Anticoagulation Essentials! Parenteral and Oral!
Anti-Xa and Anti-IIa!
Parenteral Anticoagulants! Heparin family (indirect anti-xa and anti-iia):! UFH! LMWH (enoxaparin, fondaparinux)! Direct thrombin inhibitors (anti-iia):! argatroban! bivalirudin!
Heparins: need AT!
Heparin size matters! enoxaparin! fondaparinux!
Anti-Xa vs Anti-IIa! Anti-IIa (anti-thrombin) activity a bit more potent as a thrombosis inhibitor.! Most of the time anti-xa can get the job done if enough is given.!
Anti-Xa Monitoring! Gold standard: enzymatic anti-xa assay dependent on patient s own anti-thrombin concentration.! Widely available, but has become more expensive.! Can t quantify the clinical gain for the increased cost over aptt; no studies.! Can t quantify the clinical gain of the aptt over no monitoring either; no studies.!
The aptt is Messy! Composite of increases and decreases in various factors, including anti-iia (anti-xa much less)! can cause false increases or decreases in aptt in heparinized patients.! Instruments and reagents are different.! Can t assume a fixed number range for therapeutic (e.g. 60-85 as in literature).!
Allina, 2015!
Heparin Monitoring: ANW! Anti-Xa monitoring since 1998. We will probably switch to aptt to save money.! Falsely low aptt: anti-thrombin deficiency, elevated heparin binding proteins, elevated factor VIII levels! Falsely high aptt: liver disease/vitamin K deficiency/warfarin, oral anti-xa therapy, lupus anticoagulant! Need periodic INR (not elevated by heparin)!
Are you here?! Yes! No!
Heparin Protocols! Must have institution-wide! Nurses and pharmacists! Loading doses sometimes too high or omitted! Infusion dose best if based on blood volume and age, but some are weight-only! BV = weight, height, gender!
UFH Dosing! Hospital protocols! heparin IV THERAPEUTIC protocol! heparin IV THERAPEUTIC protocol - OMIT loading dose/initial bolus! Online tools!
LMWH! enoxaparin (fondaparinux now rare)! SC; continues expensive! anti-xa based heparin/lmwh levels only way to monitor! Work in many situations, but losing to new oral anti-xa agents.!
enoxaparin! Renal dependent! Therapeutic 0.5-1.0 IU/mL to make up for loss of anti-iia activity.! Monitoring needed in extremes of weight or renal function, or excess clotting or bleeding risks.! enoxaparin SC THERAPEUTIC protocol! Online tool exists!
Heparin Bleeding! UFH is gone in 3-4 hours in most patients.! Online protamine dosing tool for rare patient.! works only a little with enoxaparin because 80% of anti-iia activity is gone!
HIT! Decreasing! 7+ days of therapy or repeat use! 50% drop in platelet count from recent level.! Venous and arterial clots!
Suspected HIT! Higher suspicion, stop heparin and test! Low suspicion, test first and stop if positive! heparin antibodies IgG specific (96% sensitive, 93% specific)! if positive, notice whether weak or strong! if negative, only 0-2% remaining chance depending on prior probability!
HIT Treatment! Stopping heparin rarely enough! argatroban pharmacy THERAPEUTIC protocol! vascular volume drug with renal clearance! anti-iia monitoring assay! TSOACs probably work! No warfarin until platelet count normal!
Oral Anticoagulants! Indirect: warfarin! reduces multiple precursor factor levels! Target specific:! dabigatran (Pradaxa): anti-iia! rivaroxaban (Xarelto): anti-xa! apixaban (Eliquis): anti-xa! edoxaban (Lixiana): anti-xa! betrixaban (??): anti-xa!
Coumarins and Vitamin K! II VII IX X C S Liver Fresh! Active Inactive Carboxylation Excess Vit K bypasses block. Active Inactive
Vitamin K factors PT VII XII PK, HMWK XI IX VIII aptt X V II Screening clotting tests! X V II TT F F
Vitamin K factor decline! Reduced II is the most important. VII IX X II
Vitamin K balance with warfarin! Normal! Therapeutic! warfarin! Large! warfarin! overdose! Vitamin K tank! Maint. K! Recycling K! Maint. K! Maint. K! Deficit! Deficit! Recycling K! Recycling K! Recycling K! In large overdose, patient may need 5 mg or more daily for up to a week to maintain normal INR.!
