Role of Direct Oral Anticoagulants (DOACs) in the Management of Venous Thromboembolism (VTE)

Transcription

1 n1 Role of Direct Oral Anticoagulants (DOACs) in the Management of Venous Thromboembolism (VTE) Todd E. H. Hecht, MD, SFHM, FACP Associate Professor of Clinical Medicine Director, Anticoagulation Management Program, HUP Director, Anticoagulation Management Center Raymond and Ruth Perelman School of Medicine, University of Pennsylvania

2 Disclosure ØI have no conflicts to disclose n2

3 First, a word about nomenclature ØDOACs have been given several names over the years Ø NOACs (Novel Oral Anticoagulants) Ø NOACs (non-vka Oral Anticoagulants) Ø DOACs (Direct Oral Anticoagulants) Ø TSOACs (Target Specific Oral Anticoagulants) Ø ODIs (Oral Direct Inhibitors) Ø SODAs (Specific Oral Direct Anticoagulants) n3

4 First, a word about nomenclature ØSurvey conducted by the SSC of ISTH Ø Choose the best term: Ø DOAC: 29.9% Ø NOAC: 28.5% Ø TSOAC: 23.4% Ø Choose all acceptable terms: Ø DOAC: 58.4% Ø TSOAC: 49.4% Ø NOAC: 39.0% ØSo, not that I m voting for the Donald, we ll use DOAC n4

5 DOAC mechanism of action Rivaroxaban Apixaban Edoxaban Dabigatran n5

6 Current guideline recommendations for VTE treatment ØACCP 9 th Guidelines (2012) Ø Recommend VKA over dabigatran and rivaroxaban (Grade 2B-2C) Ø Paucity of currently available data and data.emerging ØAHA Guidelines for PE and DVT (2011) Ø Published before any FDA approval of DOAC for VTE ØESC Guidelines on PE (2014) Ø Class IB recommendation to use all four approved DOACs Ø Rivaroxaban and apixaban at onset of diagnosis Ø Dabigatran and edoxaban after acute-phase parenteral anticoagulation n6

7 Evidence for DOACs in treatment of VTE ØRecurrent VTE n7

8 Evidence for DOACs in treatment of VTE ØMajor bleeding n8

9 Evidence for DOACs in treatment of VTE ØFatal bleeding DOAC STANDARD TREATMENT Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI DABIGATRAN STUDIES 01. RE-COVER I 02. RE-COVER II Heterogeneity: Tau² = 0.00; Chi² = 0.26, df = 1 (P = 0.61); I² = 0% Test for overall effect: Z = 0.44 (P = 0.66) % 7.2% 16.7% 1.00 [0.06, 16.02] 0.33 [0.01, 8.18] 0.63 [0.08, 5.08] RIVAROXABAN STUDIES 03. EINSTEIN DVT 04. EINSTEIN PE Heterogeneity: Tau² = 0.00; Chi² = 0.73, df = 1 (P = 0.39); I² = 0% Test for overall effect: Z = 1.29 (P = 0.20) % 22.9% 38.8% 0.20 [0.02, 1.70] 0.66 [0.11, 3.97] 0.41 [0.10, 1.60] APIXABAN STUDIES 07. AMPLIFY 1 Heterogeneity: Not applicable Test for overall effect: Z = 0.56 (P = 0.57) % 12.7% 0.50 [0.05, 5.54] 0.50 [0.05, 5.54] EDOXABAN STUDIES 09. HOKUSAI-VTE Heterogeneity: Not applicable Test for overall effect: Z = 2.08 (P = 0.04) % 31.8% 0.20 [0.04, 0.91] 0.20 [0.04, 0.91] Total (95% CI) Heterogeneity: Tau² = 0.00; Chi² = 1.95, df = 5 (P = 0.86); I² = 0% Test for overall effect: Z = 2.35 (P = 0.02) Test for subgroup differences: Chi² = 0.94, df = 3 (P = 0.81), I² = 0% 100.0% 0.36 [0.15, 0.84] Favours DOAC Favours control n9

10 Evidence for DOACs in treatment of VTE ØIntracranial bleeding DOAC STANDARD TREATMENT Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI DABIGATRAN STUDIES 01. RE-COVER I 02. RE-COVER II Heterogeneity: Tau² = 0.00; Chi² = 0.25, df = 1 (P = 0.62); I² = 0% Test for overall effect: Z = 1.80 (P = 0.07) % 19.2% 24.8% 0.14 [0.01, 2.77] 0.33 [0.07, 1.65] 0.28 [0.07, 1.13] RIVAROXABAN STUDIES 03. EINSTEIN DVT 04. EINSTEIN PE Heterogeneity: Tau² = 0.25; Chi² = 1.36, df = 1 (P = 0.24); I² = 26% Test for overall effect: Z = 1.37 (P = 0.17) % 30.8% 43.6% 0.99 [0.14, 7.04] 0.25 [0.07, 0.88] 0.40 [0.11, 1.47] APIXABAN STUDIES 07. AMPLIFY 3 Heterogeneity: Not applicable Test for overall effect: Z = 0.97 (P = 0.33) % 25.6% 0.50 [0.13, 2.01] 0.50 [0.13, 2.01] EDOXABAN STUDIES 09. HOKUSAI-VTE Heterogeneity: Not applicable Test for overall effect: Z = 1.75 (P = 0.08) % 5.9% 0.08 [0.00, 1.37] 0.08 [0.00, 1.37] Total (95% CI) Heterogeneity: Tau² = 0.00; Chi² = 3.13, df = 5 (P = 0.68); I² = 0% Test for overall effect: Z = 3.01 (P = 0.003) Test for subgroup differences: Chi² = 1.48, df = 3 (P = 0.69), I² = 0% 100.0% 0.34 [0.17, 0.69] Favours DOAC Favours control n10

