P revention with EX tended Duration Betrixaban A Multicenter Randomized ActiveControlled Efficacy and Safety Study Comparing Extended Duration Betrixaban with Standard of Care Enoxaparin for the Prevention of Venous Thromboembolism in Acute Medically Ill Patients ID: 624659
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Slide1
Acute Medically Ill VTE Preventionwith EXtended Duration BetrixabanA Multicenter, Randomized, Active-Controlled Efficacy and Safety Study Comparing Extended Duration Betrixaban with Standard of Care Enoxaparin for the Prevention of Venous Thromboembolism in Acute Medically Ill Patients
C. Michael Gibson, M.S., M.D.
on Behalf of the APEX InvestigatorsSlide2Conflict of Interest Statement
Present Research/Grant FundingAngel Medical Corporation Bayer Corp.CSL BehringGoogleIkaria, Inc.Janssen PharmaceuticalsJohnson & Johnson Corporation Portola PharmaceuticalsStealth Peptides, Inc.
St. Jude MedicalConsultant
(all with moderate support)
Boston Clinical Research Institute
Cardiovascular Research Foundation
CSL BehringGilead Sciences, Inc.The Medicines CompanyNovo NordiskPfizerSt. Jude MedicalWeb MD Consultant (with $0.00 monies received by Dr. Gibson)Bayer CorporationJanssen PharmaceuticalsJohnson & Johnson CorporationOrtho McNeilSpouse: Employee of Boston Clinical Research Institute, she has equity position
2Slide3Unmet Need for Extended Thromboprophylaxis in Acute Medically Ill Patients
Approximately 8 million acutely ill medical patients the US and 12 million in the EU are at risk of developing VTE annually.Despite standard of care agents available, more than 400,000 VTE events, including an estimated 150,000 VTE related deaths, occur in this patient population.Approximately 1 out of 2 DVT and PE events occur within 6 weeks of discharge where no agents are currently approved or guideline recommended for thromboprophylaxis.Anderson FA, Jr. et al. Am J Hematol. 2007;82(9):777-82Cohen AT et al. Thromb Haemost. 2007;98(4):756-64 Heit JA et al. Arch Intern Med. 2002;162(11):1245-8 Raskob GE et al. Arterioscler
Thromb Vasc Biol. 2014;34(11):2363-71 Vaitkus PT et al. Thromb Haemost. 2005;93(1):76-9
Gibson et. al. ISTH SSC 2016 – May 27, 2016
3Slide4Previous Novel Oral Anticoagulant Trials of Extended Thromboprophylaxis in Acute Medically Ill Patients
Incidence (%)
VTE Events
More Major Bleeding
ADOPT
Enoxaparin vs. Apixaban
MAGELLANEnoxaparin vs. Rivaroxaban
0.2%
0.5%
0.4%
1.1%
p=0.44
p=0.04
p=0.02
p<0.001
ADOPT: Goldhaber SZ et al. N
Engl
J Med. 2011;365:2167-77
MAGELLAN: Cohen AT et al. N
Engl
J Med. 2013;368:513-23
RRR=12.9%
RRR=22.8%
0
6
6
4
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide5Betrixaban
Oral factor Xa inhibitorRenal clearance of administered dose (5%)Renal clearance of absorbed dose (17%)1 day half-life (19-25 h)Not a substrate for major CYP450 enzymesRapid onset Cmax achieved at 3-4 hours
Safety and efficacy of 80 mg daily dose of Betrixaban previously described in approximately 1,200 patients in phase I and II studiesConnolly S et al. Eur Heart J 2013;34(20):1498-505
Turpie
A et al.
