Keynote lecture: Oral anticoagulation and DVT What is the evidence? Is there a need to anticoagulate every lower leg DVT?
Disclosure Speaker name:...sebastian Schellong... I have the following potential conflicts of interest to report: X X Consulting (Boehringer, Bayer, BMS, Daiichi Sankyo, Aspen) Employment in industry Stockholder of a healthcare company Owner of a healthcare company Other: speaker fees (Boehringer, Bayer, BMS, Daiichi Sankyo, Aspen) I do not have any potential conflict of interest 2
Therapy of VTE acute intermediate long term initial early maintenance long term maintenance Anticoagulation Thrombolysis Surgery Compression Therapy 3
Direct oral anticoagulants Drug Rivaroxaban(3) Apixaban(1;2) Edoxaban(5) Dabigatran(4) T max 2-4 h 3-4 h 1-2 h 0,5-2 h Bioavailability 80-100 % (man) 49 % (man) 62 % (man) 6,5 % (man) Potential for drug-drug interactions CYP3A4/ P-GP-Inhibitors CYP3A4/ P-GP- Inhibitors P-GP- Inhibitors P-GP- Inhibitors Proteinbinding 92-95 % 87 % 55 % 35 % t 1/2 5-13 h ~12 h 10-14 h 12-14 h Renal clearance 33 % 27 % 50 % 80 % 4
Acute VTE studies with novel oral anticoagulants Hokusai-VTE EINSTEIN DVT EINSTEIN PE AMPLIFY RECOVER RECOVER 2 Drug Edoxaban Rivaroxaban Apixaban Dabigatran Study design Double-blind Open-label Double-blind Double-blind Heparin lead-in* At least 5 days None None At least 5 days Dosing schedule Edoxaban 60 mg qd (30 mg qd) Rivaroxaban 15 mg bid x 3 weeks followed by 20 mg qd Apixaban 10 mg bid x 7 days followed by 5 mg bid Dabigatran 150 mg bid NI margin 1.5 2.0 1.8 2.75 Treatment duration Flexible 3 to 12 months Pre-specified 3, 6, or 12 months 6 months 6 months 5
Acute VTE studies with novel oral anticoagulants 6
Acute VTE studies with novel oral anticoagulants The HOKUSAI VTE Investigators: N Engl J Med 2013;369:1406-15; EINSTEN-DVT: The EINSTEIN. Investigators NEJM 2010; 363: 2499-2510. EINSTEIN-PE: The EINSTEIN-PE Investigators NEJM 2012; 366: 1287-97; AMPLIFY: Agnelli G et al. N Engl J Med 2013; 369: 799-808; RE_COVER: Schulman S et al. New Engl J Med 2009; 361:2342-52; RE- COVER2:Schulman S et al. Lancet 2013;
Metaanalysis 8
Metaanalysis 9
Metaanalysis 10
Approved treatment regimens of VTE Sequential therapy Traditional standard Sequential therapy NMH* s.c. VKA day 1 min. 3 months RE-COVER: Dabigatran Hokusai-VTE: Edoxaban NMH* s.c. Dabigatran 150mg b.i.d. / Edoxaban 60mg o.d. day 1 day 6-11 min. 3 months Monotherapy EINSTEIN-DVT/PE: Rivaroxaban Rivaroxaban 15mg b.i.d. for 3 weeks followed by 20 mg o.d. AMPLIFY: Apixaban *or UFH or Fondaparinux Apixaban 10mg b.i.d. for 1 week followed by 5 mg b.i.d. day 1 min. 3 months 11
Definition Small clot in the leg (ICVT) Distal Veins: Paired axial calf veins, calf muscle veins (soleal, gastrocnemial) Deep veins: axial calf veins as well as calf muscle veins Distal DVT: Isolated axial calf vein thrombosis Isolated calf muscle vein thrombosis Combined (Isolated calf vein thrombosis ICVT) Not included: Popliteal vein Trifurcation area (confluens region) 12
