- Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a major cause of morbidity and mortality worldwide. It is estimated that there are 900,000 cases of VTE per year in the US. - Recent clinical trials have found that the direct oral anticoagulants rivaroxaban, apixaban, edoxaban and dabigatran are non-inferior to standard therapy for treating VTE and reduce the risk of recurrence, while having a similar or lower risk of bleeding. - The EINSTEIN DVT and EINSTEIN PE trials found that rivaroxaban was non-infer

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 None
Consultant Bayer HealthCare, BMS, Daiichi-Sankyo,
Isis, Janssen, Johnson and Johnson,
Pfizer, Quintiles
Patents None
Stockholder None
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 2007- 2009
 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 454.4 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: 10.111/jth.12698

5. Venous Thromboembolism (VTE)
Image from VF Tapson. NEJM 2008; 358: 1037
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

6. Virchow’s triad
• Surgery
• Trauma
• Indwelling
catheter
• Atherosclerosis
• Heart valve
disease or
replacement
Venous stasis
• Acute phase postop
• Cancer
• Thrombophilia
• Estrogen therapy
• Pregnancy and
postpartum period
• Inflammatory bowel
disease
• 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. - 7 -
LACK OF AWARENESS THAT CANCER, HOSPITALIZATION, AND RECENT SURGERY
ARE MAJOR RISK FACTORS FOR VTE
16%
Among countries
measured, an average
(mean) of 16% of
respondents considered
CANCER
a risk factor for blood clots
25%
Among countries
measured, an average of
25% of respondents
considered
HOSPITAL
STAYS
a risk factor for blood clots
36%
Among countries
measured, an average of
36% of respondents
considered
SURGERY
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) 1794-1801.
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
25% risk of symptomatic recurrent VTE during 3
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 2012
Kearon et al CHEST 2012; 141: (2) Suppl: e419s-e494s
 International Union of Angiology - Consensus Statement
Nicolaides AN et al Int Angiology 2013; 32: 111-260
 Treatment of Venous Thromboembolism
Wells P et al JAMA 2014; 311: 717-728
 European Society of Cardiology
2014 ESC Guideline on the diagnosis and management
of acute pulmonary embolism
European Heart Journal 2014; doi 10.1093/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) K e a r o n e t a l C H E S T 2 0 1 2 ; 141:
(2) Suppl: e419s - e494s

12. Treatment of Venous Thromboembolism
Vitamin K Antagonists
LMWH
Heparin
LMWH
Fondaparinux
Thrombolysis
Thrombus Removal
IVC filter
Initial treatment
Long term-treatment
Vitamin K Antagonists
Extended treatment
5 to 10 days 3 to 6 months > 6 months

13. Direct oral anticoagulants
Generic
Name
Brand
Name
Enzyme
Target
Renal
Clearance
Half
Life (hr)
Dabigatran Pradaxa Thrombin 80% 14 - 17
Rivaroxaban Xarelto Xa 33% 7 - 11
Apixaban Eliquis Xa 25% 8 - 12
Edoxaban Savaysa Xa 35% 8 - 10
Wells P et al JAMA 2014; 311: 717 - 728

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
15 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
150 mg orally twice daily after 5 to 10 days of parenteral anticoagulation
 Apixaban (August 2014)
Treatment of Deep Vein Thrombosis
Treatment of Pulmonary Embolism
10 mg orally twice daily for 7 days, then 5 mg orally twice daily
Reduction in the risk of recurrence of DVT and PE
2.5 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 Double-blind Open label Double-blind
Heparin lead-in At least 5 days None None At least 5 days
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
EINSTEIN-PE
4,832
RE-COVER I
2,564
RE-COVER II
2,568
Treatment
duration
Flexible
3 to 12 months
6 months Pre-specified
3, 6, or 12 months
6 months
Adapted from Raskob et al. J Thromb Haemost 2013; 11: 1287 - 1294

