Top 5 (or so) Hematology Consults. Tom DeLoughery, MD FACP FAWM. Oregon Health and Sciences University DISCLOSURE

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1 Top 5 (or so) Hematology Consults Tom FACP FAWM Oregon Health and Sciences University DISCLOSURE Relevant Financial Relationship(s) Speaker Bureau - None Consultant/Research none 1

2 What I am Talking About Catheter directed thrombolytic When to use IVC filters Aspirin for VTE prevention Duration of anticoagulation Upper extremity thrombosis Role of new drugs in VTE treatment Surgery and anticoagulants Thrombolytic Therapy: DVT Selected patients with large very proximal DVT consider catheter directed thrombolytic therapy Symptoms < 14 days Good health status Good candidate for thrombolytic therapy Venous lesions should be corrected by angioplasty or stents 2

3 Top 5 Hematology Consults - Thomas Cil B E et al. Radiology 2004;233:

4 Cochrane Review 2014 Early patency RR: 4.91 Later patency RR: 2.37 Post thrombotic syndrome RR: 0.64 Bleeding RR: 2.23 Goal is LONG term prevention of post-thrombotic syndrome 4

5 Catheter Directed Thrombolytic Therapy Large proximal venous thrombosis Will decrease post-thrombotic syndrome Good candidates for thrombolytic therapy Age < 65 Can cool off with heparin 5

6 Aspirin to Prevent Venous Thrombosis Very appealing agent Cheap Oral Been around for 110 years What's the data? Aspirin: Effectiveness Inconsistent in studies Aspirin in orthopedics HR 0.72 ( ) LMWH in orthopedics HR 0.50 ( ) Prospective study by IMH found more VTE with aspirin (12.5% vs 1.9%) Arthroplasty Jan;27(1):1-9 6

7 Aspirin and Bleeding Aspirin is associated with a 2.2/100 excess rate of hematoma and infection Overall hematoma rates Placebo: 5.6% Aspirin: 7.8% UFH % LMWH % Arch Surg 141:790, BMJ: 1994; 308 : 235 Late Aspirin Some data aspirin effective later PEP trial after one week RCT of LMWH vs aspirin 81mg started after 10 days LMWH for 28 days N = 786 Ann Int Med2013;158(11):

8 Results LMWH Aspirin VTE 5 (1.3%) 1 (0.3%) Major Bleeding 1 (0.3%) 0 (%) Op site bleeding 5 (1.3%) 4 (1.0%) Trial being repeated with rivaroxaban Aspirin May have some effect - but more effective options with same risk of bleeding available Role may be later in prevention Reasonable to start after 10 days of LMWH/New drugs 8

9 Inferior Vena Cava Filters Overused and under studied! 9

10 Only 2 RCT One abstract only Filters No influence on mortality in anticoagulated patients Only one study showed reduction in PE ~1-2% fatal PE rate in IVC filters patients in ICU studies Raises risk of future DVT (~2x) 10

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12 Arch Bronconeumol. 2011;47:17-24 Retrievable Filters: Panacea or Pandemic? Rapid acceptance of retrievable filters Caveats 10-20% cannot be removed > 50% aren t removed Limited clinical studies Limited long term follow-up 12

13 ~ 259,000 Am J Med Jul;124(7): IVC Filter by State Wyoming : 13/100,000 NJ: 67/100,000 13

14 Retrievable Filters Need system in place to retrieve Reports of retrieval many months out Can retrieve while anticoagulated Reasons NOT to Put in a Filter Pulmonary embolism: 1 st week of anticoagulation Despite warfarin Deep venous thrombosis: With free floating thrombus Extension of DVT Despite warfarin In cancer patients Curr Opin Hem 2009 Sep;16(5):

15 Am J Med Jul;124(7): IVC Filters Still should be used with caution Indications Large DVT and temporary contraindication to anticoagulation Large DVT and poor cardiopulmonary status NOT indicated for PE prophylaxis Patients must be warned that "retrievable" filter may be permanent Will RAISE the risk of DVT! Need to anticoagulate as soon as feasible 15

16 Duration of Therapy Idiopathic versus provoked thrombosis is the biggest determinant of risk of recurrent thrombosis 16

17 Duration of Therapy Not all thrombosis are the same Can stratify patients by: Site of thrombosis Circumstances of thrombosis Most important! Presence of hypercoagulable states Superficial Thrombophlebitis Very common Strong inflammatory component Wide range of therapeutic options 17

18 STP: LMWH STTEPS Symptomatic STP 8-12 day of therapy Placebo: 30.6% (3.6%) NSAIA: 14.9% (2.1%) 40 mg LMWH: 8.3% (0.9%) 1.5 mg/kg LMWH: 6.9% (1.0%) Vesalio Study Group Greater saphenous vein STP One month of therapy Prophylactic dose: 7.2% Treatment dose: 7.2% Superficial Thrombophlebitis Fondaparinux 2.5 mg/day x 45 days Endpoint: F: 0.9% P: 5.9% DVT/PE F: 0.2% P: 1.5% No difference in bleeding Need to treat 88 patients to prevent one DVT/PE NEJM 363: ,