Thromb
Haemost 2009;101:68-76Cohen AT et al. Am Heart J 2014; 167:335-415Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide6
EvaluationExtended Prophylaxis35 – 42 days
APEX Study Design
R
1:1
Subjects enrolled
(N=7,513)
Enoxaparin
40 mg
Placebo
Betrixaban
80 mg
Follow-up safety visit
30 Days After Visit 3
(+5 days)
Betrixaban
80 mg
Primary Efficacy Endpoint:
Composite of asymptomatic proximal DVT (detected on ultrasound), symptomatic DVT (proximal or distal), non-fatal PE, and VTE-related death through Visit 3
Primary Safety Endpoint:
ISTH Major bleeding through 7 days after drug discontinuation
Net Clinical Benefit:
Composite of primary efficacy and primary safety endpoints
Dose adjustments in severe renal insufficiency (
CrCl
< 30 mL/min): Betrixaban 40 mg PO
qd
and Enoxaparin 20 mg SC
qd
Standard Prophylaxis
10 ± 4 days
Ultrasound & Visit 3
Day 35
(+7 days)
Loading dose
160 mg
6
Double blind, double dummy
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide7
Study Design: Key Inclusion Criteria
Age/Risk Factors:
≥ 75
yo
OR
60 - 74
yo
with D-dimer ≥ 2x ULN
OR
40 - 59
yo
with D-dimer ≥ 2x ULN and a history of either VTE, or cancer*
Anticipated to be severely immobilized for at least 24 hours after randomization
with a
nticipated length of hospitalization ≥ 3 days
Hospitalized for one of the following acute presentation:
Acute on chronic heart failure decompensation
Acute on chronic respiratory failure
Acute infection without septic shock
Acute rheumatic disorders
Acute ischemic stroke (w/ immobilization)
*Pre-amendment 3, other risk factors were allowed including: previous history of superficial VT, obesity, varicose veins of lower extremities, hormone therapy, thrombophilia, concomitant use of erythropoiesis stimulating agents
7
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide8
Study Design: Key Exclusion Criteria
End stage renal disease with
CrCl
<15 mL/min, or requiring dialysis (first trial to enroll patients with
CrCl
<30 mL/min)
Anticipated need for prolonged anticoagulation
Current intake of dual antiplatelet therapy
Anticipated major surgery
History of clinically significant bleeding within 6 months prior to enrollment
History of IC bleeding, head trauma, or known intracranial lesions
History of significant GI, pulmonary or GU bleeding, ongoing chronic PUD or ongoing or acute gastritis within 2 years prior to enrollment
Hgb
< 10 g/
dL
(pre-amendment 3);
Hgb
< 9.5 g/dL or unstable/declining hemoglobin (possible active bleed) (post-amendment 3)
8
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide9
Enrichment Strategy &
Analysis Cohorts
APEX was designed to enroll pre-specified high risk subpopulations, including elevated D-dimer and age ≥ 75, based on findings from the MAGELLAN study.
Based on the FDA guidance document on enrichment strategies that recommends “identifying patients with the greatest likelihood of having a disease related endpoint and that are more likely to respond to drug treatment”, the statistical analysis plan was amended with FDA and EMA approval to include the 3 primary analysis cohorts
9
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide10
Statistical Analysis for the Primary Efficacy Outcome
Closed-Testing Gate-Keeping
Procedure
Cohort 1:
D-Dimer ≥ 2 x ULN*
If p ≤ 0.05, then proceed
p > 0.05
Further testing
considered
exploratory
Cohort 2:
D-Dimer ≥ 2 x ULN*
OR Age ≥75
If p
≤
0.05, then proceed
p > 0.05
Further testing
considered
exploratory
Cohort 3:
All Patients in Overall
Efficacy Population
*D-dimer was performed at local site and central lab
10
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide11Trial Organization
Trial Leadership Executive Committee Co-Chairs: Alexander T. Cohen, Robert HarringtonSteering Committee Chair: C. Michael GibsonExecutive Committee Russell Hull, Samuel Goldhaber, Adrian Hernandez, Alex Gold, Brian Wiens
Data and Safety Monitoring Board Charles Francis, Harry R. Büller, Robin Roberts, Martin Prins, Marc Carrier, Alex Spyropoulos
Clinical Operations
PERFUSE (Beth Israel Deaconess Medical Center – Boston),
Pharmaceutical Product Development, LLC (PPD), August Research LLC (Western Europe), Crown CRO Oy (Western Europe), CONFIDENCE Pharmaceutical Research, LLC (Eastern Europe), Portola Clinical Operations
Clinical Event Committee Duke Clinical Research InstituteCompression Ultrasound Core Lab EZUS (Université Claude Bernard – France)Statistics Duke Clinical Research Institute, PERFUSE 11Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide12
35 Countries - 460 Enrolling Sites
National Lead Investigators
Argentina (215)
Australia (20)
Austria (15)
Belarus (69)
Belgium (15)
Brazil (57)
Jose Manuel
Ceresetto
David Colquhoun
Ernest
Pilger
Leonid
Polonetsky
Serge Motte
Jose Francisco
Saraiva
Bulgaria (431)
Canada (51)
Chile (44)
Croatia (92)
Czech Republic (237)
Denmark (12)
Valentina
Mincheva
Dimitar
Raev
Susan Kahn
Claudia Olivares
Branko
Malojcic
Otto Mayer Jr.
