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Symptomatic event reduction with extended-duration betrixaban in acute medically ill hospitalized patients
Accepted Manuscript Symptomatic Event Reduction with Extended-Duration Betrixaban in Acute Medically Ill Hospitalized Patients
C. Michael Gibson, Tarek Nafee, Megan K. Yee, Gerald Chi, Serge Korjian, Yazan Daaboul, Fahad AlKhalfan, Mathieu Kerneis, Samuel Z. Goldhaber, Russel Hull, Adrian F. Hernandez, Alexander T. Cohen, Robert A. Harrington PII: DOI: Reference:
S0002-8703(17)30403-9 https://doi.org/10.1016/j.ahj.2017.12.015 YMHJ 5603
To appear in: Received date: Accepted date:
6 August 2017 19 December 2017
Please cite this article as: C. Michael Gibson, Tarek Nafee, Megan K. Yee, Gerald Chi, Serge Korjian, Yazan Daaboul, Fahad AlKhalfan, Mathieu Kerneis, Samuel Z. Goldhaber, Russel Hull, Adrian F. Hernandez, Alexander T. Cohen, Robert A. Harrington , Symptomatic Event Reduction with Extended-Duration Betrixaban in Acute Medically Ill Hospitalized Patients. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Ymhj(2017), https://doi.org/10.1016/ j.ahj.2017.12.015
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ACCEPTED MANUSCRIPT
Symptomatic Event Reduction with Extended-Duration Betrixaban in Acute Medically Ill Hospitalized Patients
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C. Michael Gibson, M.S., M.D.a; Tarek Nafee, M.D.a; Megan K. Yee, M.P.H.a; Gerald Chi, M.D.a; Serge Korjian, M.D.a; Yazan Daaboul, M.D.a; Fahad AlKhalfan, M.D.a, Mathieu Kerneis, M.D.a; Samuel Z. Goldhaber, M.D.b; Russel Hull, M.B.B.S.c; Adrian F. Hernandez, M.D.d; Alexander T. Cohen, M.D.e; Robert A. Harrington M.D.f
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From PERFUSE Study Group, Cardiovascular Division, Departments of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA a; Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School b; R.A.H Faculty of Medicine, University of Calgary, Alberta, Canada; Division of Cardiology c; Duke University and Duke Clinical Research Institute d; Guy’s and St Thomas’ Hospitals, London, UK e; Department of Medicine, Stanford University, Stanford CA, USA f
Address for Correspondence: C. Michael Gibson, M.S., M.D. PERFUSE Study Group Cardiovascular Division, Department of Medicine Beth Israel Deaconess Medical Center Harvard Medical School 20 Overland Street, Suite 540 Boston, MA 02215, USA Email: [email protected] Telephone: 617-975-9950 Fax: 617-975-9955
ACCEPTED MANUSCRIPT ABSTRACT Background: Approximately 15-30% of patients in trials of medical thromboprophylaxis will have missing compression ultrasound (CUS) data. The goal of the present analysis was to perform analyses to minimize missing data.
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Methods: The APEX trial randomized 7,513 acutely medically ill hospitalized patients to
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thromboprophylaxis with either betrixaban for 35-42 days or enoxaparin for 6-14 days. An
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mITT analysis was performed and included all subjects administered study drug, irrespective of
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CUS performance, and an analysis of symptomatic events which do not require performance of a CUS (symptomatic deep vein thrombosis [DVT], non-fatal pulmonary embolism [PE], and VTE-
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related mortality.
Results: In the mITT population, betrixaban significantly reduced the primary endpoint (which
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included both symptomatic and CUS events) (165 (4.4%) vs 223 (6.0%); relative risk [RR] =
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0.75; 95% CI: 0.61to 0.91; p = 0.003; ARR = 1.6%; NNT = 63). Betrixaban also reduced
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symptomatic VTE through day 42 (35 (1.28%) vs 54 (1.88%), hazard ratio [HR] = 0.65; 95% CI: 0.42 to 0.99; p=0.044; ARR = 0.6%; NNT=167) as well as through day 77 (37 (1.02%) vs 67
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(1.89%); HR= 0.55; 95% CI: 0.37 to 0.83; p=0.003; ARR = 0.87%; NNT=115) as well as the individual endpoint of non-fatal PE (9 (0.25%) vs 20 (0.55%); HR= 0.45; 95% CI: 0.21 to 0.99;
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P=0.041; ARR = 0.30%; NNT=334). On an “as-treated” basis, 80 mg of betrixaban reduced VTE-related mortality through day 77 (10 (0.34%) vs. 22 (0.79%); HR=0.46; 95%CI: 0.22-0.96; p=0.035; ARR = 0.45%; NNT=223). Conclusion: In an mITT analysis of all patients administered study drug, extended duration betrixaban reduced the primary endpoint as well as symptomatic events. In an as treated analysis, 80 mg of betrixaban reduced VTE related death.
ACCEPTED MANUSCRIPT KEYWORDS Betrixaban, Extended duration thromboprophylaxis, Acute medically ill, Deep vein thrombosis, Pulmonary Embolism
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ABBREVIATIONS
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ANOVA – Analysis of variance
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DOAC – Direct Oral Anticoagulant DVT – Deep Vein Thrombosis
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LDUH - Low Dose Unfractionated Heparin
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LMWH – Low Molecular Weight Heparins
NNT – Number Needed to Treat
ULN – Upper Limit of Normal
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PE – Pulmonary Embolism
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VTE – Venous Thromboembolism
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NNH – Number Needed to Harm
ACCEPTED MANUSCRIPT INTRODUCTION The risk of venous thromboembolism (VTE) in medically ill patients is pervasive, persistent, and preventable. VTE risk is pervasive as there are 8-12 million medically ill patients at risk each year in the United States and Europe.1 The risk of VTE persists following discharge,
(MEDENOX)3,
dalteparin
(PREVENT)4,
fondaparinux
(ARTEMIS)5
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demonstrated in-hospital VTE is preventable.
and
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enoxaparin
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especially during the first 4-6 weeks after discharge.2 Trials of in-hospital prophylaxis with
Three global trials were undertaken to evaluate VTE prophylaxis in medically ill patients
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that extended the duration of prophylaxis beyond the hospitalization to after discharge using
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enoxaparin (EXCLAIM trial)6, apixaban (ADOPT trial)7, or rivaroxaban (MAGELLAN trial)8. While enoxaparin and rivaroxaban reduced VTE, all three of these anticoagulants caused excess Given the excess risk of major bleeding, extended duration prophylaxis
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major bleeding.
