12/27/2013

Outline Anticoagulation Reversal Common anticoagulants misc anticoagulants coumadin IIb/IIIa inhibitors Family Medicine Update Big Sky, Montana ASA LMWH January, 2014 ADP Inhibitors heparin Mark Tieszen, MD, FCCM, FCCP Sanford Medical Center—Fargo DTI/XaI associated with Critical Care Medicine Procoagulants [email protected] disease states novoseven liver disease TXA uremia DIC

Premise Coumadin

Premise of this lecture is that you have a Risk of major bleeding is 1-3 % per year patient with a life-threating bleeding Varies depending on the intensity of the complication associated with an anticoagulation and patient risk factors coagulopathy How aggressive you are in any individual patient always relies on clinical judgment

Coumadin Vitamin K

Vitamin K 10 mg IV Give IV FFP 2 units IV previous incidence of anaphylaxis was PCC 25 units/kg IV secondary to a diluent which is no longer present in the drug PO better than SC Onset 12-24 hours Duration 12-24 hours

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FFP PCC

Dosing guidelines not accurate Prothrombin-complex concentrate Recommend 2 units to start and redose Factor IX complex (Profilnine 9) Onset 30-60 minutes INR < 4: 25 units/kg Duration 2-4 hours INR > 4: 50 units/kg Onset 10 minutes Duration 60 minutes

Coumadin Reversal Protocol PCC

Order the Vit K, FFP, PCC It is a medicine not a blood product Repeat INR 10 minutes after PCC finished Dispensed by pharmacy not blood bank Give an additional 25 u/kg of PCC if INR Long shelf life still too high Expensive To OR with FFP hanging PCC-3 (3 factor PCC) Follow INR Q 4 hours and give additional FFP if INR rebounds

PCC-4 Aspirin

4 factor PCC Many of our patients are on ASA and PCC-3 plus aVIIr many of those on another Should be a better hemostatic product anticoagulant as well but no evidence based The increased risk of bleeding with the recommendations for use addition of ASA is unclear Very Expensive

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Risk of ICH ASA

ASA plus Coumadin Affects the platelet in the bone marrow at One study of 10,000 elderly risk the time the platelet was formed increased threefold not a circulating effect 0.3 % to 0.9 % per year Not dose dependent Another large case-control study showed 7 day lag no increased risk The patient on 81 mg ASA q day for at least 7 days = full antiplatelet effect Acute ASA overdose = no antiplatelet effect

Aspirin ASA reversal

7 day irreversible platelet One unit single donor platelets dysfunction Platelet dysfunction test (replaces bleeding time) add reagents (ADP, epi) and measure time to aggregation

ADP Inhibitors ADP Inhibitors Bleeding Risk clopidogrel (Plavix) Incidence of major bleeding reported as prasugrel (Effient) 4-5 % ticagrelor (Brilinta) Limited data on drug effects once a ticlopidine (Ticlid) bleeding event has occurred Limited data on how to reverse antiplatelet effect

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P2Y12 Platelet Function Test ADP Inhibitor reversal reported as % inhibition desmopressin (DDAVP) IV 24 mcg Considered reversed if < 20 % 1 unit of single donor platelets Test not accurrate if: Hgb < 26 % platelet count < 50,000 if received Glycoprotein IIb/IIIa inhibitor Integrillin within 48 hours Reopro with in 10 days

Direct Thrombin Inhibitors / DTI/XaI Reversal Factor Xa Inhibitors DTI/XaI Limited data dabagatran (Pradaxa) PCC 50 units/kg rivaroxaban (Xarelto) Recommend PCC4 if available else give apixaban (Eliquis) PCC3 Can add 1 mg of rVIIa to PCC3 to make PCC4

dabigatran rivaroxaban

PCC 50 units/kg PCC 50 units/kg 4 hours of hemodialysis may remove up Half life 5-9 hours if hepatic and renal to 68 % of active drug function (CrCl > 80) are normal Half-life depends on creatinine clearance Half life 11-19 hours if elderly CrCl > 50: 24 hours Half life 48+ hours if hepatic/renal failure CrCl < 50: 48-96 hours MOA: XaI MAO: DTI

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apixiban Procoagulants

PCC 50 units/kg Novoseven Half life 12 hours if normal hepatic and TPX renal function PCC (discussed earlier) Half life 48+ hours if elderly or hepatic/renal failure MOA: XaI

Novoseven Novoseven in trauma

Recombivent activated factor VII Small series showed benefit rVIIa Best results in diffuse multifocal A lot of enthusiasm when first released oozing No evidence based guidelines about how Not helpful in large vessel bleeding to use No longer used much Small case studies used in a variety of settings

