1. Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients August 23rd, 2016
Presenter:
Brandon Cave, PharmD
PGY-2 Cardiology Pharmacy Resident
West Palm Beach VA Medical Center
Mentor:
Paul P. Dobesh, PharmD, FCCP, BCPS – AQ Cardiology
Professor of Pharmacy Practice
College of Pharmacy
University of Nebraska Medical Center

2. Disclosure
Dr. Cave does not have (nor does any immediate family member have) :
a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity
any affiliation with an organization whose philosophy could potentially bias my presentation
The views expressed in this presentation reflect those of the author, and not necessarily those of the Department of Veterans Affairs
Dr. Dobesh has the following financial relationships to disclose:
Consultant for:
Portola
Boehringer Ingelheim
Pfizer/Bristol-Myers Squibb
Daiichi Sankyo
Janssen

3. VTE in the Acute Medically Ill
Acute medical illness increases venous thromboembolism (VTE) risk 5-fold
Risk of DVT (symptomatic + asymptomatic) in medical patients is estimated to be between 5 – 30%
IMPROVE Study (n=15,156)
Days after
Hospital Admission
In-Hospital VTE
(n=79)
Post-discharge VTE
(n=64)
All VTE
(N=143)
1-7
42 (53%)
42 (29%)
8-30
32 (41%)
24 (38%)
56 (39%)
31-60
5 (6%)
23 (36%)
28 (20%)
61-91
17 (27%)
17 (12%)
Spyropoulos AC, et al. Chest 2011;140(3):706-14
Dobesh PP. Pharmacotherapy. 2009;29(8):943-53
Heit JA, et al. J Thromb Thrombolysis. 2016;41(1):3-14

4. VTE in the Acute Medically Ill
It is estimated that every year 600,000 non-fatal VTE events occur, of which approximately 400,000 occur during or following a recent hospitalization.
Heit JA, et al. J Thromb Thrombolysis. 2016;41(1):3-14.
Spencer FA, et al. Arch Intern Med. 2007;167(14):

5. VTE Risk Factors in the Acute Medically Ill
Hazard Ratio (95% CI)
Previous Venous Thromboembolism
6.14 (4.74 – 7.96)
Postthrombotic Syndrome
2.00 (1.59 – 2.52)
Acute Infectious Disease
1.74 (1.12 – 2.75)
Heart Failure
1.72 (1.52 – 1.95)
Peripheral Artery Disease
1.68 (1.28 – 2.21)
Cancer
1.67 (1.45 – 1.93)
Neurologic Disease with paresis or
paralysis
1.35 (1.05 – 1.75)
Intensive Care Unit Admission
1.35 (1.21 – 1.50)
Chronic Obstructive Pulmonary Disease
1.33 (1.17 – 1.51)
Dobesh PP. Pharmacotherapy. 2009;29(8):943-53
Alikhan R, et al. Arch Intern Med. 2004;164(9):963-8

6. 9th Ed. ACCP Guidelines 2012
2.8 In acutely ill hospitalized patients who receive an initial course of thromboprophylaxis, we suggest against extending the duration of thromboprophylaxis beyond the period of patient immobilization or acute hospital stay (Grade 2B)
Kahn SR, et al. Chest. 2012;141(2 Suppl):e195S-226S

7. Extended Duration Thromboprophylaxis
EXCLAIM (enoxaparin)
Extended-duration enoxaparin 40mg SQ daily vs. placebo
All patients received enoxaparin 40mg daily for days prior to randomization
28-day treatment period

8. Trial Results EXCLAIM RRR = 38.0% p <0.042 NNT = 67 NNH = 200
Enoxaparin
Incidence
VTE Events
Major Bleeding
Enoxaparin Placebo
(n=2485) (n=2510)
RRR = 38.0%
p<0.05
p <0.042
NNT = 67
NNH = 200
Hull RD, et al. Ann Intern Med. 2010;153(1):8-18