Ultrasound of distal veins Frequency Elias Schellong Stevens Subramaniam Bernardi Sevestre All DVT Prox/All Dist/All MVT/Dist 204 / 623 32.8% 275 / 1646 16.7% 61 / 445 13.7% 113 / 526 21.5% 278 / 1053 26.3% 1023 / 3871 26.4% 112 / 204 54.9% 121 / 275 44% 42 / 61 68.8% 49 / 113 43.4% 213 / 278 77% 454 / 1023 44% 92 / 204 45.1% 154 / 275 56% 19 / 61 31.2% 64 / 113 56.6% 65 / 278 23% 569 / 1006 56% n.r. 76 / 154 49.4% DVT = deep vein thrombosis; prox = proximal; dist = distal; MVT = muscle vein thrombosis; n.r. = not reported n.r. n.r. n.r. n.r. 13
MASTERS registry Italy Palareti et al Thromb Haemost 2008; 99:241-4 14
Natural history of VTE Pulmonary embolism Abortion Femoral / Iliac DVT Abortion Propagation Risk factor Propagation Risk factor Trifurcation / Popliteal DVT Propagation Abortion Risk factor Deep calf vein thrombosis Propagation Abortion Risk factor Muscle vein thrombosis 15
CALTHRO-study 3470 pts with suspected DVT 370 (10.7%) proximal DVT by CUS 431 Patienten No proximal DVT High clinical probability and/or positive D-Dimer Serial CUS after 5-7 days In parallel: blinded CCUS Blinded CCUS: 65 patients with ICVT Serial CUS: 2 proximal DVT (both with former ICVT) 3 mo FU: ICVT pos 1 prox DVT, 1 PE ICVT neg 1 prox DVT 0 PE Palareti G et al, Thromb Haemost 2010 16
Natural history Galanaud et al, JTH 2014 17
CACTUS trial Righini et al, Lancet Haematol 2016 18
CACTUS trial NMH Placebo n=126 n=133 Sympt. Prox. DVT/PE (ITT) 3.3% 5.4% p=0.54 Sympt. Prox. DVT/PE (PP) 3.6% 5.6% p=0.55 ISTH major/crnm bleeding 4.1% 0.0% p=0.03 Righini et al, Lancet Haematol 2016 19
Metaanalysis of Treatment for ICVT Franco et al, JTH 2017; 15:1142-54 20
Metaanalysis of Treatment for ICVT Anticoagulation vs no anticoagulation Recurrent VTE after 3 mo 0.50 [0.31-0.79] NNT 20 Pulmonary Embolism 0.48 [0.25-0.91] NNT 100 Any bleed 2.41 [1.32-4.39] NNH 29 Major bleed 0.64 [0.15-2.73] Anticoagulation > 6 weeks vs 6 weeks Recurrent VTE after 3 mo 0.39 [0.17-0.90] Any bleed 2.07 [1.07-4.01] Major bleed 3.25 [0.53-20.0] Franco et al, JTH 2017; 15:1142-54 21
ACCP Guidelines 2016 ICVT ICVT provoked by surgery or by nonsurgical transient risk factor: Suggest anticoagulation 3 mo over shorter period Recommend anticoagulation 3 mo over longer timelimited period (eg. 6, 12, or24 mo) Recommend anticoagulation 3 mo over extended therapy (without a defined time limit) Remarks: Duration of treatment of patients with isolated distal DVT refers to patients in whom a decision has been made to treat with anticoagulation therapy; however, it is anticipated that not all patiens who are diagnosed with isolated distal DVT will be prescribed anticoagulants. 22
ACCP Guidelines 2016 ICVT Anticoagulation in case of D-Dimer is positive (particularly when markedly so without an alternative reason) thrombosis is extensive (eg. > 5 cm in length, involves multiple veins, > 7 mm in diameter) thrombosis is close to the proximal veins there is no reversible provoking factor for DVT active cancer history of VTE inpatient status 23
Discussion 24