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following discharge for an acute medical illness has not been recommended by guideline committees.9,10 It is only following the most recent revision to the VTE guidelines that data from
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the APEX trial11 , a study demonstrating that betrixaban reduces VTE without increasing major
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bleeding, has become available.12,13
The initial publication of the APEX trial focused on a composite endpoint, which
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included both asymptomatic and symptomatic events among those patients in whom an interpretable compressible ultrasound (CUS) was obtained. Approximately 15% of patients were excluded from the primary analysis due to a missing CUS. The goal of the present analysis was to perform two types of analyses to minimize the missing data due to unobtained and uninterpretable CUS: 1) analyze all patients who received study drug, irrespective of
ACCEPTED MANUSCRIPT performance of a CUS (perform an mITT analysis of all subjects administered study drug), and 2) analyze symptomatic events which do not require performance of a CUS.
METHODS
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Study Population
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The design and primary results of the Acute Medically Ill Venous Thromboembolism
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Prevention with Extended Duration Betrixaban (APEX) trial have been described previously.11,14 In brief, APEX was a randomized, double-blind, double-dummy, active-controlled, phase 3
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clinical trial that enrolled 7,513 patients who were hospitalized for specific acute medical
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illnesses (heart failure, respiratory failure, infectious disease, rheumatic disease, or ischemic stroke), who had reduced mobility, and who were at high risk of VTE.
Subjects were
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randomized in a 1:1 ratio to receive either 80 mg of oral betrixaban for 35 to 42 days, or 40 mg
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of subcutaneous enoxaparin for a standard duration of 6 to 14 days. Additional medication kits were provided at the request of the study physician to provide additional parenteral therapy.
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Following ascertainment of the primary endpoint at 35-42 days, subjects were followed for
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symptomatic events for an additional 30 to 35 days and had an end of study visit at up to 77 days. Subjects randomized to betrixaban with severe renal impairment (CrCl <30mL/min) or
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concomitant strong P-glycoprotein (P-gp) inhibitors received a reduced dose of betrixaban 40 mg daily. Subjects randomized to enoxaparin with severe renal impairment received a reduced dose of enoxaparin 20 mg. Randomization was stratified by baseline D-dimer level (≥ 2X ULN or < 2X ULN), creatinine clearance (≥ 30 mL/min vs < 30 mL/min), and concomitant use of strong Pgp inhibitors. Study Endpoints
ACCEPTED MANUSCRIPT In the APEX trial, all efficacy and safety events were adjudicated by an independent clinical events committee.
In the present analysis, the primary efficacy endpoint was the
occurrence of VTE defined as the composite of symptomatic DVT, non-fatal PE, and VTErelated death, and asymptomatic DVT (CUS events). Additional efficacy outcomes were the
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composite of symptomatic VTE (DVT, PE, VTE-related death) and each individual component
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of the symptomatic composite. Symptomatic VTE and the individual symptomatic components
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were assessed at two time points, from randomization through the active treatment period (day 35-42) and from randomization through the end of follow-up (maximum of 77 days). Safety was
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assessed as the occurrence of International Society on Thrombosis and Hemostasis (ISTH) major
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bleeds within 7 days of discontinuation of study drug. Statistical Analysis
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Efficacy analyses were performed in the modified intent-to-treat (mITT) population,
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which included all randomized subjects who received at least one dose of study drug and were evaluated for any of the efficacy endpoints irrespective of whether the subject underwent a CUS.
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Descriptive statistics were reported as frequencies and percentages for categorical variables and
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as mean and standard deviation or median and interquartile range for continuous variables. Differences in baseline characteristics were assessed between the treatment groups with the chi-
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square test of independence for categorical variables, and with the independent samples t-test or the Wilcoxon rank sum test, as appropriate, for continuous variables.
Time-to-first-event
analyses were conducted. Event rates were expressed as Kaplan-Meier estimates and the logrank p-value was calculated. Hazard ratios and 95% confidence intervals (CIs) were calculated using Cox-Proportional Hazards models.
Additionally, relative risks and 95% CIs were
calculated using a Cochran-Mantel-Haenszel model, stratified by D-dimer status (< or ≥ 2x
ACCEPTED MANUSCRIPT ULN) and dosing criteria. Bleeding events rates, relative risks, and 95% CIs were calculated using a Chi-square test of independence.
Safety analyses were conducted in the safety
population, which included all subjects who received at least one dose of active study drug. The analyses were also performed among subjects who were stratified to receive the standard, higher-
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dose treatment (80mg of betrixaban or 40mg of enoxaparin). A sensitivity analysis of was also
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performed in patients who actually received standard higher-dose treatment on an “as treated”
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basis (which included patients stratified to receive 40 mg of betrixaban who actually received 80 mg).
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This study was funded by Portola Pharmaceuticals. The authors are solely responsible for
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the design and conduct of this study, all study analyses, drafting and editing of the paper and its final contents.
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RESULTS
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Baseline characteristics were well balanced between the two treatment arms in the mITT
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population (Table 1).11
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Efficacy
In the mITT population, betrixaban significantly reduced the incidence of the primary
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endpoint in the trial (which included both symptomatic and CUS events) (165 (4.4%) vs 223 (6.0%); Relative Risk [RR] = 0.75, 95% Confidence Interval [CI]: 0.61to 0.91; p = 0.003; absolute risk reduction [ARR] = 1.6%; number needed to treat [NNT] = 63) (Figure 1). In the mITT population, betrixaban also significantly reduced symptomatic VTE through day 42 (35 (1.28%) vs 54 (1.88%); hazard ratio [HR] = 0.65; 95% CI: 0.42 to 0.99; p = 0.044; ARR = 0.60%; NNT = 167) (Figure 2A). During this time period, betrixaban was associated with a
ACCEPTED MANUSCRIPT numeric, but not statistically significant, reduction in the individual components of the composite endpoint (Supplementary Table S1).
Through day 77, betrixaban significantly reduced
symptomatic VTE events (37 (1.02%) vs 67 (1.89%); HR = 0.55; 95% CI: 0.37 to 0.83; p = 0.003; ARR = 0.87%; NNT = 115) (Figure 2B) as well as the individual endpoint of non-fatal PE
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(9 (0.25%) vs 20 (0.55%); HR = 0.45; 95% CI: 0.21 to 0.99; p = 0.041; ARR = 0.30%; NNT =
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334) (Figure 2C).