9. Extended Duration Thromboprophylaxis
ADOPT (apixaban)
Apixaban 2.5mg PO twice daily vs. Enoxaparin 40mg SQ daily (6-14 days) + placebo
30-day treatment period
MAGELLAN (rivaroxaban)
Rivaroxaban 10mg PO daily vs. Enoxaparin 40mg SQ daily (6-14 days) + placebo
35-day treatment period
Cohen AT, et al. N Engl J Med. 2013;368(6):513-23
Hull RD, et al. Ann Intern Med. 2010;153(1):8-18
Goldhaber SZ, et al. N Engl J Med. 2011;365(23):

10. Trial Results ADOPT MAGELLAN p = 0.44 RRR = 12.9% p = 0.02 RRR = 22.8%
Apixaban
MAGELLAN
Rivaroxaban
p = 0.44
RRR = 12.9%
p = 0.02
RRR = 22.8%
p=0.04
p<0.001
Incidence
VTE Events
Major Bleeding
Enoxaparin Apixaban Enoxaparin Rivaroxaban
(n=2284) (n=2211) (n=2967) (n=3057)
NNT = 77
NNH = 333
NNH = 143
Goldhaber SZ, et al. N Engl J Med. 2011;365(23):
Cohen AT, et al. N Engl J Med. 2013;368(6):513-23

11. Bottom Line
Despite positive results in VTE reduction in EXCLAIM and MAGELLAN, all previous trials come at the expense of increased major bleeding
Trials have varied in treatment duration and risk population
Studies indicate that there might be a need for extended prophylaxis, but the right mix of drug, dose, duration and population has not yet been found

12. Acute Medically Ill VTE Prevention with EXtended Duration Betrixaban
A 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
Cohen AT, et al. N Engl J Med. 2016; 375:534-44

13. Pharmacokinetics & Pharmacodynamics Direct Thrombin Inhibitor
DOACs
Pharmacokinetics & Pharmacodynamics
Property
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Betrixaban
MOA
Direct Thrombin Inhibitor
Factor Xa Inhibitor
Dose
(VTE Prophylaxis)
N/A
10 mg QD
2.5 mg BID
80 mg QD
Bioavailability
6 – 7%
80%
66%
45%
34%
Tmax
1.5 hours
2 – 4 hours
1 – 3 hours
1 – 2 hours
3 – 4 hours T½
12 – 14 hours
9 – 13 hours
8 – 15 hours
9 – 11 hours
19 – 25 hours
Hepatic Metabolism No
Yes
Drug Interactions
P-gp
CYP3A4/P-gp
Protein Binding
35%
90%
87%
55%
60%
Renal Elimination
25%
50%
5-7%
Renal Dosing
Yes*
Chan NC, et al. Vasc Health Risk Manag. 2015;11:343-51
Modified from Breuer et al. Curr Opin Anesthesiol 2014;27: 13

14. APEX - Objective
Demonstrate superiority of extended duration anticoagulation (35-42 days) with betrixaban as compared to standard of care anticoagulation (6-14 days) with enoxaparin for VTE prevention in the acute medically ill
Cohen AT, et al. N Engl J Med. 2016; 375:534-44

15. Follow-up Safety Visit 30 Days after Visit 3 (+5 days)
APEX – Study Design
Double blind, double dummy
Patients (n=7513)
Randomization 1:1
Placebo
Ultrasound - Visit 3
Day 35 (+ 7 days)
Follow-up Safety Visit
30 Days after Visit 3 (+5 days)
Loading Dose
160 mg
Standard
Prophylaxis
days
Enoxaparin 40mg
SC QD*
Betrixaban 80mg
PO QD*
Betrixaban 80mg
PO QD*
Extended
Prophylaxis
35-42 days
Evaluation
*50% dose reduction in patients with CrCl<30 ml/min
OR concomitant strong P-gp inhibitors
Cohen AT, et al. N Engl J Med. 2016; 375:534-44

16. APEX – Patient Population
Inclusion Criteria:
Age/Risk Factors:
> 75 years old OR
60 – 74 years with D-dimer > 2x ULN OR
40 – 59 years with D-dimer > 2x ULN and a history of either VTE or cancer
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)
Anticipated to be severely immobilized for at least 24 hours after randomization and expected to be severely or moderately immobile for > 3 days
Anticipated length of hospitalization > 3 days
Cohen AT, et al. N Engl J Med. 2016; 375:534-44

