1. Venous Thromboembolism (VTE) Recent Advances in Reducing the Disease Burden
Gary E. Raskob, Ph. D.
Dean, College of Public Health
Regents Professor, Epidemiology and Medicine
University of Oklahoma Health Sciences Center
CDC Division of Blood Disorders, Webinar November 6, 2014

2. Disclosures for Dr. Gary Raskob
Research Support
None
Employee
Consultant
Bayer HealthCare, BMS, Daiichi-Sankyo, Isis, Janssen, Johnson and Johnson, Pfizer, Quintiles
Patents
Stockholder
Honorarium
Bayer, BMS, Daiichi, Isis, Janssen, Johnson and Johnson, Pfizer
Scientific Advisory Board
Bayer HealthCare, BMS, Daiichi-Sankyo, Janssen, Johnson and Johnson, Pfizer, National Blood Clot Alliance

3. Objectives Describe the burden of disease from VTE
Describe the clinical features of VTE
Describe the difference between provoked and unprovoked VTE
Describe the risk factors for VTE and the steps people can take to reduce their risk of VTE
Describe the evidence-based recommendations for treatment of VTE
Describe how recent advances in oral anticoagulant therapy may help reduce the burden of VTE
Describe the evidence - based strategies for the prevention of new cases of VTE

4. Disease Burden of VTE 1 to 3 episodes per 1,000 population
2 to 7 per 1,000 population age > 70 yrs
547,596 hospitalizations with VTE in US
Estimated 900,000 cases per year in US
100,000 to 300,000 VTE-related deaths in US each year
684,000 DVT, 434,000 PE, and 543,000 VTE-related deaths in European Union 2004 (pop million)
VTE a leading cause of hospital - associated premature death and disability (DALY) world wide
Heit J, Cohen A, Anderson F. Estimated annual number of incident and recurrent, fatal and non-fatal venous thromboembolism (VTE) events in the US. Blood 2005;106:267a
Yusuf H et al. MMWR 2012; 61: 22: 401 – 404
ISTH Steering Committee for World Thrombosis Day. Thrombosis: a major contributor to global disease burden J Thromb Haemost 2014; 12: doi: /jth.12698

5. Venous Thromboembolism (VTE)
Pulmonary embolism (PE)
40% of non-fatal cases
Severity depends on size and cardiopulmonary reserve
Sub-segmental PE has important risk of recurrence
30% to 70% have residual DVT
Deep-vein thrombosis (DVT)
60% of non-fatal cases
Proximal DVT prognostic marker
for recurrence and mortality
Image from VF Tapson. NEJM 2008; 358: 1037

6. Virchow’s triad Hypercoagulable state Endothelial injury Venous stasis
Thrombosis background
Virchow’s triad
Acute phase postop
Cancer
Thrombophilia
Estrogen therapy
Pregnancy and postpartum period
Inflammatory bowel disease
Surgery
Trauma
Indwelling catheter
Atherosclerosis
Heart valve disease or replacement
Endothelial injury
Hypercoagulable state
In 1856, Virchow postulated a triad of conditions that predispose to thrombus formation.1
Virchow’s triad describes three abnormalities that promote thrombus formation:2
abnormalities in the blood vessel wall (endothelial injury)
abnormalities in blood flow (circulatory stasis)
abnormalities in blood clotting components (hypercoagulable state).
This explains why various risk factors contribute to the development of VTE.
References
1. Virchow R, ed. Gesammelte Abhandlungun zur Wissenschaftichen Medicin. Von Meidinger Sohn, Frankfurt, 1856.
2. Blann AD, Lip GYH. BMJ 2006;332:215–19.
Venous stasis
Immobility or paralysis
Heart failure
Venous insufficiency or varicose veins
Venous obstruction from tumour, obesity or pregnancy
Virchow R, ed. Gesammelte Abhandlungun zur Wissenschaftichen Medicin. Von Meidinger Sohn, Frankfurt, 1856.