Efficacy in the 80 mg Dose Group
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Betrixaban reduced the primary endpoint among subjects stratified to receive 80 mg (120
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(4.2%) vs. 180 (6.2%); RR = 0.68; 95% CI: 0.55 to 0.86; p < 0.001; ARR = 2.0%; NNT = 50) (Figure 1). Through day 42, betrixaban also demonstrated a statistically significant reduction in
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symptomatic VTE (22 (1.16%) vs 41 (1.62%); HR = 0.55; 95% CI: 0.33 to 0.92; p = 0.020; ARR
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= 0.46%; NNT = 218) as well as in the individual component of the endpoint of non-fatal PE (4 (0.14%) vs 14 (0.52%); HR = 0.29; 95% CI: 0.10 to 0.88; p = 0.020; ARR = 0.38%; NNT = 264)
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(Figure 3). Through day 77, subjects stratified to receive 80 mg of betrixaban also sustained a
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statistically significant reduction in symptomatic VTE (24 (0.86%) vs 51 (1.84%); HR = 0.48; 95% CI: 0.30 to 0.78; p = 0.002; ARR = 0.98%; NNT = 103) as well as non-fatal PE (4 (0.14%)
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vs 16 (0.56%); HR = 0.25; 95% CI: 0.09 to 0.76; p = 0.008; ARR = 0.42%; NNT = 239) (Figure 4) (Table S2).
In a sensitivity analysis, VTE-related death was assessed among subjects who actually received 80 mg of betrixaban on an “as treated basis” (which includes those patients who were stratified to the 40 mg dose but who received 80 mg). The administration of 80 mg of betrixaban significantly reduced the incidence of VTE-related death through 77 days compared to
ACCEPTED MANUSCRIPT enoxaparin (10 (0.34%) vs. 22 (0.79%); HR = 0.46; 95% CI: 0.22 to 0.96; P=0.035; ARR = 0.45%; NNT = 223) (Figure 5).
Safety
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Betrixaban administration was not associated with an increase in the primary safety
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endpoint of major bleeding, either in the mITT population (25 (0.71%) vs 21 (0.59%); HR =
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1.20; 95% CI: 0.67 to 2.14; p = 0.54) or among subjects stratified to 80 mg of betrixaban (15
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(0.54%) vs 16 (0.56%); HR = 0.94; 95% CI: 0.47 to 1.91; p = 0.87) (Figure 6).
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DISCUSSION
The primary composite endpoint of VTE thromboprophylaxis trials often contains both
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symptomatic (symptomatic VTE, non-fatal PE, and VTE related death) as well as asymptomatic
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endpoints ascertained with compression ultrasound (CUS).7,8,11 Patients may not return for a CUS, and when it is obtained, the CUS may not be interpretable in 15%,11 26%,8 and 30% of
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cases.7,5,8 To minimize missing data from these patients, the U.S. FDA pre-specified a Modified
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Intent To Treat (mITT) analysis of the APEX data that included all patients who received study drug, regardless of whether they underwent an interpretable CUS or not.
In the mITT
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population, extended duration prophylaxis with betrixaban reduced the primary endpoint of the APEX trial from 6.0% to 4.4%, as described in the U.S. FDA label. Extended-duration betrixaban reduced the primary endpoint as well as the composite endpoint of symptomatic VTE through the end of treatment (35-42 days) and through the end of the study (77 days). A reduction in non-fatal PE was also observed through 77 days in the overall study population. Among patients stratified to high dose, extended duration betrixaban reduced
ACCEPTED MANUSCRIPT the primary endpoint from 6.2% to 4.2%, meaning that only 50 patients would require treatment to prevent one event. Similarly, a reduction in the symptomatic VTE composite as well as the individual endpoint of non-fatal PE was observed through day 42 and day 77. These results are consistent with previous analyses excluding subjects without an evaluable CUS, which
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demonstrated a reduction in the primary endpoint and the composite of symptomatic VTE among
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patients receiving the high dose.15 Notably, the current sensitivity analysis demonstrated a
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reduction in the hard endpoint of VTE-related mortality among patients received 80 mg of betrixaban in an as treated analysis. Only 223 patients would need to be treated with the full 80
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mg dose to save one life.
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Symptomatic VTE represents a major cost burden to patients and the healthcare system.16,17 Within the first three months of hospitalization for a medical illness, the mean direct
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cost of symptomatic VTE is estimated to be $22,646, compared to $5,749 in matched controls
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who did not develop VTE. Within five years of the index hospitalization, the mean direct cost associated with patients who had a VTE during hospitalization is estimated to be $62,838,
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compared to $24,464 in matched controls.18
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No increase in the risk of major bleeding associated with betrixaban, despite its extended duration of administration relative to standard of care enoxaparin. This may be due to the
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distinct pharmacological characteristics of betrixaban, which may be ideally suited for the acute medical ill population. Betrixaban concentrations remain fairly stable, exhibiting a low peak-totrough ratio, as the terminal half-life is approximately 37 hours. Excretion is primarily through the gut via the hepatobiliary route, while metabolism by CYP450 enzymes is minimal. Additionally, renal excretion of betrixaban is the lowest among other factor Xa inhibitors that have been studied in the acute medically ill patients.19,20
ACCEPTED MANUSCRIPT LIMITATIONS There was inadequate power to evaluate some individual components of the composite symptomatic VTE endpoint.
The APEX study participants represent a high-risk subset of
hospitalized medically ill patients at risk of VTE, and the results reported here may not be
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generalizable to all hospitalized patients.
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CONCLUSION
In an mITT analysis of all patients administered study drug, extended duration betrixaban
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reduced the primary endpoint as well as symptomatic events. In an as treated analysis, 80 mg of
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betrixaban reduced VTE related death.
ACCEPTED MANUSCRIPT REFERENCES
8. 9.
10.
11. 12.
13.
14.
15.
16.
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7.
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6.
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5.
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2.