17. APEX – Patient Population
Selected Exclusion Criteria:
End stage renal disease with CrCl <15 ml/min, or requiring dialysis
Body weight <45 kg
Anticipated need for prolonged anticoagulation or concomitant dual antiplatelet therapy
Major surgery or procedure within 3 months prior to enrollment or anticipated during study period
History of clinically significant bleeding within 6 months prior to enrollment
History of significant GI, pulmonary or GU bleeding, ongoing chronic peptic ulcer disease or acute gastritis within 2 years prior to enrollment
History of intracranial bleeding (<3 years), head trauma (<3 months), or known intracranial lesions
Hemoglobin < 9.5 g/dL on two consecutive measurements or unstable/declining hemoglobin
Liver disease including cirrhosis; LFTs >3x ULN
Receipt of parenteral anticoagulant >96 hours or receipt of oral anticoagulant <96 hours prior to enrollment
Cohen AT, et al. N Engl J Med. 2016; 375:534-44

18. APEX – Methodology
In 2012, the FDA published a guidance document that recommended “identifying patients with the greatest likelihood of having a disease related endpoint and that are more likely to respond to drug treatment” in order to “enrich” the study population and increase the likelihood of finding a benefit
In response to this, the APEX protocol was amended and designed to enroll pre-specified high risk subpopulations with elevated D-dimer and age >75
All based on the findings from the MAGELLAN study
Cohen AT, et al. N Engl J Med. 2016; 375:534-44

19. Primary Efficacy Endpoint
MAGELLAN Subgroup
Primary Efficacy Endpoint
D-dimer > 2 x ULN:
D-dimer < 2 x ULN:
RR = 0.71; 95% CI ( )
p<0.001
RR = 1.04; 95% CI ( )
p=0.87
9.3%
6.5%
2.2%
2.3%
N=125
N=84
N=35
N=36
Cohen AT, et al. J Thromb Haemost. 2014;12(4): 19

20. D-Dimer > 2x ULN OR Age > 75
Hierarchical Design
Cohort 3
Overall Efficacy Population
Cohort 2
D-Dimer > 2x ULN OR Age > 75
Cohort 1
D-Dimer > 2x ULN
If p<0.05, then proceed
If p<0.05, then proceed
If p>0.05, then further testing considered exploratory
If p>0.05, then further testing considered exploratory
Cohen AT, et al. N Engl J Med. 2016; 375:534-44

21. APEX – Statistical Analysis
Sample size calculation determined during study (based on expected results similar to MAGELLAN) resulting in final sample size to maintain a power of 85% at 1-sided alpha in Cohort 1
Primary and secondary outcomes using chi-square tests with type I error of 0.05
Analysis of all efficacy outcomes conducted via Cochran-Mantel-Haenszel tests to calculate relative risk ratio and incidence rates, which was further stratified by the two randomization factors of elevated D-dimer and dose assignment (80mg/40mg)
Cohen AT, et al. N Engl J Med. 2016; 375:534-44

22. APEX - Endpoints Primary Efficacy Endpoint
Composite of asymptomatic proximal DVT, symptomatic proximal or distal DVT, non-fatal PE or VTE-related death
Secondary Efficacy Endpoints
Symptomatic VTE
Composite of adjudicated asymptomatic proximal DVT, symptomatic proximal or distal DVT, non-fatal PE or all-cause death
Primary Safety Endpoint
Major bleeding (ISTH definition)
Net Clinical Benefit
Composite of primary efficacy and safety endpoints
Cohen AT, et al. N Engl J Med. 2016; 375:534-44

23. APEX – Flow Diagram Patients randomly assigned to treatment (n=7513)
Enoxaparin
(n=3754)
Betrixaban
(n=3759)
Did not receive
study treatment (n=34)
Did not receive
study treatment (n=38)
mITT population
(n=3720)
mITT population
(n=3721)
Did not receive
study drug (n=4)
Did not receive
study drug (n=5)
No ultrasound OR no diagnosed clinical event
(n=546)
No ultrasound OR no diagnosed clinical event
(n=609)
Primary Efficacy
Cohort 3 (n=3174)
Primary Efficacy
Cohort 3 (n=3112)
Safety population
(n=3716)
Did not receive
study drug (n=5)
Safety population
(n=3716)
Cohort 2 (n=2893)
Cohort 2 (n=2842)
Cohort 1 (n=1956)
Cohort 1 (n=1914)
Cohen AT, et al. N Engl J Med. 2016; 375:534-44

