Anticoagulation and Reversal John Howard, PharmD, BCPS Clinical Pharmacist Internal Medicine Affiliate Associate Clinical Professor South Carolina College of Pharmacy
Disclosures I have no Financial, Industry, or Proprietary disclosures Off Label medication use will be discussed
Objectives After this presentation the audience will be able to: Discuss pharmacology of novel oral agents Describe risk factors for hemorrhage Describe agents used to stop hemorrhaging Develop an algorithm for life threatening hemorrhages
Clotting Cascade Damaged surface XII XIIa Trauma XI XIa VIIa VII IX IXa VIIIa Tissue factor X Xa X UFH Va LMWH Prothrombin II (Thrombin) Xa inhibitors Fibrinogen Fibrin VKA XIIIa DTI Fibrin clot
Agents Vitamin K antagonists Warfarin Direct Thrombin Inhibitors (DTI): Dabigatran (Pradaxa ) Factor Xa Inhibitors: Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban (Under development)
FDA Indications FDA Supported Indications Reduce the risk of systemic embolism in patients with non-valvular AFib DVT prophylaxis in knee/hip replacement Treatment of DVT/PE and extended Tx Non-FDA Approved Indications Treatment of DVT/PE DVT prophylaxis in knee/hip replacement * Investigational Acute Coronary Syndromes* Apixaban Dabigatran Rivaroxaban Rivaroxaban Rivaroxaban Apixaban Dabigatran Apixaban Dabigatran Rivaroxaban
Atrial Fibrillation Pharmacokinetic Comparison Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Dosing Interval Daily BID Daily BID Half life (t 1/2 ) hr 40 12-17 4-9 12 Onset Slow Rapid Rapid Rapid Peak Effect 5-7dys 1-2hrs 2-4hrs 3hrs Monitoring Yes No No No Drug Interactions High Drugs/food Moderate P-gp Moderate 3A4, P-gp Low 3A4, P-gp Reversal Yes No No No Renal Dose No Yes Yes Yes Bleeding ++ + + +/- Warfarin, Dabigatran, Rivaroxaban, Apixaban. LexiComp. Hudson, OH. 2013.
Hemorrhage Risk Factors Demographics Age (>75y/o) Low Body Mass (<50kg) Comorbidities Renal Insufficiency Liver Disease Prior hemorrhage Stroke Hx Peptic Ulcer Disease Concomitant Medications Intensity of anticoagulation P2Y12 inhibitor (clopidogrel, prasugrel, ticagrelor) Aspirin others Ageno. Chest 2012; 141: e44s-e88s.
Risk Stratify Safety HASBLED Risk Factor Points 14 Bleeds Hypertension 1 Abnormal Renal Function Liver Function Stroke 1 Bleeding 1 Labile INRs 1 Elderly 1 Drugs Alcohol 1 1 1 1 P e r 1 0 0 p t y r s 12 10 8 6 4 2 0 0 1 2 3 4 5 Points Pisters et al. Chest 2010; 138: 1093-100
Bleeding and Reversal Warfarin Vitamin K PO or IV Plasma Recombinant Factor VII Prothrombin Complex Concentrates (PCC)
Then Ansell. CHEST. 2008;133;160-198
Now INR Bleeding Therapeutic Options > 3.0 10 No Hold warfarin until INR returns to normal range bleeding >10 No bleeding Hold warfarin and give vitamin K 2.5-5mg PO * Any INR Serious or lifethreatening bleeding Hold warfarin and administer PCC and supplement with vitamin K 5-10mg IV * infusion and repeat as necessary Alternatively, FFP or recombinant VIIa may be supplemented with vitamin K 5-10 mg IV infusion may be used instead of PCC * Low dose reduces INRs 6.0-10 to < 4.0 in 1.4 days after PO or 24 hrs after IV. High dose IV vit K begins reducing INR within 2 hrs with a correction to normal generally by 24 hrs. Holbrook. CHEST. e152-e184
CHEST and ICH Guidelines Holbrook. CHEST. e152-e184, AHA/ASA ICH Guidelines. Stroke 2010;41:2108-2129.
Bleeding and Reversal DTI No direct antidote Prothrombin Complex Concentrates (PCC) Recombinant Factor VII Plasma Dabigatran is dialyzable Xa Inhibitors No direct antidote Under development (Andexanet alfa, Portola Pharmaceuticals) Prothrombin Complex Concentrates (PCC) Recombinant Factor VII Plasma
PCC Confusion ISMP. Aug. 8, 2013.