Cohen AT, Agnelli G, Anderson FA, et al. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost. Oct 2007;98(4):756-764. Amin AN, Varker H, Princic N, Lin J, Thompson S, Johnston S. Duration of venous thromboembolism risk across a continuum in medically ill hospitalized patients. J Hosp Med. Mar 2012;7(3):231-238. Turpie AG. Thrombosis prophylaxis in the acutely ill medical patient: insights from the prophylaxis in MEDical patients with ENOXaparin (MEDENOX) trial. Am J Cardiol. Dec 28 2000;86(12B):48M-52M. Leizorovicz A, Cohen AT, Turpie AG, et al. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation. Aug 17 2004;110(7):874-879. Cohen AT, Davidson BL, Gallus AS, et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ. Feb 11 2006;332(7537):325-329. Hull RD, Schellong SM, Tapson VF, et al. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. Jul 06 2010;153(1):8-18. Goldhaber SZ, Leizorovicz A, Kakkar AK, et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med. Dec 08 2011;365(23):21672177. Cohen AT, Spiro TE, Buller HR, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. Feb 07 2013;368(6):513-523. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. Jun 2008;133(6 Suppl):381S-453S. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. Feb 2012;141(2 Suppl):e195S-226S. Cohen AT, Harrington RA, Goldhaber SZ, et al. Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients. N Engl J Med. Aug 11 2016;375(6):534-544. Liew AY, Piran S, Eikelboom JW, Douketis JD. Extended-duration versus short-duration pharmacological thromboprophylaxis in acutely Ill hospitalized medical patients: a systematic review and meta-analysis of randomized controlled trials. J Thromb Thrombolysis. Nov 30 2016. Dentali F, Mumoli N, Prisco D, Fontanella A, Di Minno MN. Efficacy and safety of extended thromboprophylaxis for medically ill patients. A meta-analysis of randomised controlled trials. Thromb Haemost. Jan 12 2017. Cohen AT, Harrington R, Goldhaber SZ, et al. The design and rationale for the Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban (APEX) study. Am Heart J. Mar 2014;167(3):335-341. Gibson CM, Halaby R, Korjian S, et al. The safety and efficacy of full- versus reduceddose betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention With Extended-Duration Betrixaban (APEX) trial. American Heart Journal. 2017;185:93100. Raskob GE, Angchaisuksiri P, Blanco AN, et al. Thrombosis: a major contributor to global disease burden. Arterioscler Thromb Vasc Biol. Nov 2014;34(11):2363-2371.
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20.
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19.
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18.
Cohen AT, Tapson VF, Bergmann JF, et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational crosssectional study. Lancet. Feb 02 2008;371(9610):387-394. Cohoon KP, Leibson CL, Ransom JE, et al. Costs of venous thromboembolism associated with hospitalization for medical illness. Am J Manag Care. Apr 01 2015;21(4):e255-263. Chan NC, Bhagirath V, Eikelboom JW. Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vascular health and risk management. 2015;11:343-351. Samama MM, Meddahi S, Samama CM. Pharmacology and laboratory testing of the oral Xa inhibitors. Clinics in laboratory medicine. Sep 2014;34(3):503-517.
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ACCEPTED MANUSCRIPT Table 1. Baseline Characteristics of the mITT Population
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10 (7,14)
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1 (<0.1) 173 (4.7) 1584 (42.6) 1289 (34.6) 663 (17.8) 11 (0.3)
0 (0.0) 149 (4.0) 1517 (40.8) 1338 (36.0) 708 (19.0) 8 (0.2)
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Enoxaparin (N=3720) 76.2 ± 8.3 1699 (45.7) 80.7 ± 19.4 29.5 ± 6.7
3490 (93.8) 7 (0.2) 70 (1.9) 153 (4.1)
669 (18.0)
645 (17.3)
1905 (51.2)
1856 (49.9)
1672 (44.9) 1095 (29.4) 440 (11.8) 406 (10.9) 106 (2.8)
1666 (44.8) 1041 (28.0) 465 (12.5) 432 (11.6) 116 (3.1)
2314 (62.2) 2555 (68.7) 459 (12.3)
2313 (62.2) 2494 (67.0) 437 (11.7)
307 (8.3)
291 (7.8)
849 (22.8)
859 (23.1)
596 (16) 698 (18.8) 42 (1.1)
611 (16.4) 685 (18.4) 31 (0.8)
3 (0.1)
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3472 (93.3) 9 (0.2) 70 (1.9) 170 (4.6)
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Age ─ yr – mean ± SD Male ─ no. (%) Weight ─ kg - mean ± SD Body mass index ─ mean ± SD Duration of hospitalization (days) ─ median (IQR) Creatinine clearance ─ no. (%) <15 ml/min 15-30 ml/min 30 to <60 ml/min 60 to ≤90 ml/min >90 ml/min Missing Race ─ no. (%) White Asian Black/African American Other† Concomitant strong P-gp inhibitor ─ no. (%) Prior thromboprophyaxis ≤ 96 hours ─ no. (%) Acute medical conditions ─ no. (%) Acute heart failure Acute infection Acute respiratory failure Acute ischemic stroke Acute rheumatic disorder Risk factors for VTE ─ no. (%) D-dimer ≥ 2 x ULN Age ≥ 75 History of cancer History of deep-vein thrombosis or pulmonary embolism History of heart failure (New York Heart Association Class III/IV) Concurrent acute infectious disease Severe varicosis Hormone replacement therapy Thrombophilia (hereditary or acquired)
Betrixaban (N=3721) 76.6 ± 8.4 1693 (45.5) 79.9 ± 19.2 29.2 ± 6.6
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Characteristic
Table 1: Baseline characteristics were well matched except for a statistically significant but clinically modest imbalance in mean age (76.6 years vs. 76.2 years, p=0.028) and mean BMI (29.2 vs. 29.5, p=0.030) between the betrixaban and enoxaparin arms, respectively
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Figure 1. Primary endpoint in the mITT population and 80 mg stratum
ACCEPTED MANUSCRIPT Figure 2. Efficacy Analyses in the Overall mITT Population
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A. Time-To-First Symptomatic Event through Day 42
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B. Time-To-First Symptomatic Event through Day 77
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C. Time-To-First Non-Fatal PE through Day 77
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Note: Symptomatic VTE events were assessed through two separate time points. Events were assessed from randomization through the end of the active treatment period (day 35-42), with subjects being censored between day 35 and day 42 (Panel A). Events were also assessed from randomization through the end of follow-up, with subjects being censored on the last day of contact (Panel B, Panel C).
