Spontane und Tumor-assoziierte VTE:

womit wie lange antikoagulieren

Paul Kyrle

Allgemeines Krankenhaus Wien

Disclosures relevant for this presentation

Consultancies, member of advisory boards, speaker fees

Boehringer-IngelheimBayerDaiichi-SankyoBristol Myers SquibbPfizer

Spontane VTE - unprovoked VTE

Unprovoked VTE No provoking risk factor (transient or persistent)

Major transient risk factorsSurgery with general anesthesia for greater than 30 minutesConfined to bed in hospital for at least 3 days with an acute illnessCesarean section

Minor transient risk factorsSurgery with general anesthesia for less than 30 minutesAdmission to hospital for less than 3 days with an acute illnessEstrogen therapy, pregnancy or puerperiumConfined to bed out of hospital for at least 3 days with an acute illnessLeg injury associated with reduced mobility for at least 3 days

Persistent risk factors Active cancer, inflammatory bowel disease

Kearon, Ageno & Kyrle, JTH 2016

Categorization of VTE (unprovoked vs. provoked)

Unprovoked VTE No provoking risk factor (transient or persistent)

Major transient risk factorsSurgery with general anesthesia for greater than 30 minutesConfined to bed in hospital for at least 3 days with an acute illnessCesarean section

Minor transient risk factorsSurgery with general anesthesia for less than 30 minutesAdmission to hospital for less than 3 days with an acute illnessEstrogen therapy, pregnancy or puerperiumConfined to bed out of hospital for at least 3 days with an acute illnessLeg injury associated with reduced mobility for at least 3 days

Persistent risk factors Active cancer, inflammatory bowel disease

Kearon, Ageno & Kyrle, JTH 2016

Categorization of VTE (unprovoked vs. provoked)

Thrombolysis

Anticoagulation

Mechanical thrombus removal

Vena cava filter

Treatment of VTE

Heparin (LMWH) vitamin K antagonists (VKA)

(Heparin ) direct oral anticoagulant (DOAC)

Anticoagulation

TF-FVIIa

FXa

FIIa

FVIIIa, FVa

FIXa

Fibrin

FXIaRivaroxaban

Apixaban

Edoxaban

Dabigatran

courtesy of Ansgar Weltermann, modified

DOAC

DOAC

Rapid onset (~3 hrs)

Rapid offset (t1/2 ~12 hrs)

No food interactions

Few drug interactions

Flat dose/response curve

Why DOAC and not VKA?

VKA

Slow onset

Slow offset

Food interaction

Abundant drug interactions

Steep dose/response curve

Monitoring requiredMonitoring not required

12/2009 - 12/2013:

7 non-inferiority studies

3 superiority studies

32.094 pts

DOAC

DOAC vs. VKA - Overall efficacy

van Es, Blood 2015

RRR 10%

DOAC vs. VKA - Overall major bleeding

van Es, Blood 2015

RRR 39%

Apixaban

Rivaroxaban

Combined0.45 (0.27, 0.77)

Patients > 75 yrs – VTE or VTE-related death

Sandar, JAGS 2014

Dabigatran

Apixaban

Rivaroxaban

Combined1.02 (0.73, 1.43)

Patients > 75 yrs – major or CRNM bleeding

Sandar, JAGS 2014

EnoxaparinHeparin Dabigatran 150 mg BID

Apixaban 5 mg BID **

Rivaroxaban 20 mg OD *

AMPLIFY ( 2013)

HOKUSAI ( 2013) EnoxaparinHeparin Edoxaban 60 mg OD

EINSTEIN DVT, PE (2010)

Treatment of VTE with a DOAC

* 15 mg BID for 3 weeks

** 10 mg BID for 1 week

RE-COVER 1+2 (2009, 2013)

Risk of recurrence in pts with a 1st unprovoked VTE

Kyrle & Eichinger, Lancet 2010

ACCP Guideline

Kearon, Chest 2016

In patients with a first VTE that is an unprovoked

proximal DVT of the leg or PE and who have a low

or moderate bleeding risk, we suggest extended

anticoagulant therapy (no scheduled stop date)

over 3 months of therapy (Grade 2B).

