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-Ingelheim Bayer Daiichi-Sankyo Bristol Myers Squibb Pfizer
Spontane VTE - unprovoked VTE
Kearon, Ageno & Kyrle, JTH 2016 Categorization of VTE (unprovoked vs. provoked) Unprovoked VTE No provoking risk factor (transient or persistent) Major transient risk factors Surgery with general anesthesia for greater than 30 minutes Confined to bed in hospital for at least 3 days with an acute illness Cesarean section Minor transient risk factors Surgery with general anesthesia for less than 30 minutes Admission to hospital for less than 3 days with an acute illness Estrogen therapy, pregnancy or puerperium Confined to bed out of hospital for at least 3 days with an acute illness Leg 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 factors Surgery with general anesthesia for greater than 30 minutes Confined to bed in hospital for at least 3 days with an acute illness Cesarean section Minor transient risk factors Surgery with general anesthesia for less than 30 minutes Admission to hospital for less than 3 days with an acute illness Estrogen therapy, pregnancy or puerperium Confined to bed out of hospital for at least 3 days with an acute illness Leg injury associated with reduced mobility for at least 3 days Persistent risk factors Active cancer, inflammatory bowel disease
Treatment of VTE Thrombolysis Anticoagulation Mechanical thrombus removal Vena cava filter
Anticoagulation Heparin (LMWH) vitamin K antagonists (VKA) (Heparin ) direct oral anticoagulant (DOAC)
DOAC TF-FVIIa FIXa Rivaroxaban Apixaban Edoxaban FXa FVIIIa, FVa FXIa Dabigatran FIIa Fibrin courtesy of Ansgar Weltermann, modified
Why DOAC and not VKA? DOAC Rapid onset (~3 hrs) Rapid offset (t1/2 ~12 hrs) No food interactions Few drug interactions Flat dose/response curve Monitoring not required VKA Slow onset Slow offset Food interaction Abundant drug interactions Steep dose/response curve Monitoring required
DOAC 12/2009-12/2013: 7 non-inferiority studies 3 superiority studies 32.094 pts
DOAC vs. VKA - Overall efficacy RRR 10% van Es, Blood 2015
van Es, Blood 2015 DOAC vs. VKA - Overall major bleeding RRR 39%
Patients > 75 yrs VTE or VTE-related death Rivaroxaban Apixaban 0.45 (0.27, 0.77) Combined Sandar, JAGS 2014
Patients > 75 yrs major or CRNM bleeding Rivaroxaban Apixaban Dabigatran 1.02 (0.73, 1.43) Combined Sandar, JAGS 2014
Treatment of VTE with a DOAC RE-COVER 1+2 (2009, 2013) Enoxaparin Heparin Dabigatran 150 mg BID EINSTEIN DVT, PE (2010) Rivaroxaban 20 mg OD * AMPLIFY ( 2013) Apixaban 5 mg BID ** HOKUSAI ( 2013) Enoxaparin Heparin Edoxaban 60 mg OD * 15 mg BID for 3 weeks ** 10 mg BID for 1 week
Risk of recurrence in pts with a 1 st unprovoked VTE Kyrle & Eichinger, Lancet 2010
Kearon, Chest 2016 ACCP Guideline 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 1 st rather than 2 nd 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
Kearon, Chest 2016 ACCP Guideline 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 1 st unprovoked VTE Kyrle, JTH 2016
Risk of recurrence in pts with 1 st 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)
Vienna Prediction Model Risk calculator http:/www.meduniwien.ac.at/user/georg.heinze/zipfile/ Circulation 2010;121:1630-1636 data supplement (free access) 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
CLOT: dalteparin vs. warfarin in cancer-associated VTE Kaplan-Meier Competing risk HR 0.48; p=0.002 Major bleeding: 6% (LMWH) vs. 4% (VKA), p=0.3 Lee, N Engl J Med 2003; Parpia, Contemporary Clinical Trials 2011
Lee, JAMA 2015;314(7):677-686 CATCH: tinzaparin vs. warfarin in cancer-associated VTE Clot Catch
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
Kearon, Chest 2016 ACCP Guideline 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).
DOAC vs. VKA in cancer associated VTE 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%
Personal approach drug regimen LMWH (therapeutic dose, once daily) acute VTE (first 4 weeks) during systemic antitumor treatment vomiting, diarrhea otherwise DOAC no VKA
Kearon, Chest 2016 ACCP Guideline 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).
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