Steen Husted
Estonia (205)
Finland (26)
France
(293)
Georgia
(260)
Germany
(196)
Hungary
(252)
Toomas
Marandi
Riitta
Lassila
Dominique
Mottier
Tamaz
Shaburishvili
Rupert
Bauersachs
Uwe
Zeymer
Erik
Hajko
Israel
(99)
Italy (261)
Latvia (319)
Lithuania (470)
Peru (152)
Poland
(369)
David
Zeltser
Walter
Ageno
Dainis
Krievins
Alfredas
Bagdonas
Juan
Lema
Osores
Witold
Tomkowski
Romania
(170)
Russia (971)
Serbia (115)
Singapore
(1)
Slovakia
(105)
South Africa (91)
Stefan Mot
Elizaveta
Panchenko
Vladimir
Miloradovic
Ru San Tan
Ludovit
Gaspar
Barry Jacobson
Spain
(412)
Turkey
(54)
Ukraine
(886)
United Kingdom
(22)
United States (527)
Manuel
Monreal
-Bosch
Gul
Ongen
Alexander
Parkhomenko
James
Uprichard
Geno
Merli
Roger Yusen
12
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide13
CONSORT DiagramRandomized(n=7,513)
n=3,759
n=
2,842
n=3,754
n=3,720
n=
1,956
Enoxaparin
Betrixaban
Did not receive any dose of study drug
n=34
n=38
n=
2,893
n=
1,914
n=3,721
No ultrasound AND no symptomatic event
n=546
n=609
n=3,174
n=3,112
Cohort 1
Cohort 2
Cohort 1
Cohort 2
Cohort 3:
Overall
efficacy
population
Cohort 3:
Overall
efficacy
population
mITT
population
mITT
population
13
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide14
Baseline Characteristics
Enoxaparin (n=3,754)
Betrixaban (n=3,759)
Age, mean ± SD
76.2
±
8.31
76.6
±
8.46
Age ≥ 75 years, % (n)
67.0% (2,517)
68.5% (2,575)
Male gender, % (n)
45.8% (1,720)
45.4% (1,705)
D-dimer ≥ 2x ULN, % (n)
62.1% (2,332)
62.3% (2,341)
IMPROVE score ≥ 2, % (n)
25.4%
(954)
26.6%
(999)
Moderate/severe immobilization, % (n)
99.8%
(3,748)
99.8%
(3,751)
Severe renal insufficiency (<30 ml/min), % (n)
4.0% (150)
4.7% (175)
Concomitant strong P-
gp
inhibitor, % (n)
17.3%
(649)
18.0%
(677)
Prior anticoagulant use
≤ 96 hours*
, % (n)
50.1% (1,879)
51.3%
(1,928)
Values provided for all patients randomized, no significant differences between treatment arms
*Any of the following: LMWHs, Unfractionated Heparin, Fondaparinux, Warfarin, Factor
Xa
inhibitors, or Direct Thrombin Inhibitors
14
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide15
Baseline Characteristics:Primary Reasons for Hospital Admission
Enoxaparin (n=3,754)
Betrixaban (n=3,759)
Acute CHF NYHA III-IV, % (n)
44.5% (1,672)
44.6%
(1,677)
Acute infection, % (n)
28.2%
(1,058)
29.6%
(1,112)
Acute respiratory failure, % (n)
12.6%
(474)
11.9%
(448)
Acute ischemic stroke w/ immobilization,
% (n)
11.5% (432)
10.9% (411)
Acute rheumatic disorder, % (n)
3.1%
(117)
2.9% (109)
Values provided for all patients randomized, no significant differences between treatment arms.
Data not available for 2 patients in the
betrixaban
arm and 1 patient in the enoxaparin arm.
