1. Thrombosis Update Tom DeLoughery MD FACP FAWM Oregon Health and Sciences University

2. DISCLOSURE Current Relevant Financial Relationship(s) Speaker Bureau – None

3. What I am Talking About Antiplatelet agents Antithrombotics Atrial fibrillation Venous thrombosis

4. Anticoagulation Patients with hematological malignancies not immune to thrombosis DVT 3-5% –Line – 3-15% PICC > Central Coronary artery disease: –45-64: 5% – > 65: > 15%

5. Issues Antiplatelet agents Antithrombotic –Atrial fibrillation –Valves –Venous thrombosis

6. Antiplatelet Agents Increase risk of bleeding with counts < 50,000/ul –Hemophilia studies –Massive bleeding studies

7. MI: Primary and Secondary Prevention Primary prevention –Minimal short term effect –Halt aspirin for duration Secondary prevention –22% reduction in new events –Stop and restart at 50,000/ul

8. Coronary Stents Stent thrombosis devastating –30-50% fatal MI Highest Risk –Placed for AMI –Bare metal – 4 weeks –Drug eluting – 12 months Dual antiplatelet therapy for high risk period

9. Drug Eluting Stents Drugs inhibits restenosis by inhibiting cell proliferation Inhibits endothelialization of stent Increasing reports of late thrombosis even 18 months

10. Stent Management Outside “risk period” –Bare Metal > 4 weeks –Drug eluting > 12 months Aspirin until platelets < 20,000/uL

11. Stent Management Risk Period –Bare metal < 4 weeks –Drug eluting < 12 months Cardiology input Continue dual antiplatelet therapy unless severe bleeding

12. Acute Coronary Syndrome Aspirin beneficial even with severe thrombocytopenia Further therapy guided by catheterization –Angioplasty with no stenting –Short course of heparin

14. Antithrombotic Therapy UF Heparin –Short T 1/2 0.5-1 hours LMWH –Longer T 1/2 4 hours –Reversible by protamine –Need to adjust for renal disease Fondaparinux –Longest T 1/2 17-19 hours –Not reversible by protamine –Contraindicated in renal failure

15. General LMWH Plan Change warfarin patients to LMWH Continue full dose until platelets <50,000/uL “Prophylactic” dose until platelet <20,000/uL –Enoxaparin 40mg/day –Several studies have shown this dose effective for treatment

16. Dabigatran Oral Thrombin Inhibitor Bioavailability: 6.5% Onset of action: 2-3 hours Half-life : 12-14 hours Renal excretion: 80% Drug interactions: p-glycoprotein

17. Dabigatran: Bottom Line Superior to warfarin in stroke prevention GI side effects 15% 1.3x increase risk of MI – outweighed by benefit CrCl > 50 Effects aPTT

18. Drug Interactions Contraindicated –Dronedarone, azoles, rifampin, St John’s wort, carbamazepine Caution with renal disease or use of multiple of these drugs –Verapamil, amiodarone, quinidine, clarithromycin

19. Rivaroxaban Oral Xa Inhibitor Bioavailability: 80-100% Onset of action: 2.5-4 hours Half-life : 5-9 hours Renal excretion: ~66% Drug interactions: CYP 3A4

20. Rivaroxaban Approved 10mg daily for DVT prophylaxis in TKR and THR Approved 20mg daily for afib –15mg if CrCl 15-50mL/m –Contraindicated < 15mL/m Approved for DVT –15mg BID x 3 weeks –20mg daily

21. Drug interactions Ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan Potential with renal insufficiency –CSA, Erythromycin, azithromycin, diltiazem, verapamil, quinidine, ranolazine, dronedarone, amiodarone, and felodipine

22. Rivaroxaban: Bottom Line Effective in stroke prevention Superior in prevention of VTE Safer in treatment of VTE CrCl > 15 (15mg < 50) Once a day drug –BID x 3 weeks in acute VTE INR to monitor

23. Apixaban Oral Xa Inhibitor Bioavailability: 66% Onset of action: 1-3 hours Half-life : 8-15 hours Renal excretion: 25% Drug interactions: CYP 3A4 –Multiple other pathways

24. Drug interactions Ketoconazole, itraconazole, clarithromycin, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan –Cut to 2.5 mg BID Avoid due to decrease effect –Carbamazepine, phenytoin, rifampin, St. John’s wort

25. Apixaban: Bottom Line Superior in stroke prevention with less bleeding Superior in prevention of VTE Safer in therapy of VTE BID drug CrCl > 15 Does not effect INR/PTT