24. APEX – Patient Characteristics
Enoxaparin (n=3754)
Betrixaban (n=3759)
Age, mean + SD
Age > 75 years, % (n)
67.0% (2517)
68.5% (2575)
Male Gender, % (n)
45.8% (1720)
45.4% (1705)
Body-mass index
Race – White % (n)
93.7% (3518)
93.2% (3503)
D-dimer > 2x ULN, % (n)
62.1% (2332)
62.3% (2341)
Severe renal insufficiency (<30ml/min), % (n)
4% (150)
4.7% (175)
Concomitant strong P-gp inhibitor, % (n)
17.3% (649)
18.0% (677)
Prior anticoagulant use <96 hours, % (n)
50.1% (1879)
51.3% (1928)
History of cancer % (n)
11.8% (443)
12.4 (466)
History of DVT/PE
8.3% (312)
7.9% (296)
Cohen AT, et al. N Engl J Med. 2016; 375:534-44

25. APEX – Patient Characteristics (Cont.)
Primary Reason for Hospital Admission
Enoxaparin (n=3754)
Betrixaban (n=3759)
Acute CHF NYHA III-IV, % (n)
44.5% (1672)
44.6% (1677)
Acute infection, % (n)
28.2% (1058)
29.6% (1112)
Acute respiratory failure, % (n)
12.6% (474)
11.9% (448)
Acute ischemic stroke % (n)
11.5% (432)
10.9% (411)
Acute rheumatic disorder, % (n)
3.1% (117)
2.9% (1.9)
Cohen AT, et al. N Engl J Med. 2016; 375:534-44

26. APEX - Results p=0.054 p=0.029 Cohort 1 Cohort 2 Cohort 3 NNT = 70
RRR
19.4%
p=0.029
RRR
20%
RRR
24%
N=132
N=166
N=160
N=204
N=165
N=223
Cohort 1
Cohort 2
Cohort 3
Cohen AT, et al. N Engl J Med. 2016; 375:534-44

27. APEX – Secondary Endpoints
Symptomatic VTE
Enoxaparin
Betrixaban
RRR (95% CI)
p-value
Cohort 1
1.9% (44)
1.3% (30)
33% (-0.7 – 68)
0.09
Cohort 2
1.4% (49)
1.0% (35)
29% (-0.9 – 54)
0.11
Cohort 3
1.5% (54)
0.9% (35)
36% (2.0 – 58)
0.04
Asymptomatic Proximal VTE
Enoxaparin
Betrixaban
RRR (95% CI)
p-value
Cohort 1
6.6% (129)
5.5% (105) NR
Cohort 2
5.6% (162)
4.5% (128)
Cohort 3
5.5% (176)
4.3% (133)
Cohen AT, et al. N Engl J Med. 2016; 375:534-44

28. APEX – Symptomatic Events Cohort 3
Hazard Ratio, 0.65 (95% CI, 0.42 – 0.99)
P=0.046
Time to First Symptomatic Event
Betrixaban
Enoxaparin
Cohen AT, et al. N Engl J Med. 2016; 375:534-44

29. Major or Clinically Relevant
APEX - Results
p<0.001
NNH = 200
p=0.55
Major or Clinically Relevant
Non-Major Bleeding
Major Bleeding
*Results similar across all individual cohorts
Cohen AT, et al. N Engl J Med. 2016; 375:534-44

30. APEX - Results p=0.067 p=0.048 p=0.011 N=141 N=174 N=174 N=214 N=179
RRR
18%
RRR
17.7%
RRR
21.7%
N=141
N=174
N=174
N=214
N=179
N=233
Cohen AT, et al. N Engl J Med. 2016; 375:534-44

