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Acute behandeling van

longembolie

Peter Verhamme

Bloedings- en Vaatziekten

UZ Leuven

Disclosures

Research support and/or honoraria:

Bayer, Boehringer-Ingelheim,

Daiichi-Sankyo, Pfizer, BMS,

Sanofi, Leo-pharma

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Veneuze Tromboembolie

Controversies in de behandeling van

Longembolie

• Is behandeling van DVT en LE verschillend?

• NOACs voor LE?

met of zonder LMWH?

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Is behandeling van DVT en LE anders?

Is behandeling van DVT en LE anders?

Lessons from idraparinux

Idraparinux vs. Heparin/Vitamin K antagonist Open-label, non-inferiority study

Recurrent VTE

DVT PE

van Gogh Investigators. N Engl J Med 2007;357:1094-104.

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Is behandeling van DVT en LE anders?

Lessons from Ximelagatran

Ximelagatran: Eén dosis, geen LMWH

Fiessinger et al., THRIVE Treatment Study Investigators. JAMA 2005;293:681-9.

Initial treatment

5 days–3 weeks

Treatment of VTE

Continued treatment

at least 3 months

Secondary prevention

long-term

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Treatment of VTE

Continued treatment

at least 3 months

Secondary prevention

long-term

Initial treatment

5 days–3 weeks

LMWH + VKA (INR 2–3)

LMWH + VKA (INR 2‒3)

Initial treatment

5 days–3 weeks

Treatment of VTE

Continued treatment

at least 3 months

Secondary prevention

long-term

+ Dabigatran 150 mg BD

+ Edoxaban 60 mg OD

Rivaroxaban15 mg BD 3 weeks 20 mg OD

Apixaban10 mg BD 1 week 5 mg BD

1. Schulman et al. N Engl J Med 2009;361:2342–2352; 2. Schulman et al. Circulation 2014; 3. EINSTEIN Investigators.

N Engl J Med 2010;363:2499-510; 4. EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287-97; 5. Agnelli et al.;

AMPLIFY Investigators. N Engl J Med 2013;369:799-808; 6. The Hokusai-VTE Investigators. N Engl J Med

2013;369:1406-1415.

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LMWH + VKA (INR 2‒3)

Initial treatment

5 days–3 weeks

Treatment of VTE

Continued treatment

at least 3 months

Secondary prevention

long-term

+ Dabigatran 150 mg BD

+ Edoxaban 60 mg OD

Rivaroxaban15 mg BD 3 weeks 20 mg OD

Apixaban10 mg BD 1 week 5 mg BD

1. Schulman et al. N Engl J Med 2009;361:2342–2352; 2. Schulman et al. Circulation 2014; 3. EINSTEIN Investigators.

N Engl J Med 2010;363:2499-510; 4. EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287-97; 5. Agnelli et al.;

AMPLIFY Investigators. N Engl J Med 2013;369:799-808; 6. The Hokusai-VTE Investigators. N Engl J Med

2013;369:1406-1415.

Is it true for

both

DVT and PE?

Efficacy DVT/PE

Van Es et al. Blood 2014;124:1968-75.

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Which types of major bleeding are reduced?

What is the truth about gastrointestinal

bleeding?

And bleeding?

Bleeding components

Van Es et al. Blood 2014;124:1968-75.

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LMWH + VKA (INR 2-3)

Initial treatment

5 days – 3 weeks

Treatment of VTE

Continued Treatment

At least 3 months

Secondary Prevention

Long-term

+ Dabigatran 150 mg BD

+ Edoxaban 60 mg OD

Rivaroxaban15 mg BD 3 weeks 20 mg OD

Apixaban10 mg BD 1 week 5 mg BD

Are patients

with “serious”PE included?

Risk stratification of PE

ESC guidelines on acute PE; EHJ 2014.

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Simplified PESI score for assessing the

likelihood of PE-related death

Parameter Score

Age 80 years 1

History of cancer 1

Chronic cardiopulmonary disease 1

Pulse 110 beats/min 1

Systolic blood pressure 100 mm Hg 1

Arterial oxyhaemoglobin saturation level 90% 1

1 point or more = high risk of early death Jiménez D, Arch Intern Med 2010;170:1383-9.

Risk stratification of PE

ESC guidelines on acute PE; EHJ 2014.

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S. Konstantidines et al. Nejm 2014

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S. Konstantidines et al. Nejm 2014

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R

edoxaban

warfarin

3 months 6 months 12

months

initial (LMW) heparin

placebo warfarin

placebo edoxaban

Day 6‒12

Sham INR

INR

Day 1‒5

Symptomatic

confirmed

VTE event

The HOKUSAI-VTE Study

The Hokusai-VTE Investigators. N Engl J Med 2013;369:1406-1415.

HOKUSAI-VTE: Efficacy Outcomes

Edoxaban

(N=4118)

Warfarin

(N=4122)

Hazard ratio

(95% CI) P value

First recurrent VTE (%)

Overall study period 3.2 3.50.89

(0.70‒1.13)<0.001

Non-inferiority

Patients with index PE** 2.8 3.90.73

(0.50‒1.06)

Subgroup more severe PE

(ProBNP)

n/N (%)

15/454

3.3%

30/485

6.2%

0.52

(0.28‒0.98)

* Denominator is number of patients with index DVT: 2468 and 2453 in edoxaban and warfarin groups, respectively

** Denominator is number of patients with index PE: 1650 and 1669 in edoxaban and warfarin groups, respectively

The Hokusai-VTE Investigators. N Engl J Med 2013;369:1406-1415.

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What else does the clinician

want to know?