Unprovoked VTE – duration of treatment

Identification of patients with a high recurrence risk

Laboratory thrombophilia screening

Clinical characteristics

Prediction tools

Laboratory thrombophilia screening

Risk factors for 1st rather than 2nd VTE

Studies showing a clinical benefit are lacking

Normal test result in 30% of pts with recurrence

Unwanted medical consequences (over/undertreatment)

Emotional discomfort (patients/relatives)

not warranted

Clinical characteristics

Sex

Site of thrombosis

Likelihood of Recurrent VTE According to Sex

Kyrle, N Engl J Med 2004;350:2558-2563

ACCP Guideline

Kearon, Chest 2016

Remark: Patient sex and D-dimer level measured a

month after stopping anticoagulant therapy may

influence the decision to stop or extend anticoagulant

therapy.

Risk of recurrence in pts with 1st unprovoked VTE

Kyrle, JTH 2016

Risk of recurrence in pts with 1st unprovoked VTE

Kyrle, JTH 2016

Prediction tools

Rodger and coworkers (CMJA 2008)

Vienna Prediction Model (Eichinger Circulation 2010)

DASH (DD, age, sex, hormones; Tosetto JTH 2012)

http:/www.meduniwien.ac.at/user/georg.heinze/zipfile/

Circulation 2010;121:1630-1636 data supplement (free access)

Risk calculator

Vienna Prediction Model

JTH, 2015

Nomogram to predict recurrence:

Vienna Prediction Model

Extended treatment of VTE

VKA (INR 2-3)

Rivaroxaban 20mg tgl.

Dabigatran 2 x 150mg tgl.

Apixaban 2 x 2.5mg tgl.

Edoxaban 1 x 60mg tgl.

Extended treatment of VTE

VKA (INR 2-3)

Rivaroxaban 20mg tgl.

Dabigatran 2 x 150mg tgl.

Apixaban 2 x 2.5mg tgl.

Edoxaban 1 x 60mg tgl.

Cancer-associated VTE

Lee, N Engl J Med 2003; Parpia, Contemporary Clinical Trials 2011

Competing riskKaplan-Meier

HR 0.48; p=0.002

Major bleeding: 6% (LMWH) vs. 4% (VKA), p=0.3

CLOT: dalteparin vs. warfarin in cancer-associated VTE

Clot

Catch

Lee, JAMA 2015;314(7):677-686

CATCH: tinzaparin vs. warfarin in cancer-associated VTE

DOAC in cancer-associated VTE

licenced, but …

guideline panels recommend against their use

no comparison against LMWH

too few pts included in studies

interaction with anti-cancer therapy

reduced absorption from gastrointestinal tract

In “cancer-associated” thrombosis, as long-term (first

3 months) anticoagulant therapy, we suggest LMWH

over VKA therapy (Grade 2B), dabigatran (Grade

2C), rivaroxaban (Grade 2C), apixaban (Grade 2C),

or edoxaban (Grade 2C).

ACCP Guideline

Kearon, Chest 2016

Efficacy

2.0% vs. 2.2% (~ 27.000 patients)

Cancer: 3.4% vs. 5.9% (~ 1.500 patients)

No cancer: 2.4% vs. 2.5%

DOAC vs. VKA in cancer associated VTE

Safety

1.1% vs. 1.8% (~ 27.000 patients)

Cancer: 2.9% vs. 3.7% (~ 1.500 patients)

No Cancer: 0.9% vs. 1.6%

DOAC vs. VKA in cancer associated VTE

Personal approach – drug regimen

LMWH (therapeutic dose, once daily)

acute VTE (first 4 weeks)

during systemic antitumor treatment

vomiting, diarrhea

otherwise DOAC

no VKA

In patients with DVT of the leg or PE and active

cancer and who (i) do not have a high bleeding risk,

we recommend extended anticoagulant therapy (no

scheduled stop date) over 3 months of therapy (Grade

1B), or (ii) have a high bleeding risk, we suggest

extended anticoagulant therapy (no scheduled stop

date) over 3 months of therapy (Grade 2B).

ACCP Guideline

Kearon, Chest 2016

Personal approach – duration

Remission

3 – 6 months

Active cancer

Indefinite

According to bleeding risk and patient preferences

Summary

Unprovoked VTE

DOAC are at least as effective and safe as VKA

Extended anticoagulation should be considerednted, in particular in men with proximal DVT or PE

Cancer-associated VTE

LMWH still first choice

DOAC are a valuable alternative under certain conditions

Duration depends on disease activity and patient preference

Anticoagulant treatment of VTE: a changing world