31. APEX – D-dimer stratification (Efficacy)
Local Laboratory D-Dimer
Enoxaparin
Betrixaban
RRR (95% CI)
p-value
Cohort 1
8.5% (166/1956)
6.9% (132/1914)
19.4% (-0.4 – 35.3)
0.054
Cohort 2
7.1% (204/2893)
5.6% (160/2842)
20.0% (2.3 – 34.5)
0.029
Cohort 3
7.0% (223/3174)
5.3% (165/3112)
24.0% (7.7 – 37.5)
0.006
Central Laboratory D-Dimer
Enoxaparin
Betrixaban
RRR (95% CI)
p-value
Cohort 1
9.0% (165/1822)
6.4% (118/1838)
29.5% (11.6 – 43.9)
0.002
Cohort 2
7.1% (198/2771)
5.6% (154/2741)
24.7% (7.4 – 38.8)
0.007
Cohort 3
7.0% (223/3174)
5.3% (165/3112)
24.0% (7.7 – 37.5)
0.006
Cohen AT, et al. N Engl J Med. 2016; 375:534-44

32. APEX – Dose Response Stratification
Primary Efficacy Outcome
Betrixaban 80 mg
Betrixaban
40 mg
RRR*
80mg/40mg
p-value
Cohort 1
6.27% (95)
9.32% (37)
25.5%/-5.9%
0.023/0.8
Cohort 2
5.14% (117)
7.46% (42)
26.3%/-5.4%
0.009/0.804
Cohort 3
4.87% (122)
6.97% (42)
30.4%/-4.5%
0.001/0.836
Primary Safety Outcome
Betrixaban 80 mg
Betrixaban
40 mg
RRR*
80mg/40mg
p-value
Cohort 1
0.49% (9)
1.24% (6)
25%/-19.8%
0.512/0.765
Cohort 2
0.55% (15)
1.46% (10)
6.3%/-9.56%
0.857/0.210
Cohort 3
0.50% (15)
1.37% (10)
6.1%/-9.86%
0.861/0.199
*Compared to enoxaparin rates (not shown)
Cohen AT, et al. N Engl J Med. 2016; 375:534-44

33. APEX - Results p=0.038 p=0.018 p=0.003 N=132 N=166 N=160 N=204 N=165
RRR
20.9%
RRR
21.6%
RRR
25.4%
N=132
N=166
N=160
N=204
N=165
N=223
Gibson et. al. ISTH SSC 2016 – May 27, 2016

34. APEX – Author’s Conclusion
Based on protocol-specified hierarchical analysis, there was no significant difference in primary outcome in patients with D-dimer >2x ULN
However, when other larger and more inclusive cohorts are taken into account, there is evidence to suggest that the risk of VTE was lower with betrixaban than with enoxaparin+placebo
Cohen AT, et al. N Engl J Med. 2016; 375:534-44

35. Limitations/Thoughts
Hierarchical analysis – trial design
What would we be saying if the cohorts were flipped?
Superiority trial – on treatment analysis?
Overestimation of dose reduction in patients with renal insufficiency/drug-interactions
First study to include patients with CrCl <30ml/min
Enoxaparin 20mg daily
Generalizability
> 90% of patients were white

36. Limitations/Thoughts
D-Dimer
Specificity and sensitivity
Central (exploratory) vs. local (pre-specified) laboratory results
In-hospital period results
Benefit to oral versus subcutaneous injection prophylaxis?
Optimal duration of therapy
35 – 42 days
Perhaps longer?

37. Limitations/Thoughts
Clinical vs. Statistical Relevance
Underpowered?
For the primary outcome in Cohort 1, betrixaban was associated with a 19% reduction in events (p=0.054)
15% of patients were not included in analysis due to incomplete diagnostics
The authors acknowledge that Cohort 1 may have been underpowered as the sample size calculation was based on minimum number of patients in the overall cohort
Overpowered?
Alpha of used in power calculation versus alpha of 0.05 used in statistical analysis
Statistical significance found in Cohorts 2 and 3, but not Cohort ever managed to achieve a priori clinically significant 35% reduction

38. Primary Efficacy Endpoint Central D-dimer ≥ 2 x ULN:
MAGELLAN
APEX
RRR = 29.0% (8.0, 46.0)
p<0.001
RRR = 29.5% (11.6, 43.9)
p=0.002
9.3%
6.5%
9.0%
6.4%
N=125
N=84
N=165
N=118
Enoxaparin Rivaroxaban Enoxaparin Betrixaban
(n=1348) (n=1285) (n=1822) (n=1838)
Cohen AT, et al. J Thromb Haemost. 2014;12(4):
Cohen AT, et al. N Engl J Med. 2016; 375:534-44 38