ACCEPTED MANUSCRIPT Figure 3. Efficacy Analyses in Subjects Stratified to High-dose Treatment through Day 42
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ACCEPTED MANUSCRIPT Figure 4. Efficacy Analyses in Subjects Stratified to High-dose Treatment through Day 77
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Figure 5. Sensitivity Analysis of VTE-related death in Subjects Stratified to High-dose Treatment through Day 77
ACCEPTED MANUSCRIPT Figure 6. Safety Analyses through 7 days after Study Drug Discontinuation
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A. Time-To-First Major Bleed in the overall mITT Population
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B. Time-To-First Major Bleed for Subjects Stratified to High-dose Treatment
C. Michael Gibson, Tarek Nafee, Megan K. Yee, Gerald Chi, Serge Korjian, Yazan Daaboul, Fahad AlKhalfan, Mathieu Kerneis, Samuel Z. Goldhaber, Russel Hull, Adrian F. Hernandez, Alexander T. Cohen, Robert A. Harrington PII: DOI: Reference:
S0002-8703(17)30403-9 https://doi.org/10.1016/j.ahj.2017.12.015 YMHJ 5603
To appear in: Received date: Accepted date:
6 August 2017 19 December 2017
Please cite this article as: C. Michael Gibson, Tarek Nafee, Megan K. Yee, Gerald Chi, Serge Korjian, Yazan Daaboul, Fahad AlKhalfan, Mathieu Kerneis, Samuel Z. Goldhaber, Russel Hull, Adrian F. Hernandez, Alexander T. Cohen, Robert A. Harrington , Symptomatic Event Reduction with Extended-Duration Betrixaban in Acute Medically Ill Hospitalized Patients. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Ymhj(2017), https://doi.org/10.1016/ j.ahj.2017.12.015
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ACCEPTED MANUSCRIPT
Symptomatic Event Reduction with Extended-Duration Betrixaban in Acute Medically Ill Hospitalized Patients
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C. Michael Gibson, M.S., M.D.a; Tarek Nafee, M.D.a; Megan K. Yee, M.P.H.a; Gerald Chi, M.D.a; Serge Korjian, M.D.a; Yazan Daaboul, M.D.a; Fahad AlKhalfan, M.D.a, Mathieu Kerneis, M.D.a; Samuel Z. Goldhaber, M.D.b; Russel Hull, M.B.B.S.c; Adrian F. Hernandez, M.D.d; Alexander T. Cohen, M.D.e; Robert A. Harrington M.D.f
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From PERFUSE Study Group, Cardiovascular Division, Departments of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA a; Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School b; R.A.H Faculty of Medicine, University of Calgary, Alberta, Canada; Division of Cardiology c; Duke University and Duke Clinical Research Institute d; Guy’s and St Thomas’ Hospitals, London, UK e; Department of Medicine, Stanford University, Stanford CA, USA f
Address for Correspondence: C. Michael Gibson, M.S., M.D. PERFUSE Study Group Cardiovascular Division, Department of Medicine Beth Israel Deaconess Medical Center Harvard Medical School 20 Overland Street, Suite 540 Boston, MA 02215, USA Email: [email protected] Telephone: 617-975-9950 Fax: 617-975-9955
ACCEPTED MANUSCRIPT ABSTRACT Background: Approximately 15-30% of patients in trials of medical thromboprophylaxis will have missing compression ultrasound (CUS) data. The goal of the present analysis was to perform analyses to minimize missing data.
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Methods: The APEX trial randomized 7,513 acutely medically ill hospitalized patients to
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thromboprophylaxis with either betrixaban for 35-42 days or enoxaparin for 6-14 days. An
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mITT analysis was performed and included all subjects administered study drug, irrespective of
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CUS performance, and an analysis of symptomatic events which do not require performance of a CUS (symptomatic deep vein thrombosis [DVT], non-fatal pulmonary embolism [PE], and VTE-
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related mortality.
Results: In the mITT population, betrixaban significantly reduced the primary endpoint (which
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included both symptomatic and CUS events) (165 (4.4%) vs 223 (6.0%); relative risk [RR] =
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0.75; 95% CI: 0.61to 0.91; p = 0.003; ARR = 1.6%; NNT = 63). Betrixaban also reduced
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symptomatic VTE through day 42 (35 (1.28%) vs 54 (1.88%), hazard ratio [HR] = 0.65; 95% CI: 0.42 to 0.99; p=0.044; ARR = 0.6%; NNT=167) as well as through day 77 (37 (1.02%) vs 67
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(1.89%); HR= 0.55; 95% CI: 0.37 to 0.83; p=0.003; ARR = 0.87%; NNT=115) as well as the individual endpoint of non-fatal PE (9 (0.25%) vs 20 (0.55%); HR= 0.45; 95% CI: 0.21 to 0.99;
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P=0.041; ARR = 0.30%; NNT=334). On an “as-treated” basis, 80 mg of betrixaban reduced VTE-related mortality through day 77 (10 (0.34%) vs. 22 (0.79%); HR=0.46; 95%CI: 0.22-0.96; p=0.035; ARR = 0.45%; NNT=223). Conclusion: In an mITT analysis of all patients administered study drug, extended duration betrixaban reduced the primary endpoint as well as symptomatic events. In an as treated analysis, 80 mg of betrixaban reduced VTE related death.
ACCEPTED MANUSCRIPT KEYWORDS Betrixaban, Extended duration thromboprophylaxis, Acute medically ill, Deep vein thrombosis, Pulmonary Embolism
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ABBREVIATIONS
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ANOVA – Analysis of variance
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DOAC – Direct Oral Anticoagulant DVT – Deep Vein Thrombosis
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LDUH - Low Dose Unfractionated Heparin
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LMWH – Low Molecular Weight Heparins
NNT – Number Needed to Treat
ULN – Upper Limit of Normal
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PE – Pulmonary Embolism
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VTE – Venous Thromboembolism
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NNH – Number Needed to Harm
ACCEPTED MANUSCRIPT INTRODUCTION The risk of venous thromboembolism (VTE) in medically ill patients is pervasive, persistent, and preventable. VTE risk is pervasive as there are 8-12 million medically ill patients at risk each year in the United States and Europe.1 The risk of VTE persists following discharge,
(MEDENOX)3,
dalteparin
(PREVENT)4,
fondaparinux
(ARTEMIS)5
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demonstrated in-hospital VTE is preventable.
and
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enoxaparin
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especially during the first 4-6 weeks after discharge.2 Trials of in-hospital prophylaxis with
Three global trials were undertaken to evaluate VTE prophylaxis in medically ill patients
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that extended the duration of prophylaxis beyond the hospitalization to after discharge using
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enoxaparin (EXCLAIM trial)6, apixaban (ADOPT trial)7, or rivaroxaban (MAGELLAN trial)8. While enoxaparin and rivaroxaban reduced VTE, all three of these anticoagulants caused excess Given the excess risk of major bleeding, extended duration prophylaxis
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major bleeding.
