Status of anticoagulation therapy in 2016: Is there a need for venous revascularization? Rupert M. Bauersachs Dept. of Vascular Medicine, Darmstadt Center of Thrombosis Hemostasis, Mainz
Status of anticoagulation in 2016: Need for venous revascularization? Disclosures Research support / Principal Investigator : Bayer, BMS, Boehringer, Daiichi-Sankyo, Leo, Pfizer, Portola Consultant & Speakers Bureau: Bayer, BMS, Boehringer, Daiichi-Sankyo, Pfizer Rupert M. Bauersachs Dept. of Vascular Medicine, Darmstadt Center of Thrombosis Hemostasis, Mainz
Status of anticoagulation in 2016: Need for venous revascularization? Guidelines, State of the Art Current Evidence for Anticoagulation Need for Revascularization? Current Evidence
Guidelines, State of the Art Vasa European Journal of Vascular Medicine Supplement S/90 Interdisziplinäre S2 Leitlinie Diagnostik und Therapie der Venenthrombose und der Lungenembolie Kardiologe 2015 9:289 294 S2k-Leitlinie: Nr. 065-002. VASA 2016;45(S 90): in press. ACCP-Guidelines 2016 Chest. 2016;148(1): in press In proximal DVT we recommend long-term anticoagulant therapy over no such therapy (1B). we suggest dabigatran, rivaroxaban, apixaban or edoxaban over VKA therapy (all 2B). NOAC Meta-analyses: significant reduction in major bleeding 40% Significantly reduced intracranial and fatal bleedings and CR-NMB. Results consistent for several sub-groups, e.g. Body weight > 100 kg; GFR <60 ml/min; age > 75 y; cancer
Evidence: Which concepts have been studied? Standard-Therapy LMWH /VKA Heparin VKA Single-drug approach VTE MB CRB Rivaroxaban (Xarelto ) Single-drug 2x15 mg 3 wks 1x20 Rivaroxaban VTE MB CRB Apixaban (Eliquis ) Single-drug 2x10mg 1wk 2x5 mg Apixaban Dabigatran (Pradaxa ) LMWH Acute treatment Switching Parenteral AC 5d Dabigatran 2x 150 mg VTE MB CRB Edoxaban (Lixiana ) LMWH Acute treatment Parenteral AC 5d Edoxaban 1x60 mg VTE MB CRB Day 1 Day 5 11 Week 3
Evidence: Which concepts have been studied? Standard-Therapy LMWH /VKA Heparin VKA DVT PE Single-drug approach 0 5000 10000 Rivaroxaban (Xarelto ) Single-drug 2x15 mg 3 wks 1x20 Rivaroxaban DVT PE 0 5000 10000 Apixaban (Eliquis ) Single-drug 2x10mg 1wk 2x5 mg Apixaban DVT PE Dabigatran (Pradaxa ) LMWH Acute treatment Switching Parenteral AC 5d Dabigatran 2x 150 mg 0 5000 10000 DVT PE Edoxaban (Lixiana ) LMWH Acute treatment Parenteral AC 5d Edoxaban 1x60 mg 0 5000 10000 DVT PE Day 1 Day 5 11 Week 3 0 5000 10000
Evidence: Which concepts have been studied? Standard-Therapy LMWH /VKA Heparin VKA DVT PE Recurrent VTE RCT NOACs 0 5000 10000 15000 20000 25000 30000 PE PE DVT 0 5000 10000 15000 20000 25000 30000 Major Bleeding Es N, et al Blood. 2014 Sep 18;124(12):1968-75..
Evidence: Which concepts have been studied? Standard-Therapy LMWH /VKA Heparin VKA DVT PE RCT NOACs 0 5000 10000 15000 20000 25000 30000 DVT PE PE 0 5000 10000 15000 20000 25000 30000 RCT CDT PE with PTS as an endpoint 0 5000 10000 15000 20000 25000 30000
Revascularization Treatment N=90 CDT + Standard R 24 mts FU Rekanalisation 100% CDT Standard N=99 Standard 60 PTA Stents Aspiration Caval Filter 23 15 1 1 Inclusion Iliofemoral vein thrombosis: common iliac vein combined iliofemoral segment upper half of the thigh 75% 50% 25% 0% Partial Complete 50 40 30 20 10 0 Score >5 (6Mo) <5 = No PTS 5-9 = mild PTS 10-14 = moderate PTS 15 = severe PTS severe PTS Ulcer Enden T, Klow NE, Slagsvold CE, Sandvik L, Ghanima W, Hafsahl G, Holme PA, Holmen LO, Njaastad AM, Sandbaek G, Sandset PM. Longterm outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis the CaVenT study): a randomised controlled trial. Lancet 2012;6736:61875-61878
Revascularization Treatment R N=90 CDT + Standard 24 mts FU Rekanalisation 100% Quality of life CDT Standard N=99 Standard 1 75% 50% 25% 0% Partial Complete 0,8 0,6 0,4 0,2 0 EQ-5D (6 Mo) EQ-5D (24 Mo) Enden T, Wik HS, Kvam AK, Haig Y, Klow NE, Sandset PM. Health-related quality of life after catheter-directed thrombolysis for deep vein thrombosis: secondary outcomes of the randomised, non-blinded, parallel-group CaVenT study. BMJ Open. 2013;3(8):e002984.
