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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

Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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Page 1: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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

Page 2: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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

Page 3: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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

Page 4: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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

Page 5: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

Venous Thromboembolism (VTE)

Image from VF Tapson. NEJM 2008; 358: 1037

Deep-vein thrombosis (DVT)

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

60% of non-fatal cases

Proximal DVT prognostic marker

for recurrence and mortality

Page 6: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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.

Page 7: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

- 7 -

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

Page 8: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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

Page 9: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

Goals of Treatment for VTE

Prevent death from pulmonary embolism

Prevent symptomatic recurrent VTE25% risk of symptomatic recurrent VTE during 3 if inadequate therapy

Prevent and/or reduce morbidity frompost-thrombotic syndrome (PTS) 25% at 2 yr

chronic pulmonary hypertension 4% at 2 yr

Minimize the risk of bleeding and other side effects

Page 10: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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

Page 11: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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 DVTanticoagulant 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

Page 12: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

5 to 10 days 3 to 6 months > 6 months

Vitamin K Antagonists

LMWH

Heparin

LMWH

Fondaparinux

Thrombolysis

Thrombus Removal

IVC filter

Treatment of Venous Thromboembolism

Initial treatment

Long term-treatment

Extended treatment

Vitamin K Antagonists

Page 13: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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

Page 14: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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 PE2.5 mg orally twice daily

Page 15: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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

Page 16: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

Clinical Trials of Rivaroxaban for VTE

16

N=1,197

Double-blind, superiority

Rivaroxaban 20 mg od

Placebo

6 or 12 months

ROpen-label, non-inferiority

N~4,50015 mg bid

Rivaroxaban

Day 21

Enoxaparin bid for at least 5 days, plus

VKA target INR 2.5 (INR range 2–3)

20 mg od

Rivaroxaban

R

3, 6, or 12 months

15 mg bidN=3,449

Rivaroxaban

Day 21

Enoxaparin bid for at least 5 days, plus

VKA target INR 2.5 (INR range 2–3)

3, 6, or 12 months

20 mg od

Rivaroxaban

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

Page 17: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

EINSTEIN DVT Trial Recurrent VTE

1717

Cu

mu

lati

ve e

ven

t ra

te (

%)

0 30 60 90 120 150 180 210 240 270 300 330 360

0

1.0

2.0

3.0Rivaroxaban (N=1,731)

Enoxaparin/VKA (N=1,718)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)

1.00 0

0.44 1.040.68

Hazard ratio

Rivaroxaban

superior

Rivaroxaban

non-inferior

Rivaroxaban

inferior

p=0.076 for superiority (two-sided) p<0.0001 for non-inferiority (one-sided)

2.00

N Engl J Med 2010;363:2499-510

TTR = 57.7%

Page 18: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

EINSTEIN DVT Trial Bleeding Outcomes

1818

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

and/or transfusion of ≥2 units10 (0.6) 12 (0.7)

Clinically relevant non-major bleeding 126 (7.3) 119 (7.0)

Safety population N Engl J Med 2010; 363: 2499-510

Page 19: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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 wherePE cannot be ruled out

10 (0.4) 6 (0.2)

Rivaroxaban

superior

Rivaroxaban

non-inferior

Rivaroxaban

inferior

P=0.0026 for non-inferiority

(one-sided)

p=0.57 for superiority

(two-sided)

1.00 0 2.00

0.75 1.12 1.68

Absolute risk difference 0.24% , 95% CI - 0.5 to 1.02

HR

N Engl J Med 2012; 366:1287 -1297

Page 20: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

EINSTEIN PE Trial Bleeding Outcomes

2020

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

and/or transfusion of ≥2 units17 (0.7) 26 (1.1)

Clinically relevant non-major bleeding 223 (9.2) 222 (9.2)

Safety population N Engl J Med 2012; 366: 1287-1297

Page 21: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

Safety population

3.0

2.5

2.0

1.5

1.0

0.0

0.5

0 30 60 90 120 150 180 210 240 270 300 330 360

Cu

mu

lati

ve e

ven

t ra

te (

%)

Time to event (days)

Rivaroxaban

N=2412

Enoxaparin/VKA

N=2405

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

EINSTEIN PE Trial Major bleeding

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

N Engl J Med 2012; 366: 1287-1297

TTR = 62.7%

Page 22: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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

En

d o

f T

rea

tme

nt

Sa

fety

Fo

llow

-up

6 months 30-dayDay 1

Enoxaparin

1 mg/kg BID sc

Warfarin (INR 2–3)

