Anticoagulation and Bleeding. Ralph Buckley MD FACC 2016

Transcription

1 Anticoagulation and Bleeding Ralph Buckley MD FACC 2016

2 Indications Atrial fibrillation thromboembolic prophylaxis Treatment of acute DVT and pulmonary embolism Mechanical Valve thromboembolic prophylaxis DVT prophylaxis, hip replacement DVT prophylaxis, knee replacement DVT prophylaxis, restricted mobility Angina, unstable; NWQMI; STEMI

3 Warfarin (Coumadin, Jantoven) Heparin, unfractionated LMWH (Low Molecular Weight Heparin) Dabigatran (Pradaxa). T 1/ hrs Rivaroxaban (Xarelto). T 1/2 5-9 hrs Apixaban (Eliquis) T 1/ hrs Edoxaban (Savaysa) T 1/ hrs

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5 IV: agatroban and bivalirudin (angiomax)

6 Warfarin (Coumadin ) Interferes with cyclic interconversion of VIT K and its 2,3 epoxide. Modulates vitamin K depd proteins Prophylaxis in nonvalvular AF DVT / PTE treatment T ½ hrs

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8 Warfarin (Coumadin ) Lowest tercile of INR control (48% in range) had twice the rate of stroke, MI, major bleeding, and death as the top tercile of INR control (83% of time in range) Short term risk for out of range INR high: INR % at 1 month Short term risk for out of range INR low: 0.4% Triple therapy: 0-21% during 21month f/u, 0-5.9% during 30 day f/u. Danish study: threefold higher bleeding risk in triple therapy.

9 Apixaban (Eliquis ) Factor Xa inhibitor Reversible inhibition Prophylaxis in nonvalvular AF Prophylaxis in DVT (hip, knee) DVT / PTE treatment (10bid, then 5bid) Renal dosing reduce dose 80 yo, <60kg, Cr>1.5 T ½ 12 hours Aristotle pts. Superior to warfarin, less frequent non-major bleeding. Lower ICH (0.27%/y vs 0.47%/y). Similar GI (0.76%, 0.86%)

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15 Rivaroxaban (Xarelto ) Factor Xa inhibitor Reversible inhibition Prophylaxis in nonvalvular AF Prophylaxis in DVT (hip, knee) DVT / PTE treatment (10bid, then 5bid) Renal dosing reduce dose based on cr cl T ½ 5-9 hours, elderly hrs Rocket-AF patients; noninferiority to warfarin; no difference in major bleeding; ICH reduced; GI bleeding increased.

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21 Dabigatran (Pradaxa ) Direct thrombin inhibitor Prophylaxis in nonvalvular AF Prophylaxis in DVT (hip, knee) DVT / PTE treatment Renal dosing for afib indication reduce dose based on cr cl T ½ hours, 28hrs in severe renal insufficiency ReLy patients. Lower rates of stroke, similar rates of major bleeding; reduced ICH, and higher GI bleeding.

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26 Edoxaban (Savaysa ) Factor Xa inhibitor Prophylaxis in nonvalvular AF DVT / PTE treatment Renal dosing for afib indication reduce dose based on cr cl Avoid use if Cr Cl >95 T ½ hrs Engage AF TIMI 48 Study: 21,105 patients. Noninferior to first stroke,

27 Bleeding Risk: MetaAnalysis of 13 trials, 100,000 pts. Major bleeding with DOAC 7.6 mortality rate; 11% for warfarin RR reductions fatal bleeding RR 0.53 ( ) Cardiovasc mortality RR 0.88 ( ) Allcause mortality 0.91 ( ) Likely related to reduced intracerebral hemorrhage.

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33 Bleeding risk assessment HASBLED ATRIA OBRI Hemmorr2hages

34 Higher bleeding risks Age >75 years Concomitant use of antiplatelet drugs (eg aspirin, clopidogrel, nonsteroidal antiinflammatory drugs) Multiple other drug treatments (ie, polypharmacy) Uncontrolled hypertension History of bleeding (eg, peptic ulcer, cerebral hemorrhage) History of poorly controlled anticoagulation therapy

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36 Ms. Johnson has AFIB, CHADSVASC2 score of 4, and is on coumadin. Her dose is 5mg a day Her INR has been stable, but she comes in and her INR is 1.6. How do you manage her? Admit for heparin, increase dose of coumadin, bridge until therapeutic again. Lovenox, increase dose of coumadin, bridge until therapeutic again. Retest 1-2 weeks and keep dose same. Retest 1-2 weeks after increasing dose, no bridging.