15
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide16
Primary Efficacy EndpointCohort 1: D-Dimer ≥ 2 x ULNComposite of Adjudicated Asymptomatic Proximal DVT, Symptomatic Proximal or Distal DVT, non-fatal PE, or VTE-related Death
n=132
8.49%
6.90%
NNT = 62.9
p=0.054P-values reported using the Mantel-Haenszel test stratified for dosing criteria (ie. No adjustment, renal insufficiency, P-gp inhibitor).Symptomatic events from Day 1 till Day 42 or the date of Visit 3, if Visit 3 occurred before Day 42; Asymptomatic DVT between Day 32 and 47.RRR = 19.4%n=16616Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide17
Primary Efficacy EndpointCohort 2: D-Dimer ≥ 2 x ULN OR Age ≥75n=204
7.05%5.63%p=0.029P-values reported using the Mantel-
Haenszel
test stratified for dosing and entry criteria (
ie
. No adjustment, renal insufficiency, or P-gp inhibitor / DD > 2x ULN or DD < 2x ULN).Symptomatic events from Day 1 till Day 42 or the date of Visit 3, if Visit 3 occurred before Day 42; Asymptomatic DVT between Day 32 and 47.ARR = 1.42%NNT = 70.4RRR = 20.0%n=160Composite of Adjudicated Asymptomatic Proximal DVT, Symptomatic Proximal or Distal DVT, non-fatal PE, or VTE-related Death17
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide18
Primary Efficacy EndpointCohort 3: Overall Efficacy Populationn=223n=165
7.03%5.30%p=0.006P-values reported using the Mantel-
Haenszel
test stratified for dosing and entry criteria (
ie
. No adjustment, renal insufficiency, or P-gp inhibitor / DD > 2x ULN or DD < 2x ULN).Symptomatic events from Day 1 till Day 42 or the date of Visit 3, if Visit 3 occurred before Day 42; Asymptomatic DVT between Day 32 and 47.ARR = 1.73%NNT = 57.8RRR = 24.0%Composite of Adjudicated Asymptomatic Proximal DVT, Symptomatic Proximal or Distal DVT, non-fatal PE, or VTE-related Death18Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide19
Primary Efficacy EndpointCentral Lab Values to Define D-dimer Positive Patients
Local Laboratory D-dimer
Central Laboratory D-dimer
Cohort
Enoxaparin
Betrixaban
RRR
(95% CI)
p-value
Enoxaparin
Betrixaban
RRR
(95% CI)
p-value
1
8.5%
(166 / 1,956)
6.9%
(
132 / 1,914
)
19.4%
(-0.4, 35.3)
0.054
9.0%
(165 / 1,822)
6.4%
(118 / 1,838)
29.5%
(11.6, 43.9)
0.002
2
7.1%
(204 / 2,893)
5.6%
(160 / 2,842)
20.0%
(2.3, 34.5)
0.029
7.1%
(198 / 2,771)
5.6%
(154 / 2,741)
24.7%
(7.4, 38.8)
0.007
3
Overall Efficacy
7.0%
(223 / 3,174)
5.3%
(165 / 3,112)
24.0%
(7.7, 37.5)
0.006
7.0%
(223 / 3,174)
5.3%
(165 / 3,112)
24.0%
(7.7, 37.5)
0.006
Smaller numerators & denominators consistent with greater specificity in Cohort 1 which increases RRR
P-values reported using the Mantel-
Haenszel
test stratified for dosing criteria in Cohort 1 and dosing and entry criteria in Cohort 2 and PEOP.
Symptomatic events from Day 1 till Day 42 or the date of Visit 3, if Visit 3 occurred before Day 42; Asymptomatic DVT between Day 32 and 47.