Revascularization Treatment bleeding complications CDT N=90 *abdominal wall haematoma req. transfusion, compartment syndrome req. surgery puncture site haematoma Standard n=99 Total 22% 0 Severe* 3.3% 0 clin. relevant 5.6% 0 Peripheral neurolog. deficit Infection Puncture site 2 0 1 0 1 0,8 0,6 0,4 0,2 0 Quality of life CDT Standard EQ-5D (6 Mo) EQ-5D (24 Mo) Enden T, Wik HS, Kvam AK, Haig Y, Klow NE, Sandset PM. Health-related quality of life after catheter-directed thrombolysis for deep vein thrombosis: secondary outcomes of the randomised, non-blinded, parallel-group CaVenT study. BMJ Open. 2013;3(8):e002984.
Revascularization Treatment bleeding complications CDT N=90 *abdominal wall haematoma req. transfusion, compartment syndrome req. surgery puncture site haematoma Standard n=99 Total 22% 0 Severe* 3.3% 0 clin. relevant 5.6% 0 Peripheral neurolog. deficit Infection Puncture site 2 0 1 0 CDT Phlebography Puncture popliteal vein Flouroscopy Several days of bed-rest during Infusion 2nd Phlebography UFH-Infusion APTT monitoring Enden T, Klow NE, Slagsvold CE, Sandvik L, Ghanima W, Hafsahl G, Holme PA, Holmen LO, Njaastad AM, Sandbaek G, Sandset PM. Longterm outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis the CaVenT study): a randomised controlled trial. Lancet 2012;6736:61875-61878
Revascularization Treatment bleeding complications CDT N=90 Standard n=99 Total 22% 0 Severe* 3.3% 0 clin. relevant 5.6% 0 Peripheral neurolog. deficit Infection Puncture site 2 0 1 0 *abdominal wall haematoma req. transfusion, compartment syndrome reg. surgery puncture site haematoma CDT Phlebography Puncture popliteal vein Flouroscopy Several days of bed-rest during Infusion 2nd Phlebography UFH-Infusion APTT monitoring Standard..and go home Benefit with CDT (24 Months FU): moderate PTS reduced by 14.4% (55 % => 41 %) Quality of life identical Enden T, Klow NE, Slagsvold CE, Sandvik L, Ghanima W, Hafsahl G, Holme PA, Holmen LO, Njaastad AM, Sandbaek G, Sandset PM. Longterm outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis the CaVenT study): a randomised controlled trial. Lancet 2012;6736:61875-61878
Prandoni P, et al Ann Intern Med 2004;141:249-256 Revascularization Treatment 24 mts CDT Standard Compression- Tx Within INR- Target 63,3 51,5 65,4 50,0 Subtherapeutic anticoagulation is associated with increased PTS 60 40 severe mild/moderate OR (95%CI) for PTS INR <2 for >20% of the time 1.9 (1.2 3.1) 20 INR <2 for >50% of the time 2.7 (1.4 5.1) 0 Compression Control
Revascularization Treatment 24 mts CDT Standard Compression- Tx 63,3 51,5 60 severe mild/moderate Within INR- Target 65,4 50,0 40 20 Subtherapeutic anticoagulation is associated with increased PTS OR (95%CI) for PTS 0 Compression Control Prandoni P, et al Ann Intern Med 2004;141:249-256 INR <2 for >20% of the time 1.9 (1.2 3.1) INR <2 for >50% of the time 2.7 (1.4 5.1) Benefit with CDT (24 Months FU): moderate PTS reduced by 14.4% (55 % => 41 %) Quality of life identical Enden T, Klow NE, Slagsvold CE, Sandvik L, Ghanima W, Hafsahl G, Holme PA, Holmen LO, Njaastad AM, Sandbaek G, Sandset PM. Longterm outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis the CaVenT study): a randomised controlled trial. Lancet 2012;6736:61875-61878
Thrombus regression at 3 wks Rivaroxaban dose - finding studies 80 bid rivaroxaban doses Enox & VKA 70 60 50 40 0 20 40 60 Rivaroxaban total daily dose (mg) VKA +Enoxaparin 4-point improvement in thrombus burden by CCUS without recurrent VTE Without recurrent VTE Per-protocol population (n=528) Agnelli G et al. Circulation. 2007 Jul 10;116(2):180-7 Bauersachs RM,et al. N Engl J Med 2010;363(26):2499-2510.