16. Clinical Trials of Rivaroxaban for VTE
16
N=1,197
Double-blind, superiority
Rivaroxaban 20 mg od
Placebo
6 or 12 months
3, 6, or 12 months
Rivaroxaban
20 mg od
Open-label, non-inferiority R
N~4,500
Rivaroxaban
15 mg bid
Day 21
Rivaroxaban
20 mg od
Enoxaparin bid for at least 5 days, plus
VKA target INR 2.5 (INR range 2–3)
R
3, 6, or 12 months
15 mg bid
N=3,449
Rivaroxaban
Day 21
Enoxaparin bid for at least 5 days, plus
VKA target INR 2.5 (INR range 2–3)
R
Open-label, non-inferiority
Outside of the EINSTEIN programme
Patients with confirmed symptomatic DVT
or PE completing 6 or 12 months of VKA
N Engl J Med 2010;363:2499-510
N Engl J Med 2012; 366:1287 -1297

17. EINSTEIN DVT Trial Recurrent VTE
Enoxaparin/VKA (N=1,718)
17
Cumulative event rate (%)
TTR = 57.7%
0 30 60 90 120 150 180 210 240 270 300 330 360
3.0
2.0
1.0
0
Rivaroxaban (N=1,731)
4.0
Time to event (days)
Rivaroxaban
(n / N)
Enox / VKA
(n / N)
HR
(95% CI)
No. of
events
36 / 1,731
2.1%
51 / 1,718
3.0%
0.68
(0.44–1.04)
0.44 0.68 1.04
0 1.00
Hazard ratio
Rivaroxaban
superior
N Engl J Med 2010;363:2499-510
Rivaroxaban
non-inferior
2.00
Rivaroxaban
inferior
p=0.076 for superiority (two-sided) p<0.0001 for non-inferiority (one-sided)

18. EINSTEIN DVT Trial Bleeding Outcomes
18
Rivaroxaban
(N=1,718)
Enox/VKA
(N=1,711) HR (95% CI)
n (%) n (%) p-value
First major or clinically relevant
non-major bleeding
139 (8.1) 138 (8.1) 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) 3 (0.2)
Associated with fall in Hb 2 g/dL
10 (0.6) 12 (0.7)
and/or transfusion of ≥2 units
Clinically relevant non-major bleeding 126 (7.3) 119 (7.0)
Safety population N Engl J Med 2010; 363: 2499-510

19. EINSTEIN PE Trial Recurrent VTE
Rivaroxaban
(N=2419)
Enoxaparin/VKA
(N=2413)
n (%) n (%)
First symptomatic recurrent VTE 50 (2.1) 44 (1.8)
Recurrent DVT 18 (0.7) 17 (0.7)
Recurrent DVT + PE 0 2 (<0.1)
Non-fatal PE 22 (0.9) 19 (0.8)
Fatal PE/unexplained death where
10 (0.4) 6 (0.2)
PE cannot be ruled out
HR
0.75 1.12 1.68
0 1.00 2.00
Rivaroxaban
superior
Rivaroxaban
non-inferior
Rivaroxaban
inferior
P=0.0026 for non-inferiority
(one-sided)
p=0.57 for superiority
(two-sided)
Absolute risk difference 0.24% , 95% CI - 0.5 to 1.02
N Engl J Med 2012; 366:1287 -1297

20. EINSTEIN PE Trial Bleeding Outcomes
20
Rivaroxaban
(N=2,412)
Enox/VKA
(N= 2,405) HR (95% CI)
n (%) 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) 26 (1.1)
Associated with fall in Hb 2 g/dL
17 (0.7) 26 (1.1)
and/or transfusion of ≥2 units
Clinically relevant non-major bleeding 223 (9.2) 222 (9.2)
Safety population N Engl J Med 2012; 366: 1287-1297