Vitamin K! Green and leafy. Fat soluble, absorbed in jejunum.! Bacterial synthesis in gut a minor source (may be absorbed passively in terminal ileum and colon).! Body stores are not long lived (a few weeks at best).!
Warfarin is Messy! Variation in dietary vitamin K! Genetic variation in warfarin metabolism! Drug-drug interactions! Variation in laboratory PT/INR measurements!
International Normalized Ratio! INR =! ( )! PTpatient! PTnormal! ISI ISI = Measure of reagent strength/sensitivity!
Are you sleeping?! Yes! No!
INR in Allina! All Allina hospitals now use the same instruments and reagents.! INRs agree well between hospitals.! Many Allina clinics use POC INRs which don t agree as well.! ANGMA clinic INRs performed in hospital reference labs!
Therapeutic INR: A. Fib! VTE, AF = target of 2.5
Predictors of Warfarin Dose! Actual weight (dose increases with weight)! Age (dose decreases with age)! Both account for half of variation; rest is genetics and diet! It is trial and error from the beginning.! Don t give a high initial load!
Load and No-load approach!
Warfarin protocols: ANW/ ANGMA! Online warfarin initiation and chronic control protocols are used by pharmacy in hospital and nursing in clinics.! Versions of the tools are available in the online ANW tool set.!
Warfarin Control! Organized warfarin control program (face-to-face or over the phone) improves clinical outcomes.! Patient populations make a big difference in control.! Typical published results: 50-60% of INR values in therapeutic range.!
Lupus anticoagulant & INR! Falsely high in about 10% of chronic LA patients! Cannot predict for any patient.! Confirm accuracy of INR with chromogenic factor X when at steady state.! Falsely high INR means use CFX or don t use warfarin.!
CFX and INR! Control patients: some normal pre-operative, rest on warfarin CFX %!
Temporary Warfarin Reversal! Few surgeries done with elevated INR; some at 1.5.! Dental surgery often with special mouth wash.! Warfarin held for 5 doses before procedure (last dose 6 days before)! Bridging is needed only in highest risk conditions.!
The High INR! >> 4.5: vitamin K! Oral vitamin K can work! IV vitamin K: time critical or doubt about GI absorption.! Don t use SC! High vitamin K doses may make refractory to warfarin for up to 1-2 weeks.!
Bleeding with warfarin! External bleeding:! Stop warfarin and give vitamin K (pharmacy to dose order)! FFP if volume is needed (calculator to determine how much is needed)! PCC if severe or head bleed!
PCC: Kcentra! FFP! Kcentra! II! 1! 1.1! VII! 1! 0.6! IX! 1! 1! X! 1! 1.3! Protein C! 1! 1! Protein S! 1! 0.7!
TSOAC! dabigatran (Pradaxa): anti-iia *! rivaroxaban (Xarelto): anti-xa! apixaban (Eliquis): anti-xa! edoxaban (Savaysa): anti-xa! betrixaban (??): anti-xa!
The Trouble! RCTs have had different patient risk factors (e.g. CHAD scores) and different rates of warfarin control.! Treatment benefits compared to warfarin were small and varied depending on patient risks and warfarin control.! There are no RCTs comparing different drugs so we are uncertain if one is better than another.! All have been equal to warfarin in anti-thrombosis and equal to or better in bleeding.!
The Simple Approach! We could look at tables of cost, formulary coverage, pharmacokinetics, cytochrome activity, and food effects.! OR! Look at the winners!
Winners: 2015! Formulary coverage: rivaroxaban! Lowest retail charge: edoxaban ($291/month)! rest are $329/month (warfarin = $50)! Lowest renal excretion: apixaban (27%)! rivaroxaban 66%!
Reversibility! Holding with good renal function:! rivaroxaban gone in 1-2 days! apixaban and edoxaban gone in 2-3 days! With worse kidneys, older patients, or more worry about bleeding with procedures:! add another day or two; check anti-xa!
TSOAC 2015! For a retail paying patient who wants the lowest cost: edoxaban (Savaysa)! Blue Cross: rivaroxaban (Xarelto)! Other insurance: must check copays! If money isn t an issue: apixaban (Eliquis) because of lowest renal excretion!
When will warfarin be gone?! When the monthly cost of a newer agent gets to about $100-150! AND! andexanet alpha available: immediate reversal agent entering phase 3 trials with rivaroxaban and apixaban.!