7. 16% 25% 36% CANCER HOSPITAL STAYS SURGERY
LACK OF AWARENESS THAT CANCER, HOSPITALIZATION, AND RECENT SURGERY ARE MAJOR RISK FACTORS FOR VTE
16%
CANCER
Among countries measured, an average (mean) of 16% of respondents considered
a risk factor for blood clots
25%
HOSPITAL STAYS
Among countries measured, an average of 25% of respondents considered
a risk factor for blood clots
36%
SURGERY
Among countries measured, an average of 36% of respondents considered
a risk factor for blood clots

8. Clinical Presentations of VTE
Provoked (70% of all patients)
Associated with known risk factors
Hospital, surgery, cancer, medical illness
Risk factors may be continuing (cancer, APLA)
If risk factor reversible (transient), 2% per year recurrence after 3 months of anticoagulant therapy
Unprovoked (30% of all patients)
Absence of identifiable risk factor
Also called “idiopathic”
7% to 11% per year recurrence for DVT or PE if anticoagulant therapy stopped after 3, 6,12 or 24 months
Kearon C, Akl E. Blood 2014; 123 (12)
Boutitie F et al. BMJ 2011, May 24;342:d3036

9. Goals of Treatment for VTE
Prevent death from pulmonary embolism
Prevent symptomatic recurrent VTE % risk of symptomatic recurrent VTE during if inadequate therapy
Prevent and/or reduce morbidity from post-thrombotic syndrome (PTS) 25% at 2 yr
chronic pulmonary hypertension 4% at 2 yr
Minimize the risk of bleeding and other side effects

10. Evidence- based Guidelines for Treatment of VTE
AHA Guidelines PE, iliofemoral DVT, CTEPH Jaff M et al Circulation 2011; 123: 1788 – 1830
American College of Chest Physicians (ACCP) 9th ed Kearon et al CHEST 2012; 141: (2) Suppl: e419s-e494s
International Union of Angiology - Consensus Statement Nicolaides AN et al Int Angiology 2013; 32:
Treatment of Venous Thromboembolism Wells P et al JAMA 2014; 311:
European Society of Cardiology ESC Guideline on the diagnosis and management of acute pulmonary embolism European Heart Journal 2014; doi /eurheart/ehu283

11. Treatment of VTE 9th ACCP Guideline Recommendations
Anticoagulant therapy over other approaches for most acute DVT or PE (2C) parenteral therapy using LMWH or fondaparinux (1B) long-term therapy for at least 3 months (1B) evaluate risk-benefit of extended therapy
Catheter - Directed Thrombolytic (CDT) therapy for DVT anticoagulant therapy alone over CDT most patients (2C) selected patients with DVT may benefit
Anticoagulant therapy over no anticoagulation for extensive superficial vein thrombosis (2B) (fondaparinux over LMWH, 2C)
Thrombolytic therapy for PE acute PE + hypotension (2C) acute PE, high risk of hypotension, low risk of bleeding (2C) intracranial bleeding in 2 to 3% in contemporary studies
Inferior vena cava filter anticoagulants contraindicated (1B)
Kearon et al CHEST 2012; 141: (2) Suppl: e419s - e494s

12. Treatment of Venous Thromboembolism
Heparin
LMWH
Fondaparinux Thrombolysis
Thrombus Removal
IVC filter
Vitamin K Antagonists
LMWH
Initial treatment
Vitamin K Antagonists
Long term-treatment
Extended treatment
5 to 10 days to 6 months > 6 months

13. Direct oral anticoagulants
Generic Name
Brand Name
Enzyme Target
Renal Clearance
Half Life (hr)
Dabigatran
Pradaxa
Thrombin
80%
Rivaroxaban
Xarelto Xa
33%
7 - 11
Apixaban
Eliquis
25%
8 - 12
Edoxaban
Savaysa
35%
8 - 10
Wells P et al JAMA 2014; 311:

14. Direct oral anticoagulants for VTE FDA approved indications and regimens
Rivaroxaban (November 2012) Treatment of Deep Vein Thrombosis (DVT) Treatment of Pulmonary Embolism (PE) Reduction in the risk of recurrence of DVT and PE mg orally twice daily with food for first 21 days (initial treatment), then 20 mg orally once daily with food
Dabigatran (April 2014) Treatment of Deep Venous Thrombosis and Pulmonary Embolism Reduction in the risk of recurrence of DVT and PE mg orally twice daily after 5 to 10 days of parenteral anticoagulation
Apixaban (August 2014) Treatment of Deep Vein Thrombosis Treatment of Pulmonary Embolism mg orally twice daily for 7 days, then 5 mg orally twice daily Reduction in the risk of recurrence of DVT and PE mg orally twice daily

15. VTE treatment studies Direct oral anticoagulants
Hokusai-VTE
AMPLIFY
EINSTEIN-DVT
EINSTEIN-PE
RE-COVER I
RE-COVER II
Drug
Edoxaban
Apixaban
Rivaroxaban
Dabigatran
Study design
Double-blind
Open label
Heparin lead-in
At least 5 days
None
Dose
60 mg qd
30 mg qd (CrCl, bw, P-gp)
10 mg bid x 7 days then 5 mg bid
15 mg bid x 3 wk then 20 mg qd
150 mg bid
Non-inferiority margin
1.5
1.8
2.0
2.75
Sample size
8,292
5,400
EINSTEIN-DVT 3,449
4,832
2,564
2,568
Treatment duration
Flexible
3 to 12 months
6 months
Pre-specified
3, 6, or 12 months
Adapted from Raskob et al. J Thromb Haemost 2013; 11:

16. Clinical Trials of Rivaroxaban for VTE
Open-label, non-inferiority
3, 6, or 12 months
Rivaroxaban
Rivaroxaban
N=3,449
15 mg bid
20 mg od R
Day 21
Double-blind, superiority
Enoxaparin bid for at least 5 days, plus VKA target INR 2.5 (INR range 2–3)
6 or 12 months
Rivaroxaban 20 mg od
N=1,197
Open-label, non-inferiority R
3, 6, or 12 months
Placebo
Rivaroxaban
Rivaroxaban
N~4,500
15 mg bid
20 mg od
Outside of the EINSTEIN programme
Patients with confirmed symptomatic DVT or PE completing 6 or 12 months of VKA R
Day 21
Enoxaparin bid for at least 5 days, plus VKA target INR 2.5 (INR range 2–3)
N Engl J Med 2010;363:
N Engl J Med 2012; 366: 16 16 16

17. EINSTEIN DVT Trial Recurrent VTE
4.0
Enoxaparin/VKA (N=1,718)
3.0
Rivaroxaban (N=1,731)
Cumulative event rate (%)
2.0
Rivaroxaban
(n / N)
Enox / VKA HR
(95% CI)
No. of events
36 / 1,731
2.1%
51 / 1,718
3.0%
0.68
(0.44–1.04)
1.0
TTR = 57.7% 30 60 90
120
150
180
210
240
270
300
330
360
Time to event (days)
0.44
0.68
1.04
N Engl J Med 2010;363:
1.00
2.00
Hazard ratio
Rivaroxaban superior
Rivaroxaban non-inferior
Rivaroxaban inferior
p=0.076 for superiority (two-sided)
p< for non-inferiority (one-sided) 17

18. EINSTEIN DVT Trial Bleeding Outcomes
Rivaroxaban (N=1,718)
Enox/VKA (N=1,711)
HR (95% CI) n
(%)
p-value
First major or clinically relevant non-major bleeding
139
(8.1)
138
0.97 (0.76–1.22) p=0.77
Major bleeding 14
(0.8) 20
(1.2)
Contributing to death 1
(<0.1) 5
(0.3)
In a critical site 3
(0.2)
Associated with fall in Hb 2 g/dL and/or transfusion of ≥2 units 10
(0.6) 12
(0.7)
Clinically relevant non-major bleeding
126
(7.3)
119
(7.0)
Note: Patients can have one or more bleeding events
Safety population
N Engl J Med 2010; 363: 18 18 18