19
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide20Primary Efficacy Outcome by Dose Administered
Cohort
Dose of Betrixaban
Enoxaparin
Event Rate
Betrixaban
Event RateRelative Risk Reduction(95% CI)
p-value
Cohort 1
80 mg
130 / 1,549
(8.39%)
95 / 1,516
(6.27%)
0.255
(0.040, 0.423)
0.023
40
mg
35 / 404
(8.66%)
37 / 397
(9.32%)
-0.059
(-0.647, 0.319)
0.800
Cohort 2
80 mg
163 / 2,330
(7.00%)
117 / 2,276
(5.14%)
0.263
(0.072, 0.414)
0.009
40
mg
40 / 560
(7.14%)
42 / 563
(7.46%)
-0.054
(-0.599, 0.305)
0.804
Cohort 3
(Overall Efficacy Population)
80 mg
181 / 2,562
(7.06%)
122 / 2,506
(4.87%)
0.304
(0.131, 0.443)
0.001
40
mg
41 / 609
(6.73%)
42 / 603
(6.97%)
-0.045
(-0.584, 0.311)
0.836
20
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide21
mITT
Efficacy Analysis
Including All Patients Who Received Study Drug Including Those with Missing Ultrasound As Requested by US FDA
Event rate (%)
Cohort 1
D-dimer ≥ 2 x ULN
Cohort 2
D-dimer ≥ 2 x ULN
or age ≥ 75 y
Cohort 3
Overall efficacy
population
7.18%
5.70%
6.02%
4.70%
5.99%
4.43%
P = 0.018
RRR = 21.6%
P = 0.003
RRR = 25.4%
P = 0.038
RRR =
20.9%
n=166
n=132
n=204
n=160
n=223
n=165
P-values reported using the Mantel-
Haenszel
test stratified for dosing criteria in Cohort 1 and dosing and entry criteria in Cohort 2 and
mITT
.
mITT
defined as patients who received at least one dose of study drug. Symptomatic events from Day 1 till Day 42 or the date of Visit 3, if Visit 3 occurred before Day 42; Asymptomatic DVT between Day 32 and 47.
21
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide22
Symptomatic VTECohort 1Composite of Symptomatic Proximal or Distal DVT, Non-Fatal
PE, or VTE-related Death
Probability of Symptomatic Event (%)
Time (Days)
Enoxaparin
Betrixaban
2.25%
1.57%
Through Visit 3
HR = 0.70 (0.44, 1.11)
ARR = 0.68%
NNT = 147
p=0.12
Through End of Trial
*
HR = 0.60 (0.38, 0.94)
ARR = 1.04%
NNT = 96
p=0.03
2.61%
1.57%
Parenteral
Therapy
Visit 3
*End of Trial defined as final follow-up visit (30 + 5 days after Visit 3)
22
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide23
Probability of Symptomatic Event (%)
Time (Days)
Enoxaparin
Betrixaban
1.44%
0.93%Through Visit 3HR = 0.65 (0.42, 0.99)ARR = 0.51%NNT = 196p=0.043
Through End of Trial
*
HR = 0.56 (0.38, 0.84)
ARR = 0.80%
NNT = 125
p=0.004
1.84%
1.04%
Parenteral
Therapy
Visit 3
Symptomatic VTE
All Patients Randomized
Composite of
Symptomatic Proximal or Distal DVT, Non-Fatal PE, or VTE-related Death
*End of Trial defined as final follow-up visit (30 + 5 days after Visit 3)
23
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide24
Primary Safety Endpoint: ISTH Major BleedingSafety PopulationMajor bleeding events (ISTH) through 7 days after drug discontinuation
n=210.57%0.67%
p = 0.55
n=25
Safety population defined as patients who received at least one dose of active study drug. Analysis by actual treatment. NNH not reported given p=NS.
24Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide25Major Bleeds by Dose Administered
Cohort
Dose of Betrixaban
Enoxaparin
Event Rate
Betrixaban
Event RateRelative Risk Reduction(95% CI)
p-value
Cohort 1
80 mg
12 / 1,827
(0.66%)
9 / 1,827
(0.49%)
0.250
(-0.776, 0.683)
0.512
40
mg
5 / 483
(1.04%)
6
/ 484
(1.24%)
-0.198
(-2.898, 0.632)
0.765
Cohort 2
80 mg
16 / 2,719
(0.59%)
15 / 2,719
(0.55%)
0.063
(-0.892, 0.536)
0.857
40
mg
5 / 668
(0.75%)
10 / 683
(1.46%)
-0.956
(-4.693, 0.328)
0.210
Safety
Population
80 mg
16 / 2,991
(0.53%)
15 / 2,986
(0.50%)
0.061
(-0.896, 0.535)
0.861
40
mg
5 / 725
(0.69%)
10 / 730
(1.37%)
-0.986
(-4.783, 0.318)
0.199
25
Safety population defined as patients who received at least one dose of active study drug. Analysis by actual treatment.
