagulation therapy for stroke prevention in atrial fibrillation: How well do randomized trials translate into clinical practice? JAMA. 2003; 290:2685-2692.
33. Baker WL, Cios DA, Sander SD, Coleman CI. Meta-analysis to assess the quality of warfarin control in atrial fibrillation patients in the united states. J Manag Care Pharm. 2009; 15:244-252.
34. Ahmad Y, Lip GYH, Apostolakis S. New roal anticoagulants for prevention in atrial fibrillation: Impact of gender, heart failure, diabetes mellitus and paroxysmal atrial fibrillation. Expert Rev Cardiovasc Ther. 2012;10:1471-1480
35. Lip GYH, Nieuwlaat R, Pisters R, Lane DA, Crijns HJGM. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach. Chest. 2010;137:263-272
36. The Bosston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. NEngl J Med. 1990; 323:1505-1511.
37. Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: Analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994; 154:1449-1457.
38. Pullicino PM, Halperin JL, Thompson JLP. Stroke in patients with heart failure and reduced left ventricular ejection fraction. Neurology. 2000 ;54:288-294.
39. Olshansky B, Heller EN, Mitchell LB, Chandler M, Slater W, Green M, Brodsky M, Barrell P, Greene HL. Are transthoracic echocardiographic parameters associated with atrial fibrillation recurrence or stroke?: Results from the atrial fibrillation follow-up investigation of rhythm management (AFFIRM) study. J Am Coll Cardiol. 2005;45:2026-2033.
40. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009; 361:2342-2352.
41. Rose AJ, Hylek EM, Ozonoff A, Ash AS, Reisman JI, Berlowitz DR. Risk-adjusted percent time in therapeutic range as a quality indicator for outpatient oral anticoagulation. Circulation: Cardiovasc Qual Outcome. 2011; 4:22-29.
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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)
4 (42.2%) 118888888 (((((((4.4.4.4.4.4.4.0%0%0%0%0%0%0%)))))))6 (3 9%9%9%9%9%9%9%)))))))
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1010101010434343434 (((333.3.3.33%)%)%)%)%) 1111110101010102 (34.5%)
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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
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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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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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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
Rivaroxaban vs. 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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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)
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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*
Rivaroxaban vs. Warfarin
HR (95% CI)Ɨ
Rivaroxaban*
Warfarin*
Rivaroxaban vs. 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