19. EINSTEIN PE Trial Recurrent VTE
Rivaroxaban clinical development
EINSTEIN PE Trial Recurrent VTE
Rivaroxaban (N=2419)
Enoxaparin/VKA (N=2413) n
(%)
First symptomatic recurrent VTE 50
(2.1) 44
(1.8)
Recurrent DVT 18
(0.7) 17
Recurrent DVT + PE 2
(<0.1)
Non-fatal PE 22
(0.9) 19
(0.8)
Fatal PE/unexplained death where PE cannot be ruled out 10
(0.4) 6
(0.2) HR
0.75
1.12
1.68
1.00
2.00
Primary efficacy endpoint analysis
Abbreviations
CI, confidence interval; HR, hazard ratio
Rivaroxaban superior
Rivaroxaban non-inferior
Rivaroxaban inferior
p=0.57 for superiority
(two-sided)
P= for non-inferiority (one-sided)
N Engl J Med 2012; 366:
Absolute risk difference 0.24% , 95% CI to 1.02

20. EINSTEIN PE Trial Bleeding Outcomes
Rivaroxaban (N=2,412)
Enox/VKA (N= 2,405)
HR (95% CI) n
(%)
p-value
First major or clinically relevant non-major bleeding
249
(10.3)
274
(11.4)
0.90 (0.76–1.07) p=0.23
Major bleeding 26
(1.1) 52
(2.2)
P=0.003
Contributing to death 2
(<0.1) 3
(0.1)
In a critical site 7
(0.3)
Associated with fall in Hb 2 g/dL and/or transfusion of ≥2 units 17
(0.7)
Clinically relevant non-major bleeding
223
(9.2)
222
Note: Patients can have one or more bleeding events
Safety population
N Engl J Med 2012; 366: 20 20 20

21. EINSTEIN PE Trial Major bleeding
Rivaroxaban clinical development
Rivaroxaban n/N (%)
Enoxaparin/VKA n/N (%)
HR (95% CI) p-value
26/2412 (1.1)
52/2405 (2.2)
0.49 (0.31–0.79) p=0.0032
3.0
2.5
2.0
1.5
1.0
0.0
0.5
Enoxaparin/VKA
N=2405
Cumulative event rate (%)
Rivaroxaban
N=2412
TTR = 62.7%
Time to event (days) 30 60 90
120
150
180
210
240
270
300
330
360
EINSTEIN PE: principal safety outcome (composite of major or non-major clinically relevant bleeding)
Number of patients at risk
Rivaroxaban
2412
2281
2248
2156
2091
2063
1317
761
735
700
669
659
350
Enoxaparin/VKA
2405
2270
2224
2116
2036
1176
746
719
680
658
642
278
Safety population
N Engl J Med 2012; 366: 21

22. Objectively confirmed acute symptomatic proximal DVT and/or PE
AMPLIFY Trial
Randomized, double-blind, non-inferiority study
Apixaban 10 mg BID x 7 d, then 5 mg BID
Objectively confirmed acute symptomatic proximal DVT and/or PE R
Enoxaparin mg/kg BID sc
End of Treatment
Safety Follow-up
Warfarin (INR 2–3)
6 months
30-day
Day 1
Agnelli et al. N Engl J Med 2013;369: 22