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following discharge for an acute medical illness has not been recommended by guideline committees.9,10 It is only following the most recent revision to the VTE guidelines that data from
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the APEX trial11 , a study demonstrating that betrixaban reduces VTE without increasing major
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bleeding, has become available.12,13
The initial publication of the APEX trial focused on a composite endpoint, which
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included both asymptomatic and symptomatic events among those patients in whom an interpretable compressible ultrasound (CUS) was obtained. Approximately 15% of patients were excluded from the primary analysis due to a missing CUS. The goal of the present analysis was to perform two types of analyses to minimize the missing data due to unobtained and uninterpretable CUS: 1) analyze all patients who received study drug, irrespective of
ACCEPTED MANUSCRIPT performance of a CUS (perform an mITT analysis of all subjects administered study drug), and 2) analyze symptomatic events which do not require performance of a CUS.
METHODS
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Study Population
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The design and primary results of the Acute Medically Ill Venous Thromboembolism
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Prevention with Extended Duration Betrixaban (APEX) trial have been described previously.11,14 In brief, APEX was a randomized, double-blind, double-dummy, active-controlled, phase 3
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clinical trial that enrolled 7,513 patients who were hospitalized for specific acute medical
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illnesses (heart failure, respiratory failure, infectious disease, rheumatic disease, or ischemic stroke), who had reduced mobility, and who were at high risk of VTE.
Subjects were
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randomized in a 1:1 ratio to receive either 80 mg of oral betrixaban for 35 to 42 days, or 40 mg
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of subcutaneous enoxaparin for a standard duration of 6 to 14 days. Additional medication kits were provided at the request of the study physician to provide additional parenteral therapy.
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Following ascertainment of the primary endpoint at 35-42 days, subjects were followed for
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symptomatic events for an additional 30 to 35 days and had an end of study visit at up to 77 days. Subjects randomized to betrixaban with severe renal impairment (CrCl <30mL/min) or
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concomitant strong P-glycoprotein (P-gp) inhibitors received a reduced dose of betrixaban 40 mg daily. Subjects randomized to enoxaparin with severe renal impairment received a reduced dose of enoxaparin 20 mg. Randomization was stratified by baseline D-dimer level (≥ 2X ULN or < 2X ULN), creatinine clearance (≥ 30 mL/min vs < 30 mL/min), and concomitant use of strong Pgp inhibitors. Study Endpoints
ACCEPTED MANUSCRIPT In the APEX trial, all efficacy and safety events were adjudicated by an independent clinical events committee.
In the present analysis, the primary efficacy endpoint was the
occurrence of VTE defined as the composite of symptomatic DVT, non-fatal PE, and VTErelated death, and asymptomatic DVT (CUS events). Additional efficacy outcomes were the
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composite of symptomatic VTE (DVT, PE, VTE-related death) and each individual component
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of the symptomatic composite. Symptomatic VTE and the individual symptomatic components
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were assessed at two time points, from randomization through the active treatment period (day 35-42) and from randomization through the end of follow-up (maximum of 77 days). Safety was
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assessed as the occurrence of International Society on Thrombosis and Hemostasis (ISTH) major
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bleeds within 7 days of discontinuation of study drug. Statistical Analysis
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Efficacy analyses were performed in the modified intent-to-treat (mITT) population,
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which included all randomized subjects who received at least one dose of study drug and were evaluated for any of the efficacy endpoints irrespective of whether the subject underwent a CUS.
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Descriptive statistics were reported as frequencies and percentages for categorical variables and
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as mean and standard deviation or median and interquartile range for continuous variables. Differences in baseline characteristics were assessed between the treatment groups with the chi-
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square test of independence for categorical variables, and with the independent samples t-test or the Wilcoxon rank sum test, as appropriate, for continuous variables.
Time-to-first-event
analyses were conducted. Event rates were expressed as Kaplan-Meier estimates and the logrank p-value was calculated. Hazard ratios and 95% confidence intervals (CIs) were calculated using Cox-Proportional Hazards models.
Additionally, relative risks and 95% CIs were
calculated using a Cochran-Mantel-Haenszel model, stratified by D-dimer status (< or ≥ 2x
ACCEPTED MANUSCRIPT ULN) and dosing criteria. Bleeding events rates, relative risks, and 95% CIs were calculated using a Chi-square test of independence.
Safety analyses were conducted in the safety
population, which included all subjects who received at least one dose of active study drug. The analyses were also performed among subjects who were stratified to receive the standard, higher-
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dose treatment (80mg of betrixaban or 40mg of enoxaparin). A sensitivity analysis of was also
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performed in patients who actually received standard higher-dose treatment on an “as treated”
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basis (which included patients stratified to receive 40 mg of betrixaban who actually received 80 mg).
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This study was funded by Portola Pharmaceuticals. The authors are solely responsible for
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the design and conduct of this study, all study analyses, drafting and editing of the paper and its final contents.
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RESULTS
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Baseline characteristics were well balanced between the two treatment arms in the mITT
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population (Table 1).11
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Efficacy
In the mITT population, betrixaban significantly reduced the incidence of the primary
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endpoint in the trial (which included both symptomatic and CUS events) (165 (4.4%) vs 223 (6.0%); Relative Risk [RR] = 0.75, 95% Confidence Interval [CI]: 0.61to 0.91; p = 0.003; absolute risk reduction [ARR] = 1.6%; number needed to treat [NNT] = 63) (Figure 1). In the mITT population, betrixaban also significantly reduced symptomatic VTE through day 42 (35 (1.28%) vs 54 (1.88%); hazard ratio [HR] = 0.65; 95% CI: 0.42 to 0.99; p = 0.044; ARR = 0.60%; NNT = 167) (Figure 2A). During this time period, betrixaban was associated with a
ACCEPTED MANUSCRIPT numeric, but not statistically significant, reduction in the individual components of the composite endpoint (Supplementary Table S1).
Through day 77, betrixaban significantly reduced
symptomatic VTE events (37 (1.02%) vs 67 (1.89%); HR = 0.55; 95% CI: 0.37 to 0.83; p = 0.003; ARR = 0.87%; NNT = 115) (Figure 2B) as well as the individual endpoint of non-fatal PE
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(9 (0.25%) vs 20 (0.55%); HR = 0.45; 95% CI: 0.21 to 0.99; p = 0.041; ARR = 0.30%; NNT =
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334) (Figure 2C).