21. EINSTEIN PE Trial Major bleeding
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Enoxaparin/VKA
N=2405
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
TTR = 62.7%
0 30 60 90 120 150 180 210 240 270 300 330 360
Cumulative event rate (%)
Safety population
Time to event (days)
Rivaroxaban
N=2412
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 2063 2036 1176 746 719 680 658 642 278
N Engl J Med 2012; 366: 1287-1297

22. 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
End of Treatment
Safety Follow-up
Enoxaparin
1 mg/kg BID sc
Warfarin (INR 2–3)
Day 1 6 months 30-day
Agnelli et al. N Engl J Med 2013;369: 799 - 808

23. AMPLIFY Trial Efficacy Outcomes
Apixaban
n=2609
Enoxaparin/
Warfarin
n=2635
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: 799 - 808

24. AMPLIFY Trial
First Recurrent VTE or VTE-related Death
Enoxaparin/Warfarin ( 71/2704)
For warfarin-treated subjects,
TTR was 60.9%
0 30 60 90 120 150 180 210 240 270 300
100
90
80
70
60
50
40
30
20
10
0
Percent of patients
0 30 60 90 120 150 180 210 240 270 300
3
2
1
0
Apixaban (59/2691)
2691 2606 2586 2563 2541 2523 62 4 1 0 0
2704 2609 2585 2555 2543 2533 43 3 1 1 0
Apixaban
Eno/War
Days to VTE/VTE-related death
No. of patients at risk
TTR, time in therapeutic range. Agnelli et al N Engl J Med 2013;369: 799 - 808

25. AMPLIFY Trial Bleeding Outcomes
Event
Apixaban
n=2676
Enoxaparin/
Warfarin
n=2689
Relative Risk
(95% CI)
P Value
†
, n (%) 15 (0.6) 49 (1.8)
Major bleeding
0.31
(0.17–0.55)
<0.0001
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 = 83 NNT for CRNM bleeding = 24
Agnelli et al N Engl J Med 2013; 369: 799 - 808

26. AMPLIFY Trial Major Bleeding
Enoxaparin/Warfarin (events: 49/2689)
Apixaban (events: 15/2676)
0 30 60 90 120 150 180 210 240 270 300
100
90
80
70
60
50
40
30
20
10
0
Percent of patients
2
1
0
0 30 60 90 120 150 180 210 240 270 300
2676 2519 2460 2409 2373 2339 61 4 1 0 0
2689 2488 2426 2383 2339 2310 43 3 1 1 0
Apixaban
Eno/War
Days to major bleeding
No. of patients at risk
RR, 0.31; 95% CI, 0.17 - 0.55
RR, relative risk. Agnelli et al N Engl J Med 2013;369: 799 - 808

27. Hokusai VTE Study Design
R
edoxaban 60 mg/30 mg
Sham INR
INR
warfarin
Day 6- 12 3 Months 12 Months
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;11:1287-94
Hokusai -VTE Investigators N Engl J Med 2013; 369:1406-15

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
(0.70-1.13)
<0.001
Noninferiority
Patients with index DVT* 83 (3.4) 81 (3.3) 1.02
(0.75-1.38)
Patients with index PE** 47 (2.8) 65 (3.9) 0.73
(0.50-1.06)
On-treatment period 66 (1.6) 80 (1.9) 0.82
(0.60-1.14)
<0.001
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 : 1650 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
(0.71-0.94)
0.004
superiority
Major – no. (%) 56 (1.4) 66 (1.6) 0.84
(0.59-1.21)
0.35
superiority
Fatal 2 (<0.1) 10 (0.2)
Intracranial 0 6 (0.1)
Non-Fatal in Critical Sites 13 (0.3) 25 (0.6)
Intracranial 5 (0.1) 12 (0.3)
Non-Fatal in Non-Critical Sites 41 (1.0) 33 (0.8) †
Clinically Relevant Non-
Major– no. (%)
N Engl J Med 2013; 369:1406-15
NNT = 56
298 (7.2) 368 (8.9) 0.80
(0.68-0.93)
0.004
superiority
29
† some patients have more than 1 bleeding

