New Insights into the Diagnosis & Management of Venous Thromboembolism (VTE) Michael Miller, M.D.

Transcription

1 New Insights into the Diagnosis & Management of Venous Thromboembolism (VTE) Michael Miller, M.D. Professor of Cardiovascular Medicine University of Maryland School of Medicine Copyright A.P. Wheeler 2009 Disclosures None 1

2 Objectives Discuss VTE risks Using conventional therapy Assess novel AC therapy (NOAC) Analyze optimal management Objectives Discuss VTE risks Using conventional therapy Assess novel AC therapy (NOAC) Analyze optimal management 2

3 Venous Thromboembolism Epidemiology 5 million VTE s 900,000 PE s 290,000 fatalities Heit J. Blood. 2005;106:910. VTE: A Major Source of Mortality and Morbidity VTE is primary cause of fatality in 50% More than HIV, MVAs, Breast CA combined 10% of hospital deaths May be the #1 preventable cause Huge costs and morbidity (recurrence, postthrombotic syndrome, chronic PAH) Surgeon General s Call to Action to Prevent DVT and PE 2008 DHHS 3

4 Virchow s triad Advancing age (>40) Immobilization Stroke - cord injury Anesthesia Heart or lung failure Hyperviscosity Surgery Prior DVT Central line access Trauma Sepsis Vasculitis Hypercoagulable State Cancer Estrogen Family history Sepsis HIT Protein C, S or AT III deficiency Activated protein C resistance (Leiden) Hyperhomocystenemia Antiphospholipid antibody Prothrombin mutation 4

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6 Quality of Life after VTE Post-thrombotic syndrome develops in 25-40% of DVTs. DVT recurs in ~30% after anticoagulation stopped Permanent disability for 15 million Americans Objectives Discuss VTE risks Using conventional therapy Assess novel AC therapy (NOAC) Analyze optimal management 6

7 ACCP: Choice of Initial Anticoagulant Regimen in Patients With Proximal DVT In patients with acute DVT of the leg, we suggest LMWH (once daily) or fondaparinux over IV UFH (Grade 2C) and over SC UFH (Grade 2B for LMWH; Grade 2C for fondaparinux). Remarks: Local considerations such as cost, availability, and familiarity of use dictate the choice between fondaparinux and LMWH. LMWH and fondaparinux are retained in patients with renal impairment, whereas this is not a concern with UFH. Copyright: American College of Chest Physicians

8 Duration of Treatment Guidelines 1st event, reversible risk factor 1st event, spontaneous 3-6 months >= 6 months 2nd event 2nd spontaneous event, or 1st spontaneous and life threatening 3rd event or Ongoing risk factors >=12 months or lifelong Lifelong Lifelong 8

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11 Optimal Candidates for Warfarin Patients who: Have (borderline) renal insufficiency Are taking stable dose of warfarin and do not find INR testing burdensome Have access to self-testing machine Are concerned about the lack of an evidence-based reversal strategy 21 Objectives -Discuss VTE risks -Using conventional therapy -Assess novel AC therapy (NOAC) -Analyze optimal management 11

12 Emerging Therapies Factor Xa Inhibitors and Direct Thrombin Inhibitors Tissue Factor/VIIa X IX Idrabiotaparinux VIIIa Va Xa IXa Rivaroxaban Betrixaban Apixaban YM150 DU-176b II IIa Dabigatran AZD-0837 Fibrinogen Fibrin Harenberg J. Semin Thromb Hemost. 2009;35:

13 Clinical Challenges With New Anticoagulants No validated tests to measure anticoagulation effect No established therapeutic range No antidote for most agents Assessment of compliance more difficult than with vitamin K antagonists Potential for unknown long-term adverse events Balancing cost against efficacy Lack of head-to-head studies comparing new agents Sobieraj-Teague M, et al. Semin Thromb Hemost. 2009;35:

14 APPROVED 8/2014 APPROVED 4/2014 Objectives Discuss VTE risks Using conventional therapy Assess novel AC therapy (NOAC) Analyze optimal management 14

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16 RE-COVER Study Dabigatran 150 mg, BID for 6 months Double Blind, Non-Inferiority Schulman S, et al NEJM 2009;361:

17 RE-COVER Study Dabigatran 150 mg, BID VTE Major Bld 2.4% 1.6% VTE Warfarin INR % 1.9% Parenteral Anticoagulant Median 9 days 6 months Schulman S, et al NEJM 2009;361: RE-COVER Study 2.4% Dabigatran = 150mg, BID 2.1% INR = 60% TTR HR = 1.1 ( ) TTR = Therapeutic Time in Range Schulman S, et al NEJM 2009;361:

18 RE-COVER Study Dabigatran Major Bld 1.6% Warfarin Major Bld 1.9% Schulman S, et al NEJM 2009;361:

19 RE-COVER A limitation of the study is that the first dose of dabigatran, was given only after initial parenteral anticoagulation therapy had been administered for median of 9 days There is no data to support the use of dabigatran monotherapy for acute venous thromboembolism Schulman S, et al NEJM 2009;361: Rivaroxaban 15 mg, PO, BID x 3 weeks then 20mg, Qday Enoxaparin 1mg/kg/Q12hrs bridge to Warfarin INR 2-3 Open Label, Non-Inferiority trial Einstein Investigators NEJM 2010;363:

20 Einstein DVT DVT Proximal DVT Rivaroxaban 15 mg, BID x 3 wks 20 mg, Qday Enoxaparin Warfarin INR 2-3 3, 6, 12 months VTE Major Bld 2.1% 8.1% 3.0% 8.1% Warfarin TTR = 57.7% Einstein Investigators NEJM 2010;363: Acute DVT Study Einstein Acute DVT Study INR = 57.7% TTR 3.0% 2.1% TTR = Therapeutic Time in Range Einstein Investigators NEJM 2010;363:

21 41 Warfarin to NOAC Agent Recommendation Rivaroxaban Start when INR < 3.0 (we recommend < 2.0) Apixaban Start when INR < 2.0 Dabigatran Start when INR < 2.0 NOAC= New Oral Anticoagulants 21

22 Major Bleeding 22

23 Package Insert Recommendations Dabigatran FFP, Prothrombin Complex Concentrate Activated Factor VII Dialysis Rivaroxaban & Apixaban Prothrombin Complex Concentrate Four Factor Concentrate (KCentra) FFP 23

24 VTE: Summary NOACS: Non inferior for prevention of stroke/embolism in Afib Non inferior for treatment of DVT/PE NNT for clinical benefit are large Probable reduced hemorrhagic stroke rate Reduced rate of fatal bleeding events Increased incidence of GI bleeds Cost of drug/year $