Efficacy in the 80 mg Dose Group
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Betrixaban reduced the primary endpoint among subjects stratified to receive 80 mg (120
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(4.2%) vs. 180 (6.2%); RR = 0.68; 95% CI: 0.55 to 0.86; p < 0.001; ARR = 2.0%; NNT = 50) (Figure 1). Through day 42, betrixaban also demonstrated a statistically significant reduction in
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symptomatic VTE (22 (1.16%) vs 41 (1.62%); HR = 0.55; 95% CI: 0.33 to 0.92; p = 0.020; ARR
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= 0.46%; NNT = 218) as well as in the individual component of the endpoint of non-fatal PE (4 (0.14%) vs 14 (0.52%); HR = 0.29; 95% CI: 0.10 to 0.88; p = 0.020; ARR = 0.38%; NNT = 264)
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(Figure 3). Through day 77, subjects stratified to receive 80 mg of betrixaban also sustained a
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statistically significant reduction in symptomatic VTE (24 (0.86%) vs 51 (1.84%); HR = 0.48; 95% CI: 0.30 to 0.78; p = 0.002; ARR = 0.98%; NNT = 103) as well as non-fatal PE (4 (0.14%)
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vs 16 (0.56%); HR = 0.25; 95% CI: 0.09 to 0.76; p = 0.008; ARR = 0.42%; NNT = 239) (Figure 4) (Table S2).
In a sensitivity analysis, VTE-related death was assessed among subjects who actually received 80 mg of betrixaban on an “as treated basis” (which includes those patients who were stratified to the 40 mg dose but who received 80 mg). The administration of 80 mg of betrixaban significantly reduced the incidence of VTE-related death through 77 days compared to
ACCEPTED MANUSCRIPT enoxaparin (10 (0.34%) vs. 22 (0.79%); HR = 0.46; 95% CI: 0.22 to 0.96; P=0.035; ARR = 0.45%; NNT = 223) (Figure 5).
Safety
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Betrixaban administration was not associated with an increase in the primary safety
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endpoint of major bleeding, either in the mITT population (25 (0.71%) vs 21 (0.59%); HR =
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1.20; 95% CI: 0.67 to 2.14; p = 0.54) or among subjects stratified to 80 mg of betrixaban (15
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(0.54%) vs 16 (0.56%); HR = 0.94; 95% CI: 0.47 to 1.91; p = 0.87) (Figure 6).
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DISCUSSION
The primary composite endpoint of VTE thromboprophylaxis trials often contains both
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symptomatic (symptomatic VTE, non-fatal PE, and VTE related death) as well as asymptomatic
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endpoints ascertained with compression ultrasound (CUS).7,8,11 Patients may not return for a CUS, and when it is obtained, the CUS may not be interpretable in 15%,11 26%,8 and 30% of
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cases.7,5,8 To minimize missing data from these patients, the U.S. FDA pre-specified a Modified
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Intent To Treat (mITT) analysis of the APEX data that included all patients who received study drug, regardless of whether they underwent an interpretable CUS or not.
In the mITT
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population, extended duration prophylaxis with betrixaban reduced the primary endpoint of the APEX trial from 6.0% to 4.4%, as described in the U.S. FDA label. Extended-duration betrixaban reduced the primary endpoint as well as the composite endpoint of symptomatic VTE through the end of treatment (35-42 days) and through the end of the study (77 days). A reduction in non-fatal PE was also observed through 77 days in the overall study population. Among patients stratified to high dose, extended duration betrixaban reduced
ACCEPTED MANUSCRIPT the primary endpoint from 6.2% to 4.2%, meaning that only 50 patients would require treatment to prevent one event. Similarly, a reduction in the symptomatic VTE composite as well as the individual endpoint of non-fatal PE was observed through day 42 and day 77. These results are consistent with previous analyses excluding subjects without an evaluable CUS, which
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demonstrated a reduction in the primary endpoint and the composite of symptomatic VTE among
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patients receiving the high dose.15 Notably, the current sensitivity analysis demonstrated a
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reduction in the hard endpoint of VTE-related mortality among patients received 80 mg of betrixaban in an as treated analysis. Only 223 patients would need to be treated with the full 80
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Symptomatic VTE represents a major cost burden to patients and the healthcare system.16,17 Within the first three months of hospitalization for a medical illness, the mean direct
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cost of symptomatic VTE is estimated to be $22,646, compared to $5,749 in matched controls
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who did not develop VTE. Within five years of the index hospitalization, the mean direct cost associated with patients who had a VTE during hospitalization is estimated to be $62,838,
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compared to $24,464 in matched controls.18
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No increase in the risk of major bleeding associated with betrixaban, despite its extended duration of administration relative to standard of care enoxaparin. This may be due to the
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distinct pharmacological characteristics of betrixaban, which may be ideally suited for the acute medical ill population. Betrixaban concentrations remain fairly stable, exhibiting a low peak-totrough ratio, as the terminal half-life is approximately 37 hours. Excretion is primarily through the gut via the hepatobiliary route, while metabolism by CYP450 enzymes is minimal. Additionally, renal excretion of betrixaban is the lowest among other factor Xa inhibitors that have been studied in the acute medically ill patients.19,20
ACCEPTED MANUSCRIPT LIMITATIONS There was inadequate power to evaluate some individual components of the composite symptomatic VTE endpoint.
The APEX study participants represent a high-risk subset of
hospitalized medically ill patients at risk of VTE, and the results reported here may not be
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generalizable to all hospitalized patients.
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CONCLUSION
In an mITT analysis of all patients administered study drug, extended duration betrixaban
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reduced the primary endpoint as well as symptomatic events. In an as treated analysis, 80 mg of
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betrixaban reduced VTE related death.
ACCEPTED MANUSCRIPT REFERENCES
8. 9.
10.
11. 12.
13.
14.
15.
16.
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7.
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6.
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5.
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3.
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2.
