spontane und tumor-assoziierte vte: womit wie … und tumor-assoziierte vte: womit wie lange...
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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