37 Ms. Johnson has AFIB, CHADSVASC2 score of 4, and is on coumadin. Her dose is 5mg a day Her INR has been stable, but she comes in and her INR is 1.6. How do you manage her? Admit for heparin, increase dose of coumadin, bridge until therapeutic again. Lovenox, increase dose of coumadin, bridge until therapeutic again. Retest 1-2 weeks and keep dose same. Retest 1-2 weeks after increasing dose, no bridging.

38 Mr. Smith is 75 yo, has AFIB, and has a CHADSVASC score of 3. He is on coumadin, 5 mg a day, and his INR is 4.5. He has no bleeding. You should manage his coumadin by: Stop coumadin permanently Hold coumadin one day and reduce dose and recheck in 1-2 weeks. Administer vitamin K 2.5 mg po and reduce dose of coumadin, and recheck 1-2 weeks. Admit for treatment with FFP, IV vitamin K, and resume coumadin once INR normalizes.

39 Mr. Smith is 75 yo, has AFIB, and has a CHADSVASC score of 3. He is on coumadin, 5 mg a day, and his INR is 4.5. He has no bleeding. You should manage his coumadin by: Stop coumadin permanently Hold coumadin one day and reduce dose and recheck in 1-2 weeks. Administer vitamin K 2.5 mg po and reduce dose of coumadin, and recheck 1-2 weeks. Admit for treatment with FFP, IV vitamin K, and resume coumadin once INR normalizes.

40 Mr. Mozart is 72 yo, and has AFIB, and is on coumadin. His chadsvasc score is 3. His INR is 12. He is not bleeding. Proper management could be: Stop coumadin, admit to hospital, monitor, and give FFP, vitamin K Hold coumadin two days and reduce dose and recheck in 1-2 weeks. Administer vitamin K 2.5 mg po, hold comadin 2 days and reduce dose of coumadin, and recheck 1-2 weeks. Stop coumadin permanently. Too risky.

41 Mr. Mozart is 72 yo, and has AFIB, and is on coumadin. His chadsvasc score is 3. His INR is 12. He is not bleeding. Proper management could be: Stop coumadin, admit to hospital, monitor, and give FFP, vitamin K Hold coumadin two days and reduce dose and recheck in 1-2 weeks. Administer vitamin K 2.5 mg po, hold comadin 2 days and reduce dose of coumadin, and recheck 1-2 weeks. Stop coumadin permanently. Too risky.

42 Vitamin K IV vitamin K Life-threatening Bleeding: 10 mg IV SLOW over minutes. May repeat at 12 hour intervals Oral Vitamin K mg Subcut vit K 10mg

43 Metaanalysis of 21 trials. Vit K for high INRs % corrected at 24 hours Placebo Subcutaneous IV Oral

44 Mr. Bach presents to the ER with active GI bleeding and a hematocrit of 22, hemoglobin of 7. His INR is 3.2. He is on coumadin. He has AFIB and a CHADSVASC score of 4. Management of his bleeding and high INR should include: Stop coumadin. Administer PRBC. Resume coumadin when INR returns to normal and bleeding stops. Stop coumadin. Administer PRBC. Administer Vitamin K. Administer four factor prothrombin complex concentrate. Continue coumadin, but lower dose, and administer PRBC. Administer Praxbind

45 Mr. Bach presents to the ER with active GI bleeding and a hematocrit of 22, hemoglobin of 7. His INR is 3.2. He is on coumadin. He has AFIB and a CHADSVASC score of 4. Management of his bleeding and high INR should include: Stop coumadin. Administer PRBC. Resume coumadin when INR returns to normal and bleeding stops. Stop coumadin. Administer PRBC. Administer Vitamin K. Administer four factor prothrombin complex concentrate. Continue coumadin, but lower dose, and administer PRBC. Administer Praxbind

46 Plasma products Fresh frozen plasma (volume, pulm injury TRALI) Unactivated prothrombin complex concentrates 4 factor Kcentra - II, VII, IX, X in inactive forms 3 factor - II, IX, X Activated PCC 4 factor FEIBA NF coag factors II, VII, IX, X

47 Recombinant activated VII (rfviia) Nonspecific procoagulant Onset 5-10 minutes. Low doses of 1mg IV have normalized the INR for warfarin patients.