AMPLIFY Trial

Agnelli et al. N Engl J Med 2013;369: 799 - 808

Page 23: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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: DVT38/1698

(2.2)

47/1736

(2.7)0.83 (0.54–1.26)

Index event: PE ± DVT21/900

(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

Page 24: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

AMPLIFY Trial

First Recurrent VTE or VTE-related Death

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

Perc

ent

of patients

0 30 60 90 120 150 180 210 240 270 300

3

2

1

0

Apixaban (59/2691)

Enoxaparin/Warfarin ( 71/2704)

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 deathNo. of patients at risk

TTR, time in therapeutic range. Agnelli et al N Engl J Med 2013;369: 799 - 808

Page 25: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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)

<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)

Agnelli et al N Engl J Med 2013; 369: 799 - 808

NNT for major bleeding = 83 NNT for CRNM bleeding = 24

Page 26: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

AMPLIFY Trial Major Bleeding

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

Perc

en

t of patients

2

1

0

0 30 60 90 120 150 180 210 240 270 300

Enoxaparin/Warfarin (events: 49/2689)

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 bleedingNo. 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

Page 27: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

R

edoxaban 60 mg/30 mg

warfarin

3 Months 12 MonthsDay 6- 12

Sham INR

INR

Day 1- 5

Objectively confirmed VTE Stratified randomization:

PE or DVTRisk factorsEdoxaban dose adjustment

Hokusai VTE Study Design

edoxabanplacebo edoxaban warfarinplacebo warfarin(LMW) heparin

Raskob et al. J Thromb Haemost 2013;11:1287-94

Hokusai -VTE Investigators N Engl J Med 2013; 369:1406-15

Page 28: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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

Page 29: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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. (%)

298 (7.2) 368 (8.9) 0.80

(0.68-0.93)

0.004 superiority

29† some patients have more than 1 bleeding

N Engl J Med 2013; 369:1406-15

NNT = 56

Page 30: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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, 2500.1 % 0.2 %

van Es N et al. Blood 2014; doi 10.1182/blood-2014-04-571233

Page 31: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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

Page 32: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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

Page 33: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

Stop

anticoagulant

therapy in all

Continue

anticoagulant

therapy in all

Identify selected patients at low risk

to stop anticoagulant therapy

Management of unprovoked VTE

3 months

ASA therapy

Page 34: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

Duration of Anticoagulant Therapy

Factors Influencing Decision

Risk of recurrent VTE

Risk of bleeding

Patient preference

Page 35: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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

En

d o

f T

rea

tme

nt

Safe

ty F

ollo

w-u

p

12 Months 30 DaysDay 1

AMPLIFY Extended Treatment Trial

Agnelli et al N Engl J Med 2013; 368: 699 - 708

Page 36: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

AMPLIFY Extended Treatment Trial Recurrent VTE

100

80

60

40

20

0

0 1 2 3 4 5 6 7 8 9 10 11 12

Cum

ula

tive e

vent ra

te (

%)

Months

1211109876543210

0

1

2

3

4

5

6

7

8

9

10

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

Cum

ula

tive e

vent ra

te (

%)

Agnelli et alN Engl J Med 2013; 368: 699 - 708

NNT to prevent one

recurrent event = 14

Page 37: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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

Page 38: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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

Page 39: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

5 to 10 days 3 to 6 months > 6 months

Vitamin K Antagonists

LMWH

Oral XaI or dabigatran

Heparin

LMWH

Fondaparinux

Thrombolysis

Thrombus Removal

IVC filter

Rivaroxaban

Apixaban

Treatment of Venous Thromboembolism

Initial (acute) treatment

Long term-treatment

Extended treatment

Vitamin K Antagonists

ASA 100 mg

Oral XaI or dabigatran

Page 40: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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

Page 41: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

Fatal PE More Common in Medical Patients Than Surgical Patients

Sandler DA, et al. J R Soc Med. 1989;82:203-205.

75%

25%

Medical patients

Surgical patients

Page 42: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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.

Page 43: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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

Page 44: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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

Clinical Trials of Extended Duration (28 - 35 days)

vs 10 days of Prophylaxis in Medical Patients

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

Page 45: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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

Page 46: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

Primary Endpoint: Composite of Symptomatic VTE or VTE-Related Death

Sample size Placebo RRR ARR Events Power for

superiority

2 sided α

8,000 2.5% 40% 1.0% 161 90% 5%

Estimated Sample Size

Page 47: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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

Page 48: Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden

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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