23. AMPLIFY Trial Efficacy Outcomes
Apixaban
n=2609
Enoxaparin/Warfarin
n=2635
Relative Risk (95% CI)
P Value
First recurrent VTE or VTE-related death, n (%)
59 (2.3)
71 (2.7)
0.84 (0.60–1.18)
<0.0001
Noninferiority
Index event: DVT
38/1698 (2.2)
47/1736
(2.7)
0.83 (0.54–1.26)
Index event: PE ± DVT
21/900 (2.3)
23/886
(2.6)
0.90 (0.50–1.61)
VTE or CV-related death, n (%)
61 (2.3)
77 (2.9)
0.80 (0.57–1.11)
VTE or all-cause death, n (%)
84 (3.2)
104 (4.0)
0.82 (0.61–1.08)
Agnelli et al N Engl J Med 2013;369:

24. AMPLIFY Trial First Recurrent VTE or VTE-related Death
100 90 3
Enoxaparin/Warfarin ( 71/2704) 80 70 2
Apixaban (59/2691) 60
Percent of patients 50 1
For warfarin-treated subjects, TTR was 60.9% 40 30 20 30 60 90
120
150
180
210
240
270
300 10 30 60 90
120
150
180
210
240
270
300
Days to VTE/VTE-related death
No. of patients at risk
Apixaban
2691
2606
2586
2563
2541
2523 62 4 1
Eno/War
2704
2609
2585
2555
2543
2533 43 3 1 1
Agnelli et al N Engl J Med 2013;369:
TTR, time in therapeutic range.

25. AMPLIFY Trial Bleeding Outcomes
Event
Apixaban
n=2676
Enoxaparin/Warfarin
n=2689
Relative Risk (95% CI)
P Value
Major bleeding†, n (%)
15 (0.6)
49 (1.8)
0.31
(0.17–0.55)
< Superiority
CRNM bleeding, n (%)
103 (3.9)
215 (8.0)
0.48
(0.38–0.60)
Major or CRNM bleeding, n (%)
115 (4.3)
261 (9.7)
0.44
(0.36–0.55)
NNT for major bleeding = NNT for CRNM bleeding = 24
Agnelli et al N Engl J Med 2013; 369:

26. AMPLIFY Trial Major Bleeding
100 90
Enoxaparin/Warfarin (events: 49/2689) 2 80 70 60 1
Percent of patients 50
Apixaban (events: 15/2676) 40
RR, 0.31; 95% CI, 30 20 30 60 90
120
150
180
210
240
270
300 10 30 60 90
120
150
180
210
240
270
300
Days to major bleeding
No. of patients at risk
Apixaban
2676
2519
2460
2409
2373
2339 61 4 1
Eno/War
2689
2488
2426
2383
2339
2310 43 3 1 1
RR, relative risk.
Agnelli et al N Engl J Med 2013;369:

27. Hokusai VTE Study DesignR
edoxaban 60 mg/30 mg
warfarin
3 Months
12 Months
Day 6- 12
Sham INR
INR
Day 1- 5
Objectively confirmed VTE
Stratified randomization:
PE or DVT
Risk factors
Edoxaban dose adjustment
edoxaban
placebo edoxaban
warfarin
placebo warfarin
(LMW) heparin
Raskob et al. J Thromb Haemost 2013;11:
Hokusai -VTE Investigators N Engl J Med 2013; 369:

28. Hokusai VTE Trial Efficacy outcomes
Edoxaban
(N=4118)
Warfarin
(N=4122)
Hazard ratio
(95% CI)
P Value
First recurrent VTE - no. (%)
Overall study period
130 (3.2)
146 (3.5)
0.89
( )
<0.001
Noninferiority
Patients with index DVT*
83 (3.4)
81 (3.3)
1.02
( )
Patients with index PE**
47 (2.8)
65 (3.9)
0.73
( )
On-treatment period
66 (1.6)
80 (1.9)
0.82
( )
noninferiority)
Subgroup severe PE
(RV dysfunction ProBNP)
15/454 (3.3)
30/485 ( 6.2)
0.52
(0.28 to 0.98)
* Denominator is number of patients with index DVT: 2468 and 2453 in edoxaban and warfarin group respectively
** Denominator is number of patients with index PE : and 1669 in edoxaban and warfarin group respectively