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide26
Secondary Safety EndpointSafety PopulationMajor or clinically relevant non-major bleeding events (ISTH) through 7 days after drug discontinuation
n=591.59%3.12%
p < 0.001
n=116
Safety population defined as patients who received at least one dose of active study drug. Analysis by actual treatment.
26Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide27
Fatal Bleeding and ICHSafety Population
n=9
Event rate (%)
Enoxaparin
(N=3,716)
0.03%
0.03%
0.19%
0.05%
n=7
n=2
p = 0.18
n=1
n=1
Betrixaban
(N=3,716)
Enoxaparin
(N=3,716)
Betrixaban
(N=3,716)
Fatal Bleeding
ICH
Safety population defined as patients who received at least one dose of active study drug. Analysis by actual treatment.
27
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide28
Subgroup Analysis: Primary EfficacyOverall Efficacy Population (Cohort 3)
Age ≥ 75 years
Age < 75 years
≥ 2 VTE risk factors
< 2 VTE risk factors
No dosing modification
P-
gp
inhibitor
Severe renal insufficiency
Male
Female
Acute decompensated HF
Acute infection
Acute respiratory failure
Acute ischemic stroke
Acute rheumatic disorders
Composite of Asymptomatic Proximal DVT, Symptomatic Proximal or Distal DVT, Nonfatal PE, or VTE-related Death
Reason for Hospital Admission
Dosing Criteria
Additional VTE Risk Factors
Gender
Age
Overall
RR
(95% CI)
0.76 (0.63, 0.92)
0.75 (0.60, 0.95)
0.77 (0.54, 1.09)
0.82 (0.62, 1.09)
0.70 (0.54, 0.92)
0.68 (0.51, 0.89)
0.84 (0.64, 1.10)
1.06 (0.67, 1.70)
0.88 (0.40, 1.94)
0.70 (0.56, 0.87)
0.85 (0.62, 1.16)
0.72 (0.50, 1.02)
0.89 (0.53, 1.49)
0.58 (0.34, 1.02)
0.63 (0.22, 1.78)
Event Rate
(Enoxaparin)
Event Rate
(Betrixaban)
223 / 3174
165 / 3112
152 / 2136
115 / 2138
71 / 1038
50 / 974
102 / 1447
121 / 1727
81 / 1406
84 / 1706
114 / 1253
109 / 1921
77 / 1252
88 / 1860
180 / 2511
33 / 553
120 / 2426
33
/ 540
10 / 110
12 / 146
83 / 1481
69 / 854
69 / 1428
49 / 883
29 / 375
24 / 353
33 / 363
18 / 353
9 / 101
5 / 94
Enoxaparin Better
Betrixaban
Better
1
0.8
0.6
0.4
0.2
0.1
2
3
4
6
5
P-value for interaction is non-significant for all analyses.
All analysis were stratified for dosing and entry criteria.
28
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide29
RaceGeography
Overall
North America
USA
Europe
Western EuropeEastern EuropeLatin America
White
Black
Other
Ethnicity
Not Hispanic or Latino
Hispanic or Latino
0.94 (0.45, 1.92)
0.70 (0.55, 0.90)
0.69 (0.43, 1.08)
0.92 (0.45, 1.84)
0.70 (0.57, 0.87)
0.74 (0.60, 0.90)
0.97 (0.29, 3.32)
0.72 (0.58, 0.88)
RR
(95% CI)
Event Rate
(Enoxaparin)
Event Rate
(Betrixaban)
Subgroup Analysis: Primary Efficacy
Overall Efficacy Population (Cohort 3) -
ctnd
0.76 (0.63, 0.92)
Composite of Asymptomatic Proximal DVT, Symptomatic Proximal or Distal DVT, nonfatal PE, or VTE-related Death
1.30 (0.32, 5.26)
1.15 (0.64, 2.09)
15 / 214
14 / 196
13 / 208
12 / 186
198 / 2765
135 / 2704
39 / 507
31 / 594
159 / 2258
104 / 2110
223 / 3174
165 / 3112
10 / 195
16 / 199
1.58 (0.72, 3.46)
211 / 2992
150 / 2915
5 / 59
5 / 53
4 / 79
7 / 86
199 / 2768
139 / 2707
21 / 352
23 / 339
Enoxaparin Better
Betrixaban
Better
1
0.8
0.6
0.4
0.2
0.1
2
3
4
6
5
P-value for interaction is non-significant for all analyses.