30. Anticoagulant Treatment of VTE
Risk-Benefit of DOAC vs. Vitamin K Antagonist
DOAC VKA
Absolute risk of recurrent VTE
RR 0.90 (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
0.1 % 0.2 %
van Es N et al. Blood 2014; doi 10.1182/blood-2014-04-571233

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 2.0- 3.0) (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:10.1093/eurheartj/ehu283

32. Duration of Anticoagulant Therapy
9th ACCP Recommendations
First episode VTE
Provoked
(surgery or reversible risk factor) 3 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)
Kearon et al CHEST 2012; 141:(2) Suppl: e419s - e494s

33. Management of unprovoked VTE
Stop
anticoagulant
therapy in all
Continue
anticoagulant
therapy in all
ASA therapy
3 months
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

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
Day 1 12 Months 30 Days
Agnelli et al N Engl J Med 2013; 368: 699 - 708

36. AMPLIFY Extended Treatment Trial Recurrent VTE
100
80
60
40
20
0
NNT to prevent one
recurrent event = 14
0 1 2 3 4 5 6 7 8 9 10 11 12
10
9
8
7
6
5
4
3
2
1
0 1 2 3 4 5 6 7 8 9 10 11 12
Cumulative event rate (%)
Months
0
Baseline
840
813
826
Month 3
836
807
796
Month 6
825
799
768
Month 9
818
791
743
Month 12
533
513
471
No. at risk
Apixaban 2.5 mg
Apixaban 5 mg
Placebo
Placebo
Apixaban 2.5 mg
Apixaban 5 mg
Cumulative event rate (%)
Agnelli et alN Engl J Med 2013; 368: 699 - 708

37. AMPLIFY Extended Treatment Bleeding Outcomes
Event
Apixaban
2.5 mg
N=840
Apixaban
5 mg
N=811
Placebo
N=826
Apixaban
2.5 mg vs
placebo
RR (95% CI)
Apixaban
5 mg vs placebo
RR (95% CI)
Apixaban
2.5 mg vs 5 mg
RR (95% CI)
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: 699 - 708

38. 38
Extended Treatment of VTE
Risk-Benefit of DOAC and ASA vs. Placebo
DOAC ASA
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: 2499-510, N Engl J Med 2013; 368: 699 – 708,
N Engl J Med 2012; 366: 1959-67, N Engl J Med 2012; 367: 1979-87

39. Treatment of Venous Thromboembolism
Vitamin K Antagonists
LMWH
Oral XaI or dabigatran
Heparin
LMWH
Fondaparinux
Thrombolysis
Thrombus Removal
IVC filter
Rivaroxaban
Apixaban
Initial (acute) treatment
Long term-treatment
Vitamin K Antagonists
ASA 100 mg
Oral XaI or dabigatran
Extended treatment
5 to 10 days 3 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; 28:370-372

41. Fatal PE More Common in Medical
Patients Than Surgical Patients
75%
Sandler DA, et al. J R Soc Med. 1989;82:203-205.
25%
Medical patients
Surgical patients

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: 381-453.
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: 625-632.

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
Kahn et al. CHEST 2012; 141:(2 Suppl): e195S-226S

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) - 1.5 % + 0.5 %
enoxaparin 40 mg od NNT 67 NNH 200
MAGELLAN (n= 8,101) - 1.3 % + 0.7 %
rivavoxaban 10 mg od NNT 77 NNH 143
ADOPT (n= 6,528) - 0.39 % (NS) + 0.3 %
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: 513 - 523
Goldhaber et al. N Engl J Med 2011; 365: 2167-2177

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)
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

48. We’re starting a global movement.
Help us stop blood clots and save lives.
Join us and 100+ organizations from around the world.
Learn how at WorldThrombosisDay.org
WorldThrombosisDay
@ThrombosisDay #JoinWTDay #WTDay14
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