19 50% of events at day 10 Decousus H et al. N Engl J Med 2010;363: Superficial Thrombophlebitis Small and distal: NSAIA and heat Painful, large (> 5cm) or greater saphenous vein At least 10 days of prophylactic dose LMWH or fondaparinux 19

20 Calf Vein Thrombosis Muscular vein thrombosis 10 days of LMWH or observation Other sites: high risk of progression Up to 30% progression Timing unpredictable 6 weeks therapy for most patients 20

21 Muscular vein Thrombosis 10 days LMWH Therapy Outcome at 3 months Placebo LMWH Progression to calf DVT 25% 0% Recurrent muscular vein DVT 16% 2% Recanalization 50% 86% Schwarz, T;, SBlood Coagulation & Fibrinolysis. 12(7): , October Calf Vein Thrombosis Therapy Lancet Sep 7;2(8454):

22 Calf Vein DVT Circulation, May 2001; 103: Duration of Therapy: Proximal DVT 3 months Provoked DVT Especially estrogen related No benefit with 6 months but will have more bleeding 22

23 Proximal DVT Circulation, May 2001; 103: Campbell, I A et al. BMJ 2007;334:674 23

24 Duration of Therapy What is an Idiopathic Thrombosis? No trauma, surgery or hospital stay for 1-3 months No estrogens No long travel No cancer or major risk factors Varies from study to study Balancing the risk of recurrent DVT vs risk of warfarin 1 st Idiopathic DVT High rates (20-30%) of recurrence off anticoagulation RCT show benefit of long term anticoagulation Marked increase in recurrence when stopping anticoagulation 24

25 D-Dimers Much interest in D-dimers checked off therapy to predict risk Meta-analysis 7 studies Positive D-Dimer: 10%/yr Negative D-Dimer: %/yr Unclear if repeat testing helps 0.5% of patients had recurrent thrombosis before D-dimer test Cuts-off vary between laboratories Idiopathic DVT Only consider stopping anticoagulation after three months if Negative D-dimer (??????) Not life-threatening PE Female Thrombus resolution NOT predictive Still need better prediction rules! Safer anticoagulants may shift balance toward longer treatment 25

26 Duration of Therapy Indefinite >1 DVT (except upper ext) Acquired hypercoagulable states Idiopathic unusual site Idiopathic severe pulmonary embolism 3 months Provoked pulmonary embolism 3 months - 3 months - 3 months - 14 days 3 months - 6 weeks Soleus days 26

27 What about Hypercoagulable States? Increasing controversy over the role of hypercoagulable states in predicting risk of relapse JAMA May 18;293(19):

28 Hypercoagulable State Clear risk factor for 1 st DVT No evidence with classic genetic ones for prediction of recurrence Multiple guidelines against checking in provoked thrombosis Acquired ones still severe True APLA Cancer Myeloproliferative syndrome PNH 28

29 Upper Extremity Thrombosis Mechanical defects Catheter PICC 3-5% Local venous trauma Prophylaxis ineffective Low risk of serious sequela 29

30 Upper Extremity Thrombosis PICC Catheter Key is removing catheter No new one for at least 10 days Benefit of anticoagulation uncertain No change in recanalization Increased bleeding Ports/Central Venous May benefit from anticoagulation 3 months Upper Extremity Thrombosis Spontaneous /Effort Up to 80% with underlying vascular issues Thrombolytic therapy Allow identification of lesions Prevent s post-thrombotic syndrome 30

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32 New Drugs in VTE Abundant data for direct oral anticoagulants in venous thrombosis No monitoring No food interactions Minimal drug interactions Rivaroxaban: Acute Venous Thrombosis N = 3,449 with DVT/ 4,832 with PE RCT Rivaroxaban 15mg BID then 20mg after 3 weeks Enoxaparin -> Warfarin N Engl J Med 2010; 363: N Engl J Med 2012; 366:

33 Results Rivaroxaban (4150) LMWH/Warfarin (4131) Recurrent VTE 86 (2%) 96 (2.3%) Any Bleeding 388 (9%) 412 (10%) Major Bleeding 40 (1.0%) 70 (1.7%) ICH 5 (0.1%) 14 (0.3%) Apixaban: Acute Venous Thrombosis N = 5395 with VTE 33% with PE RCT Apixaban 10mg BID then 5 mg BID after 7 days Enoxaparin -> Warfarin N Engl J Med 2013; 369:

34 Results Apixaban (2691) LMWH/Warfarin (2704) Recurrent VTE 59 (2.3%) 71 (2.7%) Any Bleeding 115 (4.3%) 261 (9.7%) Major Bleeding 15 (0.6%) 49 (1.8%) ICH 3 (0.1%) 6(0.2%) Apixaban: Chronic Venous Thrombosis N = 2482 with VTE 34% with PE 6-12 months of therapy RCT Apixaban 5 mg BID Apixaban 2.5 mg BID Placebo N Engl J Med 2013; 368:

35 Results Apixaban 2.5mg BID (840) Apixaban 5mg BID (813) Placebo (829) Recurrent VTE 32 (3.8%) 34 (4.2%) 96 (11.6%) Any Bleeding 27 (3.2%) 35 (4.3%) 19 (2.3%) Major Bleeding 2 (0.2%) 1 (0.1%) 4 (0.5%) 35

36 Long Term Treatment of VTE Drug VTE- D VTE - P RRR Bleed-A Bleed -P Warfarin 1.3%/yr 27.4%/yr %/yr 0.0% Rivaroxaban 1.3% 7.1% % 0.0% Dabigatran 0.4% 5.6% % 0.0% Apixaban 1.7% 8.8% % 0.5% Aspirin 14% 19% % 2.0% 36

37 New Direct Oral Anticoagulants Easier to use and safer Both rivaroxaban and apixaban tested without heparin Both use higher initial doses Irreversibility Less need to reverse No difference in bleeding outcomes in multiple studies Reversal Drugs we have no antidote for: Low molecular weight heparin, fondaparinux, aspirin, abciximab, tirofiban, eptifibatide, clopidogrel, ticagrelor, prasugrel, dabigatran, rivaroxaban, apixaban, edoxaban, vorapaxar 37

38 Who NOT to use New Anticoagulants Dialysis patients Mechanical Valves < 50 or > 150 kg Remember loading dose for venous disease Role of New Drugs Cost effective in acute thrombosis Need to be sure patient gets follow-up Low dose options for long term care Safer! 38

39 Surgery When to stop anticoagulants When to bridge 39

40 Antiplatelet Agents Aspirin Stop 5 days before Clopidogrel, Prasugrel Stop 7 days before Ticagrelor 5 days before Vorapaxar 7-12 days??? Cardiac Stents Bare metal < 4 weeks: need combined therapy > 4 weeks: aspirin Drug eluting stents < 6-12 months: need combined therapy Bridging with GP IIb/IIIa inhibitors > 6-12 months: shortest possible duration of stopping clopidogrel 40

41 Approaches to Anticoagulation and Procedures Continue agents Stop drug Bridging therapy 41

42 Continue Warfarin Recommended approach for low risk procedures Dental extractions Cataracts Simple endoscopy/colonoscopy Pacemaker/ICD placement Hip arthroplasty Works best if INR < 3.0 Stop all Drugs Approach associated with least risk of bleeding but (in theory) highest risk of thrombosis Warfarin and antiplatelet agents must be stopped 5-7 days before procedure Can take 2-5 days to get INR back up Best approach for patients not at high risk of thrombosis 42

43 Bridging Covering the patient with LMWH while off warfarin Increasing data Increases risk of bleeding No substantial decrease in thrombosis Shift away from aggressive bridging Mechanical Heart Valve Patients Author n Aortic Mitral Both Clot Bleed Douketis (04) % Pengo (09) ? 1.6% Kovacs (04) 112??? 4.5% Hammerstingl (07) % 0.5% 1.2% 7.1% 0.9% Mayo (2007) % 3.6% Total % 2.7% Courtesy Robert D. McBane, M.D 43

44 Factors Which Increase Risk for Bleeding Pre-procedure Trough LMWH level too high Need to stop q12 LMWH 24 hours before and q24 maybe 36-48% Too aggressive LMWH in patients with renal disease Post-procedure Starting therapeutic LMWH too soon!! Need 48 hours or more Do not use fondaparinux Start LMWH Stop Warfarin Stop LMWH ~24 hour before Restart Warfarin Restarting LMWH Simple procedure after procedure Complex Prophylactic hrs - Therapeutic 48 hrs or more 44

45 Valves Who We Bridge Mitral valve replacement Multiple valves Non-bileaflet aortic valve Bileaflet AVR with other risk factors Who We Bridge Atrial fibrillation History of stroke CHADS2 > 4 Cardiac thrombus 45

46 Who We Bridge Venous Thrombosis Thrombus within 3 months One month IVC filter? Cancer and thrombosis Virulent thrombophilia New Drugs Dabigatran hours (48-72 renal) Rivaroxaban 24 (48 with renal) Apixaban hours 46

47 What I am Talking About Catheter directed thrombolytic When to use IVC filters Aspirin for VTE prevention Duration of anticoagulation Upper extremity thrombosis Role of new drugs in VTE treatment Surgery and anticoagulants 47