Cohen AT, Agnelli G, Anderson FA, et al. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost. Oct 2007;98(4):756-764. Amin AN, Varker H, Princic N, Lin J, Thompson S, Johnston S. Duration of venous thromboembolism risk across a continuum in medically ill hospitalized patients. J Hosp Med. Mar 2012;7(3):231-238. Turpie AG. Thrombosis prophylaxis in the acutely ill medical patient: insights from the prophylaxis in MEDical patients with ENOXaparin (MEDENOX) trial. Am J Cardiol. Dec 28 2000;86(12B):48M-52M. Leizorovicz A, Cohen AT, Turpie AG, et al. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation. Aug 17 2004;110(7):874-879. Cohen AT, Davidson BL, Gallus AS, et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ. Feb 11 2006;332(7537):325-329. Hull RD, Schellong SM, Tapson VF, et al. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. Jul 06 2010;153(1):8-18. Goldhaber SZ, Leizorovicz A, Kakkar AK, et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med. Dec 08 2011;365(23):21672177. Cohen AT, Spiro TE, Buller HR, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. Feb 07 2013;368(6):513-523. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. Jun 2008;133(6 Suppl):381S-453S. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. Feb 2012;141(2 Suppl):e195S-226S. Cohen AT, Harrington RA, Goldhaber SZ, et al. Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients. N Engl J Med. Aug 11 2016;375(6):534-544. Liew AY, Piran S, Eikelboom JW, Douketis JD. Extended-duration versus short-duration pharmacological thromboprophylaxis in acutely Ill hospitalized medical patients: a systematic review and meta-analysis of randomized controlled trials. J Thromb Thrombolysis. Nov 30 2016. Dentali F, Mumoli N, Prisco D, Fontanella A, Di Minno MN. Efficacy and safety of extended thromboprophylaxis for medically ill patients. A meta-analysis of randomised controlled trials. Thromb Haemost. Jan 12 2017. Cohen AT, Harrington R, Goldhaber SZ, et al. The design and rationale for the Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban (APEX) study. Am Heart J. Mar 2014;167(3):335-341. Gibson CM, Halaby R, Korjian S, et al. The safety and efficacy of full- versus reduceddose betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention With Extended-Duration Betrixaban (APEX) trial. American Heart Journal. 2017;185:93100. Raskob GE, Angchaisuksiri P, Blanco AN, et al. Thrombosis: a major contributor to global disease burden. Arterioscler Thromb Vasc Biol. Nov 2014;34(11):2363-2371.
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20.
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19.
CE
18.
Cohen AT, Tapson VF, Bergmann JF, et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational crosssectional study. Lancet. Feb 02 2008;371(9610):387-394. Cohoon KP, Leibson CL, Ransom JE, et al. Costs of venous thromboembolism associated with hospitalization for medical illness. Am J Manag Care. Apr 01 2015;21(4):e255-263. Chan NC, Bhagirath V, Eikelboom JW. Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vascular health and risk management. 2015;11:343-351. Samama MM, Meddahi S, Samama CM. Pharmacology and laboratory testing of the oral Xa inhibitors. Clinics in laboratory medicine. Sep 2014;34(3):503-517.
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ACCEPTED MANUSCRIPT Table 1. Baseline Characteristics of the mITT Population
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1 (<0.1) 173 (4.7) 1584 (42.6) 1289 (34.6) 663 (17.8) 11 (0.3)
0 (0.0) 149 (4.0) 1517 (40.8) 1338 (36.0) 708 (19.0) 8 (0.2)
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Enoxaparin (N=3720) 76.2 ± 8.3 1699 (45.7) 80.7 ± 19.4 29.5 ± 6.7
3490 (93.8) 7 (0.2) 70 (1.9) 153 (4.1)
669 (18.0)
645 (17.3)
1905 (51.2)
1856 (49.9)
1672 (44.9) 1095 (29.4) 440 (11.8) 406 (10.9) 106 (2.8)
1666 (44.8) 1041 (28.0) 465 (12.5) 432 (11.6) 116 (3.1)
2314 (62.2) 2555 (68.7) 459 (12.3)
2313 (62.2) 2494 (67.0) 437 (11.7)
307 (8.3)
291 (7.8)
849 (22.8)
859 (23.1)
596 (16) 698 (18.8) 42 (1.1)
611 (16.4) 685 (18.4) 31 (0.8)
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3472 (93.3) 9 (0.2) 70 (1.9) 170 (4.6)
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Age ─ yr – mean ± SD Male ─ no. (%) Weight ─ kg - mean ± SD Body mass index ─ mean ± SD Duration of hospitalization (days) ─ median (IQR) Creatinine clearance ─ no. (%) <15 ml/min 15-30 ml/min 30 to <60 ml/min 60 to ≤90 ml/min >90 ml/min Missing Race ─ no. (%) White Asian Black/African American Other† Concomitant strong P-gp inhibitor ─ no. (%) Prior thromboprophyaxis ≤ 96 hours ─ no. (%) Acute medical conditions ─ no. (%) Acute heart failure Acute infection Acute respiratory failure Acute ischemic stroke Acute rheumatic disorder Risk factors for VTE ─ no. (%) D-dimer ≥ 2 x ULN Age ≥ 75 History of cancer History of deep-vein thrombosis or pulmonary embolism History of heart failure (New York Heart Association Class III/IV) Concurrent acute infectious disease Severe varicosis Hormone replacement therapy Thrombophilia (hereditary or acquired)
Betrixaban (N=3721) 76.6 ± 8.4 1693 (45.5) 79.9 ± 19.2 29.2 ± 6.6
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Characteristic
Table 1: Baseline characteristics were well matched except for a statistically significant but clinically modest imbalance in mean age (76.6 years vs. 76.2 years, p=0.028) and mean BMI (29.2 vs. 29.5, p=0.030) between the betrixaban and enoxaparin arms, respectively
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Figure 1. Primary endpoint in the mITT population and 80 mg stratum
ACCEPTED MANUSCRIPT Figure 2. Efficacy Analyses in the Overall mITT Population
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A. Time-To-First Symptomatic Event through Day 42
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B. Time-To-First Symptomatic Event through Day 77
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C. Time-To-First Non-Fatal PE through Day 77
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Note: Symptomatic VTE events were assessed through two separate time points. Events were assessed from randomization through the end of the active treatment period (day 35-42), with subjects being censored between day 35 and day 42 (Panel A). Events were also assessed from randomization through the end of follow-up, with subjects being censored on the last day of contact (Panel B, Panel C).
ACCEPTED MANUSCRIPT Figure 3. Efficacy Analyses in Subjects Stratified to High-dose Treatment through Day 42
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ACCEPTED MANUSCRIPT Figure 4. Efficacy Analyses in Subjects Stratified to High-dose Treatment through Day 77
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Figure 5. Sensitivity Analysis of VTE-related death in Subjects Stratified to High-dose Treatment through Day 77
ACCEPTED MANUSCRIPT Figure 6. Safety Analyses through 7 days after Study Drug Discontinuation
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A. Time-To-First Major Bleed in the overall mITT Population
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B. Time-To-First Major Bleed for Subjects Stratified to High-dose Treatment