29. Hokusai VTE Trial Bleeding outcomes
Edoxaban
(N=4118)
Warfarin
(N=4122)
Hazard ratio
(95% CI)
P Value
First major or clinically relevant non major – no. (%)
349 (8.5)
423 (10.3)
0.81
( )
0.004
superiority
Major – no. (%)
56 (1.4)
66 (1.6)
0.84
( )
0.35
Fatal
2 (<0.1)
10 (0.2)
Intracranial
6 (0.1)
Non-Fatal in Critical Sites
13 (0.3)
25 (0.6)
5 (0.1)
12 (0.3)
Non-Fatal in Non-Critical Sites
41 (1.0)
33 (0.8) †
Clinically Relevant Non-Major– no. (%)
298 (7.2)
368 (8.9)
0.80
( )
N Engl J Med 2013; 369:
NNT = 56
† some patients have more than 1 bleeding

30. Anticoagulant Treatment of VTE Risk-Benefit of DOAC vs
Anticoagulant Treatment of VTE Risk-Benefit of DOAC vs. Vitamin K Antagonist
DOAC
VKA
Absolute risk of recurrent VTE
RR (95% CI 0.77 to 1.06)
2.0 %
2.2 %
Absolute risk of major bleeding
NNT = 147
1.1 %
1.8 %
Absolute risk of intracranial bleeding
NNT = 588
0.1 %
0.3 %
Absolute risk of fatal bleeding
NNT = 1, 250
0.2 %
van Es N et al. Blood 2014; doi /blood

31. Acute PE without shock or hypotension ESC 2014 Guideline Recommendations
Anticoagulant is recommended with objective to prevent both early death and recurrent symptomatic or fatal VTE parenteral anticoagulation LMWH or fondaparinux (I A) in parallel, VKA target INR 2.5 (range ) (I B)
Alternative to combined parenteral anticoagulation with VKA rivaroxaban 15 mg bid x 3 weeks, followed by 20 mg daily (I B) apixaban 10.0 mg bid x 7 days, followed by 5.0 mg bid (I B)
Alternative to VKA treatment , following parenteral anticoagulation dabigatran 150 mg bid (110 mg age > 80 yr, or verapamil) (I B) edoxaban (subject to regulatory review) (I B)
European Heart Journal 2014
doi: /eurheartj/ehu283

32. Duration of Anticoagulant Therapy 9th ACCP Recommendations
First episode VTE
Provoked
(surgery or reversible risk factor) months over longer therapy (1B)
Unprovoked at least 3 months (1B), evaluate for extended therapy
(low bleeding risk, extended therapy (2B), high bleeding risk 3 months (1B)
Cancer LMWH over VKA (2B), extended therapy (1B or 2B)
Second episode VTE, unprovoked extended therapy (1B or 2B)
Recommendations for anticoagulant therapy duration are as follows:
Following first episode VTE:
At least 3 months of therapy for those patients with time-limited risk factors (ie, transient immobilization, trauma, surgery, etc.)
At least 6 months of therapy for those patients with idiopathic etiology
At least 12 months of therapy is recommended for patients with deficiency of protein C or S, or antithrombin III.
Cancer patients, until the disease is resolved, may require indefinite therapy.
[Although the optimal duration of treatment for those with factor V Leiden abnormality is uncertain, the ACCP recommends those with homozygous factor V Leiden should probably be treated indefinitely, while those with the heterozygous state should receive 3 months of treatment.]
Following a recurrent VTE:
12 months to indefinitely for all patients.
Of course, these recommendations are subject to modification based on individual patient characteristics, such as age and comorbidity.
Hyers T, Agnelli G, Hull R, et al. Antithrombotic therapy for venous thromboembolic disease. Chest 1998;114(suppl 5):561S–578S.
Kearon et al CHEST 2012; 141:(2) Suppl: e419s - e494s