39. Summary
Extended-duration betrixaban resulted in a non-significant reduction of the primary efficacy outcome in patients with a D-Dimer >2x ULN prior to randomization (p=0.054); however, there was significant benefit 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), but not in the first two pre-defined cohorts (p=0.09 and p=0.11).
Stratification through central laboratory D-dimer, was associated a statistically significant reduction in the primary efficacy endpoint with betrixaban in the first primary analysis cohort (p=0.002)
Betrixaban was not associated with a significant increase in major (p=0.55) or fatal bleeding in the overall safety population; however was associated with an increase in major plus non-major clinically relevant bleeding (p<0.001)
Betrixaban had a favorable net-clinical benefit in the overall efficacy study population. (p=0.011)
Cohen AT, et al. N Engl J Med. 2016; 375:534-44

40. Where Do We Stand Now? ADOPT EXCLAIM APEX MAGELLAN p = 0.44
Apixaban
EXCLAIM
Enoxaparin
APEX
Betrixaban
MAGELLAN
Rivaroxaban
p = 0.44
RRR = 12.9%
p = 0.02
RRR = 22.8%
p = 0.006
RRR = 24.0%
p=0.04
p<0.001
p=0.55
Incidence
VTE Events
Major Bleeding
Enoxaparin Placebo Enoxaparin Apixaban Enoxaparin Rivaroxaban Enoxaparin Betrixaban
(n=2485) (n=2510) (n=2284) (n=2211) (n=2967) (n=3057) (n=3174) (n=3112)
RRR = 38.0%
p<0.05
p <0.042
Cohen AT, et al. N Engl J Med. 2016; 375:534-44
Goldhaber SZ, et al. N Engl J Med. 2011;365(23):
Cohen AT, et al. N Engl J Med. 2013;368(6):
Hull RD, et al. Ann Intern Med. 2010;153(1):8-18.

41. On the Horizon… Total Study Duration (75 days)
Follow-Up (30 days)
Primary Efficacy Endpoint:
Symptomatic VTE + VTE-related death
Primary Safety Endpoint:
Major Bleeding
Rivaroxaban*
10mg PO QD
~8000
patients
Randomization 1:1
End of Prevention (45 days)
Placebo
*7.5mg po daily w/ CrCl ml/min
Raskob GE, et al. Thromb Haemost. 2016;115(5)

42. Questions?

43. References
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. 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. 2016; 375:534-44
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. 2014;167(3):
Goldhaber SZ, Leizorovicz A, Kakkar AK, et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med. 2011;365(23):
Raskob GE, Spyropoulos AC, Zrubek J, et al. The MARINER trial of rivaroxaban after hospital discharge for medical patients at high risk of VTE. Design, rationale, and clinical implications. Thromb Haemost. 2016;115(5)
Cohen AT, Spiro TE, Büller HR, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013;368(6):
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. 2010;153(1):8-18.
Heit JA, Spencer FA, White RH. The epidemiology of venous thromboembolism. J Thromb Thrombolysis. 2016;41(1):3-14.
Chan NC, Bhagirath V, Eikelboom JW. Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vasc Health Risk Manag. 2015;11:
Cohen AT, Spiro TE, Spyropoulos AC, et al. D-dimer as a predictor of venous thromboembolism in acutely ill, hospitalized patients: a subanalysis of the randomized controlled MAGELLAN trial. J Thromb Haemost. 2014;12(4):
Dobesh PP. Economic burden of venous thromboembolism in hospitalized patients. Pharmacotherapy. 2009;29(8):
Alikhan R, Cohen AT, Combe S, et al. Risk factors for venous thromboembolism in hospitalized patients with acute medical illness: analysis of the MEDENOX Study. Arch Intern Med. 2004;164(9):963-8.
Spyropoulos AC, Anderson FA, Fitzgerald G, et al. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest. 2011;140(3):
Spencer FA, Lessard D, Emery C, Reed G, Goldberg RJ. Venous thromboembolism in the outpatient setting. Arch Intern Med. 2007;167:1471–5.