What is the efficacy/safety in the frail and

elderly?

Elderly

Van Es et al. Blood 2014;124:1968-75.

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Controversies in the Management of

Pulmonary Embolism

• Is treatment of PE different than of DVT?

• NOACs for PE: With or without LMWH?

• Will NOACs change treatment duration?

Duration of therapy – Unprovoked PE

• We recommend that after 3 months of

anticoagulant therapy, all patients with

unprovoked PE should be evaluated for the risk-

benefit ratio of long-term therapy (Grade 1C).

ACCP Guidelines, Chest 2008;133(6 Suppl)

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Duration of therapy – Unprovoked PE

• We recommend that after 3 months of

anticoagulant therapy, all patients with

unprovoked PE should be evaluated for the risk-

benefit ratio of long-term therapy (Grade 1C).

• For patients with a first unprovoked PE in whom

risk factors for bleeding are absent and for whom

good anticoagulant monitoring is achievable, we

recommend long-term treatment (Grade 1A).

ACCP Guidelines, Chest 2008;133(6 Suppl)

Secondary prevention of VTE

DURAC II1

(odds ratio)LAFIT2 PREVENT3 Einstein

Ext5THRIVE III6 AMPLIFY

Ext8

1

0.9

0.7

0.5

0.2

0

0.8

0.6

0.4

0.3

0.1

WARFASA9 ASPIRE10RE-SONATE7

HR

(9

5%

CI)

eff

icac

y ac

tive

dru

g vs

pla

ceb

o

ASAApixaban

DabigatranRivaroxabanXimelagatranWarfarin Low dose

Warfarin

1. Schulman S et al N Engl J Med 1997;336:393–8; 2. Kearon C et al. N Engl J Med 199;340:901–7; 3. Ridker PM et al N Engl J Med 2003;348:1425–34;

4. The van Gogh Investigators N Engl J Med 2007;357:1105–12; 5. The EINSTEIN Investigators N Engl J Med 2010;363:2499–510;

6. Schulman S et al. N Engl J Med 2003;349:1713–21; 7. Schulman S et al. N Engl J Med 2013;368:709–18; 8. Agnelli G et al. N Engl J Med 2013;368:699–708;

9. Becattini C et al. N Engl J Med 2012;366:1959–67; 10. Brighton T et al. N Engl J Med 2012;367:1979–87

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Secondary prevention of VTE

DURAC II1

(odds ratio)LAFIT2 PREVENT3 Einstein

Ext5THRIVE III6 AMPLIFY

Ext8

1

0.9

0.7

0.5

0.2

0

0.8

0.6

0.4

0.3

0.1

WARFASA9 ASPIRE10RE-SONATE7

HR

(9

5%

CI)

eff

icac

y ac

tive

dru

g vs

pla

ceb

o

ASAApixaban

DabigatranRivaroxabanXimelagatranWarfarin Low dose

Warfarin

1. Schulman S et al N Engl J Med 1997;336:393–8; 2. Kearon C et al. N Engl J Med 199;340:901–7; 3. Ridker PM et al N Engl J Med 2003;348:1425–34;

4. The van Gogh Investigators N Engl J Med 2007;357:1105–12; 5. The EINSTEIN Investigators N Engl J Med 2010;363:2499–510;

6. Schulman S et al. N Engl J Med 2003;349:1713–21; 7. Schulman S et al. N Engl J Med 2013;368:709–18; 8. Agnelli G et al. N Engl J Med 2013;368:699–708;

9. Becattini C et al. N Engl J Med 2012;366:1959–67; 10. Brighton T et al. N Engl J Med 2012;367:1979–87

Secondary prevention of VTE

DURAC II1

(odds ratio)LAFIT2 PREVENT3 Einstein

Ext5THRIVE III6 AMPLIFY

Ext8

1

0.9

0.7

0.5

0.2

0

0.8

0.6

0.4

0.3

0.1

WARFASA9 ASPIRE10RE-SONATE7

HR

(9

5%

CI)

eff

icac

y ac

tive

dru

g vs

pla

ceb

o

ASAApixaban

DabigatranRivaroxabanXimelagatranWarfarin Low dose

Warfarin

1. Schulman S et al N Engl J Med 1997;336:393–8; 2. Kearon C et al. N Engl J Med 199;340:901–7; 3. Ridker PM et al N Engl J Med 2003;348:1425–34;

4. The van Gogh Investigators N Engl J Med 2007;357:1105–12; 5. The EINSTEIN Investigators N Engl J Med 2010;363:2499–510;

6. Schulman S et al. N Engl J Med 2003;349:1713–21; 7. Schulman S et al. N Engl J Med 2013;368:709–18; 8. Agnelli G et al. N Engl J Med 2013;368:699–708;

9. Becattini C et al. N Engl J Med 2012;366:1959–67; 10. Brighton T et al. N Engl J Med 2012;367:1979–87

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LMWH + VKA (INR 2–3) NR 2-3

Initial treatment

5 days–3 weeks

Treatment of VTE

Continued treatment

at least 3 months

Secondary prevention

long-term

+ Dabigatran 150 mg BD

+ Edoxaban 60 mg OD 60 mg/30 mg OD

Rivaroxaban15 mg BD 3 weeks 20 mg OD

Apixaban10 mg BD 1 week 5 mg BD

150 mg/110 mg BD

20 mg /15 mg /10 mg OD

5 mg / 2.5 mg BD

Controversies in the Management of

Pulmonary Embolism

• Is treatment of PE different than of DVT?

• NOACs for PE: With or without LMWH?

• Will NOACs change treatment duration?

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