33. Management of unprovoked VTE
ASA therapy
Stop anticoagulant
therapy in all
3 months
Continue anticoagulant
therapy in all
Identify selected patients at low risk
to stop anticoagulant therapy

34. Duration of Anticoagulant Therapy Factors Influencing Decision
Risk of recurrent VTE
Risk of bleeding
Patient preference
Many factors influence the decision of how long a patient should be taking anticoagulation therapy for VTE. The risk of recurrence weighed against the risk of major bleeding are primary factors. All decisions should incorporate research evidence, good clinical judgement, and patient preference.
Patients should not be slated as being on warfarin “for life.” Rather, the treatment duration should be “indefinitely.” Long-term treatment should be reassessed at regular intervals. In this way, any changes in patient characteristics (such as increased bleeding risk) may be reassessed in order to provide optimal treatment recommendations.

35. AMPLIFY Extended Treatment Trial
Randomized, double blind, placebo-controlled, superiority
Placebo BID
Apixaban 2.5 mg BID
Apixaban 5 mg BID
DVT/PE patients who have completed 6–12 months of anticoagulant treatment R
End of Treatment
Safety Follow-up
12 Months
30 Days
Day 1
Agnelli et al N Engl J Med 2013; 368: 35

36. AMPLIFY Extended Treatment Trial Recurrent VTE10
Placebo
Apixaban 2.5 mg
Apixaban 5 mg
100 9 8 7 80 6 5
Cumulative event rate (%) 60 4
NNT to prevent one
recurrent event = 14 3
Cumulative event rate (%) 2 40 1 20 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12
Months
No. at risk
Apixaban 2.5 mg
Apixaban 5 mg
Placebo
Baseline
840
813
826
Month 3
836
807
796
Month 6
825
799
768
Month 9
818
791
743
Month 12
533
513
471
Agnelli et alN Engl J Med 2013; 368:

37. AMPLIFY Extended Treatment Bleeding Outcomes
Event
Apixaban mg
N=840
Apixaban 5 mg
N=811
Placebo
N=826
Apixaban mg vs placebo
RR (95% CI)
Apixaban 5 mg vs placebo
Apixaban mg vs 5 mg
Major bleed
2 (0.2)
1 (0.1)
4 (0.5)
0.49
(0.09, 2.64)
0.25
(0.03, 2.24)
1.93
(0.18, 21.25)
Clinically relevant non-major bleed
25 (3.0)
34 (4.2)
19 (2.3)
1.29
(0.72, 2.33)
1.82
(1.05, 3.18)
0.71
(0.43, 1.18)
Major or clinically relevant non-major bleeding
27 (3.2)
35 (4.3)
22 (2.7)
1.20
(0.69, 2.10)
1.62
(0.96, 2.73)
0.74
(0.46, 1.22)
Major Bleeds
2.5 mg: 2 events, both Intraocular
5.0 mg: 1 event, Gastrointestinal
Placebo: 4 events, Intraocular, Stroke, Urogenital, Gastrointestinal
Agnelli et al N Engl J Med 2013; 368:

38. Extended Treatment of VTE Risk-Benefit of DOAC and ASA vs. Placebo
Absolute risk reduction in recurrent VTE
5% to 7%
RRR 80%
4.6%, 1.7%
RRR 25, 42%
NNT to prevent one recurrent VTE
14 to 20
22 to 59
Absolute risk of major bleeding
0.1% to 0.7%
0.5% to 0.6%
NNH to cause one major bleed
143 to 1,000
167 to 200
Absolute risk of clinically relevant bleeding (major or non-major)
3% to 7 %
1% to 2%
N Engl J Med 2010; 363: , N Engl J Med 2013; 368: 699 – 708, N Engl J Med 2012; 366: , N Engl J Med 2012; 367:

39. Treatment of Venous Thromboembolism
Heparin
LMWH
Fondaparinux Thrombolysis
Thrombus Removal
IVC filter
Rivaroxaban
Apixaban
Vitamin K Antagonists
ASA 100 mg
Oral XaI or dabigatran
Vitamin K Antagonists
LMWH
Oral XaI or dabigatran
Initial (acute) treatment
Long term-treatment
Extended treatment
5 to 10 days to 6 months > 6 months

40. Hospital Associated VTE
Age, hospital, surgery, prior VTE, cancer are the major risk factors
60% of incident VTE associated with recent hospitalization
Risk period often extends beyond hospital stay
Hospital is opportune access point to implement prevention
Heit JA. The epidemiology of Venous Thromboembolism in the Community Arteriosclerosis, Thrombosis, and Vascular Biology 2008; 28:

41. Fatal PE More Common in Medical Patients Than Surgical Patients
75%
25%
Medical patients
Surgical patients
Fatal PE More Common in Medical Patients Than Surgical Patients
Sandler DA, et al. J R Soc Med. 1989;82:

42. Hospitalized Medical Patients
ACCP Evidence-based Practice Guidelines 2008
LMWH, Unfractionated Heparin, or Fondaparinux (Grade 1A) Mechanical methods if above contraindicated
Patients with heart failure, sever respiratory disease, or confined to bed with1 or more risk factors (cancer, previous VTE, sepsis, acute neurologic disease, IBD)
Duration not specified, 4 to 14 days in clinical trials
ACP Clinical Practice Guideline 2011
Risk assessment for VTE and bleeding, heparin or related drug unless bleeding risk outweighs benefit
Geerts et al. Prevention of venous thromboembolism. American College of Chest Physicians Evidence Based Practice Guidelines (8th edition). CHEST 2008;133:
Qaseem A et al. Venous thromboembolism prophylaxis in hospitalizedpatients: A Clinical Practice Guideline from the American College of Physicians. Annals of Internal Medicine 2011; 155:

43. American College of Chest Physicians Guidelines: 9th Edition
For the Non-surgical and Non-orthopedic surgical chapters, a primary shift is towards an individualized approach of risk assessing the patients’ bleeding risk factors as well as their VTE risk factors for the appropriate thromboprophylactic strategy
Format
Kahn et al. CHEST 2012; 141:(2 Suppl): e195S-226S 43

44. Clinical Trials of Extended Duration (28 - 35 days) vs 10 days of Prophylaxis in Medical Patients
Absolute Risk Differences
Study Major VTE Major Bleeding
EXCLAIM (n= 5,963) % %
enoxaparin 40 mg od NNT NNH 200
MAGELLAN (n= 8,101) % %
rivavoxaban 10 mg od NNT NNH 143
ADOPT (n= 6,528) % (NS) %
apixaban 2.5 mg bid NNT ? NNH 333
Hull R et al Ann Intern Med 2010; 153: 8-18.
Cohen et al. N Engl J Med 2013; 368:
Goldhaber et al. N Engl J Med 2011; 365:

45. 9th ACCP Recommendations
2.8. For acutely ill hospitalized medical
patients who receive an initial course of
thromboprohylaxis, we suggest against
extending the duration of
thromboprophylaxis beyond the period
of patient immobilization
or acute hospital stay (Grade 2B)
Format
Kahn et al. CHEST 2012;141;e195S-e226S

46. Primary Endpoint: Composite of Symptomatic VTE or VTE-Related Death
Estimated Sample Size
Sample size
Placebo
RRR
ARR
Events
Power for superiority
2 sided α
8,000
2.5%
40%
1.0%
161
90% 5%

47. Reducing the Disease Burden of VTE
VTE is a “winnable battle”
Improve utilization of effective prevention
If you are hospitalized or having surgery, ask about your VTE risk and prevention
New oral anticoagulants improve safety and enhance secondary prevention of recurrent VTE
Improve public awareness of VTE, risk factors and prevention
Continued research