27. Comparing Trials

28. Atrial Fibrillation DrugStrokeBleeding ApixabanBetterSafer DabigatranBetterEqual RivaroxabanEqual Warfarin: $4/month + monitoring ($20-50/visit) Apixaban: $320/month Dabigatran: $235/month Rivaroxaban: $247/month

29. ICH – Atrial Fibrillation StrokeIntracranial Hemorrhage Events/ 100 years RREvents/ 100 years RR Dabigatran 110 1.530.91 (0.74-1.11))0.230.31 (0.20-0.47) Dabigatran 150 1.110.66 (0.53-0.82)0.300.40 (0.27-0.60) Rivaroxaban1.760.79 (0.66-0.96)0.490.67 (0.47-0.94) Apixaban1.190.79 (0.65-0.95)0.330.42 (0.30-0.58) Potential for 10-12,000 less ICH in USA

30. Atrial Fibrillation Dabigatran –Robust trial data for all CHADS2 Apixaban –More effective than warfarin –Better in patients at risk for bleeding –Safer – “the sweet spot” Rivaroxaban –Effective

31. Venous Thrombosis DrugThrombosisBleeding ApixabanEqualSafer DabigatranEqual RivaroxabanEqualSafer Warfarin: $4/month + monitoring ($20-50/visit) LMWH: $100-120/day Apixaban: $320/month Rivaroxaban: $247/month Dabigatran: $235/month

32. Venous Thrombosis Rivaroxaban – FDA approved –Cost effective for acute DVT –Safer Dabigatran with robust data –Two trials and extended therapy Apixaban –Effective and safer DVT treatment

33. Reversal Drugs we have no antidote for: –Low molecular weight heparin, fondaparinux, aspirin, clopidogrel, ticagrelor, prasugrel, dabigatran, rivaroxaban, apixaban

34. What We Do Life or limb threatening bleeding 50 units/kg of 4 factor PCC (kcentra)

36. Atrial Fibrillation Leading indications for warfarin anticoagulation Warfarin reduced risk of stroke from 5%/yr to 1%/yr Risk predicated by CHADS2 score

37. CHADS2 CHADS2 Score Stroke/yrRisk Level 01.9Low 12.8Low/moderate 24.0Moderate 35.9Moderate 48.5High 512.5High 618.2High

38. Management CHAD2 <1: nothing >1: LMWH protocol or new anticoagulant Highest risk –Previous stroke –CHADS2>4 –Cardiac thrombus

39. Cardiac Valves Bioprosthetic –Asprin until platelets < 50,000/uL Mechanical –New drugs absolutely contraindicated!!! –Aortic bileaflet – LMWH protocol –Higher risk Monitored LMWH Continue until platelets < 30,000/uL –Prophylactic throughout

40. Venous Thrombosis On anticoagulants > 3 months since thrombosis –Hold anticoagulation –Prophylaxis < 3 months since thrombosis –LMWH protocol

41. New Thrombosis Calf vein/Muscular vein –Thrombocytopenic Doppler 3 days and then weekly until resolved or 4 weeks –Not thrombocytopenia Muscular – 10 days Calf – 6 weeks

42. Proximal Vein/PE New proximal thrombosis –IVC filter controversial Yes if extensive leg DVT Can be nidus for thrombosis Pulmonary embolism –Filter if leg thrombosis

43. Prophylaxis? Range of DVT is 1.2-5.8% Would mandate prophylaxis in other situations! Stockings? Pharmacologic?

45. Upper Extremity DVT No RCT Lower incidence of –PE –Recurrence –Recannulization –Thrombophilia Higher incidence of –Underlying vascular lesions

46. Catheter Related DVT Common with PICCs –Less with tunneled catheters High risk of thrombosis –3-8% symptomatic –20-50% asymptomatic No benefit of prophylaxis

47. Catheter Related DVT Therapy: High rates of bleeding! –By definition PICC placed in sick patients –RCT 4% incidence life threatening bleeding –OHSU 25% halted due to bleeding

48. Catheter Related DVT Increasing interest in conservative approach –NeuroICU study > 75% no anticoagulation –OHSU – anticoagulation made no difference in outcomes –NCCN No anticoagulation if at risk for bleeding

49. Catheter Related DVT Suggested approach –Pull line –No new one for 10 days –Consider anticoagulation if Patient very symptomatic No bleeding risk factors

50. What I Talked About Antiplatelet agents Antithrombotics Atrial fibrillation Venous thrombosis