All analysis were stratified for dosing and entry criteria.
29
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide30
Subgroup Analysis: Primary SafetySafety Population
Age ≥ 75 years
Age < 75 years
≥ 2 VTE risk factors
< 2 VTE risk factors
No dosing modification
P-
gp
Inhibitor
Severe r
enal
insufficiency
Male
Female
RR
Acute decompensated HF
Acute infection
Acute respiratory failure
Acute ischemic stroke
Acute rheumatic disorders
Major bleeding events through 7 days after drug discontinuation
Reason for Hospital Admission
Dosing Criteria
Additional VTE Risk Factors
Gender *
Age
Overall
Enoxaparin Better
Betrixaban
Better
1
1
.53
(
0.79
, 2.99)
0.45
(
0.12
, 1.74)
0.46
(
0.18
, 1.22)
2.37
(
1.04
, 5.40)
1.40
(
0.54
, 3.67)
1.08
(
0.52
, 2.24)
1.02
(
0.51, 2.03
)
2.57
(
0.27
, 24.4)
1.45
(
0.41
, 5.11)
1.49
(
0.53, 4.19
)
0.45
(
0.12, 1.74
)
1.43
(
0
.40, 5.04
)
1.87
(
0.55, 6.33
)
1.19
(
0.67
, 2.12)
(95% CI)
Event Rate
(Enoxaparin)
Event Rate
(Betrixaban)
---
---
21 / 3716
25 / 3716
14 / 2489
22 / 2551
7 / 1226
3 / 1166
13 / 1696
8 / 2019
6 / 1691
19 / 2026
7 / 1482
14 / 2233
10 / 1511
15 / 2206
16 / 2921
4 / 645
16 / 2875
6 / 668
1 / 149
3 / 174
6 / 1663
4 / 1040 9 / 1670 6 / 1095 7 / 464 3 / 440
4 / 432 7 / 405 0 / 116
0 / 105 0.80.6
0.40.20.1
2
345
6
7
8
10*P-value for interaction between gender and treatment = 0.01.Safety population defined as patients who received at least one dose of active study drug. Analysis by actual treatment.30Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide31
RaceGeography
Overall
North America
USA
Europe
Western EuropeEastern EuropeLatin America
White
Black
Other
Ethnicity
Not Hispanic or Latino
Hispanic or Latino
5.72 (0.69, 47.2)
0.91 (0.43, 1.90)
1.07 (0.29, 3.96)
2.89 (0.59, 14.2)
0.95 (0.50, 1.80)
1.34 (0.73, 2.47)
0.99 (0.06, 15.4)
1.10 (0.59, 2.05)
RR
(
95
% CI)
Event Rate
(Enoxaparin)
Event Rate
(Betrixaban)
2 / 272
1 / 248
6 / 282
6 / 260
19 / 3208
18 / 3206
4 / 658
5 / 772
15 / 2550
13 / 2434
0 / 235
1 / 228
--- ---
18 / 3487
24 / 3468
1 / 69
1 / 70
0 / 91
0 / 99
19 / 3215
21 / 3224
0 / 421
3 / 400
Subgroup Analysis: Primary Safety
Safety Population -
ctnd
1
.19
(
0.67
, 2.12)
21 / 3716
25 / 3716
--- ---
--- ---
Major bleeding events through 7 days after drug discontinuation
Enoxaparin Better
Betrixaban Better
1
0.8
0.6
0.4
0.2
0.1
2
3
4
5
6
7
8
10
P-value for interaction is non-significant for all analyses.
Safety population defined as patients who received at least one dose of active study drug. Analysis by actual treatment.