11 Evidence for DOACs in treatment of VTE ØClinically relevant non-major bleeding DOAC STANDARD TREATMENT Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI DABIGATRAN STUDIES 01. RE-COVER I 02. RE-COVER II Heterogeneity: Tau² = 0.00; Chi² = 0.03, df = 1 (P = 0.87); I² = 0% Test for overall effect: Z = 4.14 (P < ) % 14.2% 28.7% 0.59 [0.42, 0.82] 0.61 [0.43, 0.87] 0.60 [0.47, 0.76] RIVAROXABAN STUDIES 03. EINSTEIN DVT 04. EINSTEIN PE Heterogeneity: Tau² = 0.00; Chi² = 0.30, df = 1 (P = 0.59); I² = 0% Test for overall effect: Z = 0.07 (P = 0.94) % 18.4% 35.2% 1.05 [0.83, 1.34] 0.97 [0.81, 1.15] 0.99 [0.86, 1.15] APIXABAN STUDIES 07. AMPLIFY Heterogeneity: Not applicable Test for overall effect: Z = 6.26 (P < ) % 17.2% 0.48 [0.38, 0.61] 0.48 [0.38, 0.61] EDOXABAN STUDIES 09. HOKUSAI-VTE Heterogeneity: Not applicable Test for overall effect: Z = 2.80 (P = 0.005) % 18.9% 0.81 [0.70, 0.94] 0.81 [0.70, 0.94] Total (95% CI) % Heterogeneity: Tau² = 0.07; Chi² = 33.74, df = 5 (P < ); I² = 85% Test for overall effect: Z = 2.54 (P = 0.01) Test for subgroup differences: Chi² = 33.36, df = 3 (P < ), I² = 91.0% 0.73 [0.58, 0.93] Favours DOAC Favours control n11

12 Network meta-analysis of all treatment options n12

13 Network meta-analysis of all treatment options n13

14 DOACs in cancer patients Recurrent VTE Major bleeding n14

15 DOAC regimens for treatment of acute VTE ØDabigatran 150mg twice daily (BID) ØEdoxaban 60mg once daily (30mg daily if weight < 60kg) Ø Initiate each after 5 days of parenteral anticoagulation ØRivaroxaban 15mg BID for 3 weeks, then 20mg once daily ØApixaban 10mg BID for 1 week, then 5mg BID Ø Can be given at onset of VTE diagnosis n15

16 Renal precautions with DOACs ØDabigatran Ø Creatinine clearance (CrCl)<30cc/min or HD: excluded from trial ØRivaroxaban Ø CrCl<30: avoid use ØApixaban Ø Creatinine > 1.5mg/dL and either weight < 60kg or age > 80 Ø Use 2.5mg BID instead of 5mg BID ØEdoxaban Ø CrCl15-50: 30mg daily Ø CrCl<15: avoid use n16

17 Half-lives and cessation for procedures Half-life Discontinuation for procedures Dabigatran hours 1-2 days (CrCl 50) or 3-5 days (CrCl<50) Rivaroxaban 5-9 hours 24 hours Apixaban ~12 hours 48 hours (moderate/high bleeding risk); 24 hours (low) Edoxaban hours 24 hours n17

18 Dabigatran Comparable VTE rate to usual care? X Less major bleeding than usual care? Summary Less major bleeding than Dabi/Edoxa? No need for 5 days of parenteral anticoagulation? Steady state dose is once daily? Rivaroxaban X X X X Apixaban X X X X Edoxaban X X n18

19 QUESTIONS? n19

20 Reversal of DOACs ØIdarucizumab ØAndexanet alpha ØAripazine n20

21 Summary ØDOACs have good evidence to support their use for VTE Ø Comparable rate of VTE recurrence Ø Lower rate of numerous bleeding endpoints ØDOAC dosing may be impacted by numerous factors Ø Time from VTE diagnosis (riva and apixa) Ø Renal impairment (all agents) Ø Weight (apixa and edoxa) ØIndividual DOACs may have different profiles Ø Dosing frequency varies among products Ø Rivaroxaban (after 1 st 3 weeks) and edoxaban are once daily Ø Apixaban and Rivaroxaban have two other advantages Ø Lower rates of bleeding than usual care or other DOACs Ø No need for 5 days of parenteral anticoagulation n21