Novoseven in ICH Novoseven use

Decreased the size of the To be effective must reverse: intracranial hemorrhage by acidosis imaging criteria hypofibrinogenemia No benefit in clinical recovery hypothermia Studied in both coumadin and non- Should only be used after 10 u RBC and coumadin bleeds without clear adequate FFP, platelets and cyro benefit

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Dose rFVIIa Tranexamic acid (TXA)

30-90 mcg/kg Inhibits fibrinolysis by competitively inhibiting plasmin activity and plasminogen activation Dose can be repeated in 30 minutes Half-life approximately 2 hours New evidence indicates smaller Multiple dosing regimens are employed based doses just as effective as larger on indication doses Tranexamic acid is associated with cerebral infarction in studies of patients with 3,000 - 9,000 dollars a dose subarachnoid hemorrhage; however, thromboembolism with the use of tranexamic acid is rare

CRASH 2 CRASH 2 Entrance Criteria

Multicenter RCT 20,211 adult trauma Adult trauma patients with significant patients with, or at risk of, significant hemorrhage systolic blood pressure bleeding within 8 h of injury to either <90 mm Hg or heart rate >110 beats per tranexamic acid or placebo min, or both, loading dose 1 g over 10 min then or who were considered to be at risk of infusion of 1 g over 8 h significant hemorrhage, and who were within 8 h of injury

CRASH 2 Results

All-cause mortality was significantly IIb/IIIa inhibitors reduced with tranexamic acid LMWH 14.5% vs 16.0%; relative risk 0.91, 95% heparin CI 0.85–0.97; p=0.0035) The risk of death due to bleeding was significantly reduced 4.9% vs 5.7%; relative risk 0.85, 95% CI 0.76–0.96; p=0.0077

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Glycoprotein IIb/IIIa abciximab (Reopro)

Antibodies and receptor antagonists Biological half-life 8 hours Strategies for reversal dependent on Unbound fraction low individual agents half-lifes and – Platelet transfusion will reverse unbound fractions abciximab eptifibatide tirofiban roxifiban* orbofiban* sirofiban* *not available in US yet

eptifibatide (Integrillin) Glycoprotein IIb/IIIa Reversal tirofiban (Aggrastat) Biological half-life is 4 hours No evidence based Unbound fraction large meaning platelet recommendations transfusion will not reverse 2 units platelets most commonly Renal clearance used strategy – Unclear if dialyzable

Low Molecular Weight LMWH monitoring Heparin Typical half-life is 12 hours PTT not useful Unless in renal failure Anti-factor Xa assay CrCl < 30 not available every place half-life doubled does not account for all the anticoagulant activity of LMWH Recommendation is to use one half typical dose in renal dysfunction

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LMWH antidotes Protamine and LMWH

No evidence based Protamine completely neutralizes the recommendations antithrombin activity of LMWH but not the all of the anti-Xa activity Protamine 1 mg protamine for every 100 units anti- DDAVP Xa activity 25 mcg IV – enoxaparin (Lovenox) 1 mg = 100 anti-Xa can give every 12 hours units May repeat half the dose if bleeding tachyphlaxsis at 6 doses continues

Protamine Toxicity Heparin

Is a weak anticoagulant Unfractionated heparin (UFH) – Given repeat dose once the initial heparin Most bleeding occurs with appropriate has been reversed will result in more administration of heparin with PTT in bleeding the therapeutic range Does cause hypotension and bradycardia Half-life is 90 minutes – Give slow – Do not have to treat the bolus of heparin if – Calcium helps bolus is over 2 hours ago Can cause anaphylaxis

Heparin Reversal = Protamine Protamine Toxicity

Dose 1 mg IV per 100 units of UFH Is a weak anticoagulant Bolus of 5000 units within the last 2 – Given repeat dose once the initial heparin hours = 50 mg of protamine has been reversed will result in more bleeding Infusion of 1250 u/hr = 25 mg of protamine Does cause hypotension and bradycardia – Give slow – 1250/h x 2 hours = dose of 2500 – Calcium helps May check PTT to confirm reversal Can cause anaphylaxis May repeat dose if PTT still elevated

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Coagulopathies associated Liver disease with disease states Liver disease Vitamin K as in coumadin Uremia 2-4 units FFP DIC Do not expect INR to completely correct

Uremic platelet dysfunction DIC

Platelet transfusion does not work Factor replacement if bleeding Mechanism of dysfunction occurs von Willebrand factor dysfunction Platelets if count low DDAVP FFP if PT/INR high Cryoprecipitate Cryoprecipitate if fibrinogen low Acute hemodialysis typically keep fibrinogen > 150 k

Questions

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