48 Another small before-after study of 12 patients reported that the six patients receiving three-factor PCC compared with six age- and sexmatched historical controls given FFP had a mean INR correction time of 41 min for PCC vs 115 min for FFP

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50 Anticoag is reversed fully: Agent Half Life Fully resolved by: Dabigatran Pradaxa hours days Rivaroxaban Xarelto 5-9 hours 1-2 days Apixaban Eliquis 8-15 hours days Edoxaban Savaysa 6-11 hours days

51 Risk of bleeding - NOACs Lower or similar to warfarin. Higher risk of GI bleeding in patients over 65 receiving dabigatran vs warfarin Compared with warfarin DOACs rr major bleeding 0.72, fatal bleeding 0.53, ICH 0.43, major gi bleeding crossed 1.0 Major bleeding in af patients: 2-3 % Aspirin doubles risk

52 Managing Bleeding --- NOACS Blood Products FFP Activated PCC (FEIBA) prothrombin complex concentrate, factor VIII inhibiting bypass activity. PRBC Platelet transfusions

53 Plasma products Fresh frozen plasma (volume, pulm injury TRALI) Unactivated prothrombin complex concentrates (25x concentrated) 4 factor Kcentra - II, VII, IX, X in inactive forms 3 factor - II, IX, X Activated PCC 4 factor FEIBA NF coag factors II, VII, IX, X

54 Apixaban (Eliquis) Hepatic renal clearance 9-14 hours Consider apcc (Kcentra), or FEIBA Not dialyzable.

55 Dabigatran (pradaxa) Eliminated renal hours Agents to reverse: Idarucizumab, FEIBA, KCENTRA, or hemodialysis.

56 Rivaroxaban Hepatic / Renal 5-9 hours. K CENTRA, FEIBA Not dialyzable

57 Idarucizumab (Praxbind) PRAXBIND is a humanized monoclonal antibody fragment (Fab) indicated in patients treated with Pradaxa when reversal of the anticoagulant effects of dabigatran is needed: For emergency surgery/urgent procedures In life-threatening or uncontrolled bleeding Fab binds directly to dabigatran and its metabolites with higher affinitiy than dabigatran to thrombin; this neutralizes dabigatran s anticoagulant effect.

58 Idarucizumab (Praxbind) Dose: 5 gm Preparation: 2 separate vials of 2.5 mg/50ml idarucizumab Store vials at 2-8 C; up to 48h at room temp in box; 6 hrs exposed to light IV as two consecutive infusions or bolus injection Fab binds directly to dabigatran and its metabolites with higher affinitiy than dabigatran to thrombin; this neutralizes dabigatran s anticoagulant effect. Renal impairment doesn t affect reversal

59 Idarucizumab (Praxbind) CONTRAINDICATIONS: NONE Risks: elevation of thromboembolic risk; hypersensitivity. Metabolism: biodegrated and incorporated into general protein synthesis.

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61 Idarucizumab (Praxbind) RE-VERSE AD Trial Single cohort case series 123 patients. 66 patients with serious bleeding 57 requiring urgent procedure. Primary Endpoint: maximum reversal of dtt or Ecarin clotting time (ECT) Results: medium maximal reversal in first 4 hours was 100%. >89 % achieve complete reversal. Unbound dabigatran concentration was <20 ng.ml in all but one patient. Thrombotic events occurred in 5 patients dvt, pte, nstemi, cva. ONLY ONE OCCURRED <72 hrs after drug. Time to cessation of bleeding: 11.4 hours

62 Idarucizumab (Praxbind) In conclusion, idarucizumab rapidly and completely reversed the anticoagulant activity of dabigatran in 88 to 98% of patients. There were no safety concerns among the 90 patients involved in this study including patients who were given idarucizumab on clinical grounds but were later found to have had normal results on clotting tests at baseline or among the more than 200 volunteers who were administered idarucizumab in previous studies.

63 Stop anticoagulant Vitamin K - IV PO - SQ - FFP PCC prothrombin complex concentrate K centra apcc FEIBA PRAXBIND

64 Future directions Small molecule antidote PER977; Perosphere binds direct thrombin inhibitors, factor Xa inhibitors and heparins. Factor Xa inhibitor antidote andexanet alfa

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66 Managing Anticoagulation after a GI bleed Up to 15% of patients on anticoagulant will have GI bleed. >25% will not restart them (personal preference or doctor directed) AF patients are 4 x more likely to die of stroke than GI bleed. If CHADSVASC score is 2 then resume anticoag. Lean towards warfarin or eliquis (they seem to have less GI bleeding risk) Pradaxa seems to be more risky for GI bleeding Try to start anticoag 7 days after GI bleeding stops and try not more than 2 weeks.

67 New guidelines 2016 NOACs are suggested OVER warfarin for intial and long term treatment of VTE without cancer Routine use of compression stockings is no longer pushed New isolated subsegmental pulmonary embolism treatment

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69 Anticoagulation and Bleeding Ralph Buckley MD FACC 2016