Clotting Cascade Damaged surface XII XIIa Trauma XI XIa VIIa VII IX IXa VIIIa Tissue factor X Xa X Xa inhibitors VKA Prothrombin Va II (Thrombin) DTI Fibrinogen Fibrin XIIIa Fibrin clot
Agents Generic Name Brand Name Approved Uses PCC - 4 Factor Kcentra (Octaplex, Beriplex) Reversal of acute major bleeding due to warfarin Activated PCC - 4 Factor Feiba Hemophilia A and B PCC 3 Factor Recombinant Factor VIIa Profilnine SD NovoSeven RT Hemophilia B with factor IX deficiency Patients with factor VII deficiency or with hemophilia A or B Kcentra Package Insert. CSL. April;2013. Feiba. Medical letter. Baxter. 2;2011. Profilnine SD. Factor Levels. Grifols. 03/12. NovoSeven. LexiComp. Hudson, OH. 2013.
Factor Content Kcentra 4 18 11 16 23 19 14 Feiba NF 4 18 12 21 19 15 15 Profilnine SD 3 40 Trace 37 23 rfviia N/A 100 Kcentra Package Insert. CSL. April;2013. Feiba. Medical letter. Baxter. 2;2011. Profilnine SD. Factor Levels. Grifols. 03/12. NovoSeven. LexiComp. Hudson, OH. 2013.
Pro Con Table Agent C o s t A v a i l V o l u m e Infus Time Admix Time O n s e t Effectiv eness Infect Risk Thrombo sis Risk FFP + Lg 120 min - - - ++ - Kcentra $$ - Sm 20 min ++ ++ ++ + + FEIBA $$$ - Sm 15 min + ++ ++ + ++ Profilnine $ - Sm 15 min + + + + + NovoSeven $$ - Sm Push + + - - +++ Kcentra. LexiComp. Hudson, OH. 2013. Feiba. LexiComp. Hudson, OH. 2013. Profilnine SD. LexiComp. Hudson, OH. 2013. NovoSeven. LexiComp. Hudson, OH. 2013. Cupp. Pharmacist s Letter 291012. Oct. 2013.
Rebound Drug Effects Anticoagulation Reversal Pharmacokinetics Agent Onset Duration Rebound of Anticoagulant Protamine 5 min Irreversible Likely with SBQ dosing from postponed drug delivery Vitamin K 4-12hrs Days for INR Dose dependent Fresh Frozen Plasma (FFP) 1-4hrs 6hrs 4-6hrs Prothrombin 10- Complex 15min Concentrate (PCC) 12-24hrs 12hrs rfactor VII 10min 4-6hrs 6-12hrs
Full Anticoagulation Reversal for Life Threatening Hemorrhage Oral Drug Generic Brand Reversal Strategy Vit K Antagonist Warfarin Coumadin PCC - 4 factor + Vitamin K 10mg IV Factor Xa Inhibitor Rivaroxaban Apixaban Edoxaban Xarelto Eliquis PCC - 4 factor DTI Dabigatran Pradaxa PCC - 4 factor UFH Heparin N/A LMWH Factor Xa Inhibitor Enoxaparin Dalteparin Lovenox Fragmin Immediately after IV UFH bolus: 1mg protamine per 100 units heparin 8hrs since dose: 1mg of protamine per 1 mg of enoxaparin 8hrs since dose: 1 mg of protamine per 100 anti-xa units Fondaparinux Arixtra PCC - 4 Factor 30-60min post UFH: 0.5mg protamine per 100 units heparin 8-12hrs since dose: 0.5mg of protamine per 1 mg of enoxaparin 8-12hrs since dose: 0.5 mg of protamine per 100 anti-xa units
Dosing As literature comes forth, focus on the outcome! Laboratory reversal versus hematoma reduction! The goal is to stop the bleed, not the surrogate marker lab value that may lag behind. Pre-Treatment INR Dose of 4F-PCC (Units of Factor IX) Maximum Dose (Units of Factor IX) 2 to <4 25 units/kg 2500 units 4-6 35 units/kg 3500 units >6 50 units/kg 5000 units Which dose should your warfarin, rivaroxaban, dabigatran, apixaban patient receive? CHEST guidelines suggest?
Questions?
Which of the following would you order for a 65y/o male with a life threatening ICH on warfarin with an INR of 3.0 GFR of 60ml/min? A. Vitamin K 10mg IV B. Plasma C. Vitamin K 10mg IV + Plasma D. PCC - 3 factor + Vitamin K 10mg IV E. PCC - 4 factor + Vitamin K 10mg IV
Which of the following would you order for a 65y/o male with a major bleed on warfarin with an INR of 5.0 and GFR of 60ml/min? A. Vitamin K 10mg IV B. Plasma C. Vitamin K 10mg IV + Plasma D. PCC - 3 factor + Vitamin K 10mg IV E. PCC - 4 factor + Vitamin K 10mg IV
Which of the following agents has the highest thrombosis risk? PCC - 3 factor Factor VII containing products Plasma Vitamin K infusion Does multiple doses of PCCs increases thrombosis risk? True False What is surgical risk of thrombosis from routine use of PCCs? Pt is on anticoagulant for a reason (prothrombotic) Addition of PCC thrombosis risk, infection risk, cost Safer to delay surgery until anticoagulant eliminated?