PTS- Score > 5 Rivaroxaban Phase III studies Rivaroxaban Enox / VKA 40 N=335 Age (yrs) 58 16 RR 0.74; (0.54 1.01). Male 59 % Follow-up 57 mts (48-64) 20 Rivaroxaban/VKA 48 / 52 % Good Compliance 94% (R) vs 75 % (E) ECS 69% (R) vs 80 % (E) 0 Rivaroxaban Enox / VKA Bauersachs RM,et al. N Engl J Med 2010;363(26):2499-2510 Middeldorp S et al JTH 2015, 13 (Suppl. 2) 219-220
Institutional Volume on Outcome in CDT Hi-Vol Centers 6/y Low-Vol Centers <6/y NOACs n 1.310 1.310 13.512 Complication - Period 6 days 6 days 6 months Age 53.3 53.2 55 (18 97) Intracranial hemorrhage, (%) 0.4 1.0 0.1 Blood transfusion, (%) 10.4 10.8 All major: 1.0 GI bleed, (%) 1.4 1.8 GI: 0.4 Pulmonary embolism, (%) 18.4 17.9 1.0 Hematoma, (%) 2.8 2.2 - IVC filters, (%) 37.0 32.8 - Not hospitalized 0 0 49.4 Charges, median, $ 75.870 65.500 5.257 25th, 75th percentile 48.439-110 867 44.321-102.279 Jarrett H, Zack CJ, Aggarwal V, Lakhter V, Alkhouli MA, Zhao H, Comerota A, Bove AA, Bashir R. Circulation. 2015 Sep 22;132(12):1127-35.2015/07/23. Merli GJ, et al. Costs of hospital visits among patients with deep vein thrombosis treated with rivaroxaban and LMWH/warfarin. J Med Econ. 2016 Jan;19(1):84-90.
Institutional Volume on Outcome in CDT Hi-Vol Centers 6/y Low-Vol Centers <6/y NOACs n 1.310 1.310 13.512 FU 6 days 6 days 6 months Intracranial hemorrhage (%) 0.4 1.0 0.1 Blood transfusion (%) 10.4 10.8 All major: 1.0 GI bleed, (%) 1.4 1.8 0.4 Pulmonary embolism, (%) 18.4 17.9 1.0 Hematoma, (%) 2.8 2.2 - IVC filters, (%) 37.0 32.8 - Not hospitalized 0 0 49.4 Charges, median, $ 75.870 65.500 5.257 Jarrett H, Zack CJ, Aggarwal V, Lakhter V, Alkhouli MA, Zhao H, Comerota A, Bove AA, Bashir R. Circulation. 2015 Sep 22;132(12):1127-35.2015/07/23. Merli GJ, et al. Costs of hospital visits among patients with deep vein thrombosis treated with rivaroxaban and LMWH/warfarin. J Med Econ. 2016 Jan;19(1):84-90.
Treatment satisfaction score 1. Bamber L, Wang MY, Prins MH, Ciniglio C, Bauersachs R. Thromb Haemost. 2013 Oct;110(4):732-41. 2. Prins MH Bamber L, Cano SJ, Wang MY, Erkens P, Bauersachs R, et al. Thromb Res. 2014 Feb;135(2):281-8. Anticoagulation 2016 -Need for revascularization? Conclusion Abundance of evidence High efficacy (2.0% rec.vte) and high safety (1.1% Major Bleed) High QoL Scores Any proposed additional treatment has to provide evidence that it surpasses the current standard DVT treatment ACTS Burdens* 1 57 56 55 54 53 52 51 50 0 2 4 6 8 10 12 Rivaroxaban Enox/VKA
Thank you very much for your attention!
Thank you very much for your attention!