31
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide32
Net Clinical BenefitPrimary Efficacy Endpoint or Major Bleed Through Visit 3 / Day 42
n=1,914Event rate (%)
Cohort 1
D-dimer ≥ 2 x ULN
Cohort 2
D-dimer ≥ 2 x ULNor age ≥ 75 y Cohort 3Overall EfficacyPopulation8.90%7.37%7.40%
6.12%
7.34%
5.75%
n=174
n=141
n=214
n=174
n=233
n=179
Net clinical benefit analysis from Day 1 till Day 42 or the date of Visit 3, if Visit 3 occurred before Day 42
Net clinical benefit is the composite of the primary efficacy endpoint and the primary safety endpoint
32
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide33
Fatal or Irreversible Outcomes
Cohort 1 (D-Dimer ≥ 2 x ULN)
Non-hemorrhage cardiopulmonary death + Non-fatal PE + MI + ischemic stroke
+
Fatal bleeding + ICH
Through End of Trial*HR = 0.70 (95% CI: 0.54, 0.90)ARR = 1.91% NNT = 52Probability of Event (%)Time in DaysEnoxaparin
Betrixaban
6.27%
4.36%
p = 0.005
Through Visit 3
HR = 0.74 (95% CI: 0.56, 0.98)
ARR = 1.26%
NNT = 79
p = 0.037
4.80%
3.54%
visit
3
33
*End of Trial defined as final follow-up visit (30 + 5 days after Visit 3)
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide34
Fatal or Irreversible Outcomes
All Patients Randomized
Non-hemorrhage cardiopulmonary death + Non-fatal PE + MI + ischemic stroke
+
Fatal bleeding + ICH
34*End of Trial defined as final follow-up visit (30 + 5 days after Visit 3)Through End of Trial*HR = 0.70 (95% CI: 0.57, 0.88)ARR = 1.53%
NNT = 65
Enoxaparin
Betrixaban
5.17%
3.64%
p = 0.002
Through Visit 3
HR = 0.71 (95% CI: 0.56, 0.91)
ARR = 1.18%
NNT = 85
p = 0.006
4.08%
2.90%
visit
3
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide35RRR = 29.0% (8.0, 46.0)p<0.001
9.30%6.50%p=HR = (95% CI)n=n=%
%9.0%
6.4%
MAGELLAN
Primary Efficacy Endpoint
Central D-dimer ≥ 2 x ULN: MAGELLAN vs. APEXAPEX
RRR = 29.5% (11.6, 43.9)
p=0.002
MAGELLAN and APEX analyses through 35 days
Cohen A et al. J
Throm
Haemost
. 2014;12:479-87
9.3%
6.5%
n=125
n=84
n=165
n=118
35
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide36
Comparison to Previous Novel Oral Anticoagulant Trials of Extended Thromboprophylaxis in Acute Medically Ill Patientsp<0.001
Incidence (%)
VTE Events
Major Bleeding
ADOPT
ApixabanMAGELLANRivaroxabanAPEX
Betrixaban
Enoxaparin Apixaban Enoxaparin Rivaroxaban Enoxaparin Betrixaban
p=0.04
p<0.001
p=0.55
p = 0.44
p = 0.02
p* = 0.006
* Overall efficacy population analysis used for comparison purposes
RRR = 12.9%
RRR = 22.8%
RRR* = 24.0%
0
8
2
4
36
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide37Summary
Among patients in the first primary analysis cohort who had a D-Dimer ≥ 2 x ULN, extended-duration betrixaban was associated with a reduction in the primary efficacy endpoint that approached statistical significance (p=0.054), compared with standard-duration enoxaparin.When using central laboratory D-dimer, extended-duration betrixaban was associated with a robust clinical and statistically significant reduction in primary efficacy endpoint in the first primary analysis cohort (p=0.002).
Betrixaban was associated with a reduction in the primary efficacy endpoint in the overall efficacy study population (p=0.006).Betrixaban was associated with a reduction in the rate of symptomatic events through 35 days in the overall study population (p=0.003).Betrixaban was not associated with a significant increase in major or fatal bleeding.
When both the primary safety and primary efficacy endpoints were taken into account, betrixaban was associated with a favorable net clinical benefit in the overall efficacy study population (p=0.011).
37
Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide38Conclusion
In a pre-specified subgroup of medically ill patients who were D-Dimer +, extended duration
betrixaban demonstrated a reduction in VTE events that approached statistical significance. In pre-specified
exploratory analyses of central lab D-dimer values,
and progressively larger
cohorts
(including all study patients), the totality of the data demonstrated a consistent and significant reduction in VTE without excess major bleeding.38Gibson et. al. ISTH SSC 2016 – May 27, 2016Slide3939