Venous Thromboembolism Part II

Venous Thromboembolism Part II Catherine Van, PharmD, BCPS Assistant Professor, Pharmacy Practice 1 VTEcovers DUTandPE a of paralysis effects cording spiral obis itg bloodflow IAbnormal dysfunction hypockguality pregnancy BTthcondal lipid Antipopho VTE Treatments (Cont.) • Pharmacological options • Duration of therapy 3 importantl GUIDELINE - VTE PHASES OF MANAGEMENT a  Initiation phase (~5-21 days depending on anticoagulant regimen selected): The initial vid provision of anticoagulants following VTE diagnosis 2  Treatment phase (3 months): The period after initiation that completes treatment for the acute VTE event 3  Extended phase (3 months-no planned stop date): The period of anticoagulant use at full or reduced dose for the goal of secondary prevention it Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report. CHEST 2021;160(6):22474 2259. PHARMACOLOGICAL TREATMENT OPTIONS Patient Population Options Acute DVT of the leg or PE and no cancer DOAC (dabigatran, rivaroxaban, apixaban, or edoxaban) is suggested over warfarin therapy (Grade 2B) Acute DVT of the leg or PE and no cancer who O with are not treated DOAC to cost warfarin therapy is suggested over LMWH for long-term therapy (Grade 2C) Acute DVT of the leg or PE and cancer (cancerassociated thrombosis) Oral Xa inhibitor (apixaban, edoxaban, rivaroxaban) recommended over LMWH for the initiation and treatment phases of therapy (New 2021 recommendation) Apixaban or LMWH may be the preferred option in patients with luminal GI malignancies D e o Goran Antithrombotic Therapy and Prevention of Thrombosis, 9th ED: ACC Guidelines. CHEST 2012;141(2)(Suppl):7S-47S. Antithrombotic Therapy for VTE Disease. CHEST 2016;149(2):315–352. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. Pharmacotherapy: A Pathophysiologic Approach, 10e., Ch19: Venous Thromboembolism. New York: McGraw-Hill Education, 2017. Antithrombotic Therapy for VTE Disease. CHEST 2021;160(6):2247-2259 5 PHARMACOLOGICAL TREATMENT OPTIONS Patient Population Acute DVT of the leg or PE treated with warfarin Options Initial treatment with LMWH, fondaparinux, IV UFH, or SC UFH is recommended (Grade 1B) g Recommend early initiation of warfarin (eg, same day as parenteral therapy is started), and continuation of parenteral anticoagulation for a minimum of 5 days and until the international normalized ratio (INR) is 2 or above for at least 24 hours (Grade 1B) g Is Therapeutic INR range of 2-3 (target INR of 2.5) is recommended for all treatment durations (Grade 1B) Antithrombotic Therapy and Prevention of Thrombosis, 9th ED: ACC Guidelines. CHEST 2012;141(2)(Suppl):7S-47S. 6 PHARMACOLOGICAL TREATMENT OPTIONS Patient Population Options Acute DVT of the leg LMWH or fondaparinux is suggested or PE over IV UFHto monitor frequently (Grade 2C [2B for fondaparinux in PE]) and over SC UFH (Grade 2B for LMWH; Grade 2C for fondaparinux) Antithrombotic Therapy and Prevention of Thrombosis, 9th ED: ACC Guidelines. CHEST 2012;141(2)(Suppl):7S-47S. 7 Duration of Therapy Proximal DVT or PE Provoked 3 months (Grade 1B) Cancerassociated Unprovoked potato moist Low bleeding risk Moderate bleeding risk Extended therapy Extended therapy (first (first VTE - Grade 2B, second VTE Grade 1B) VTE - Grade 2B, second VTE - Grade 2B) Extended therapy piers Trist High bleeding risk (Grade 1B) 3 months (first VTE - Grade 1B, second VTE - Grade 2B) Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report, 10th ed: American College of Chest Physicians Evidence-Based Clincal Practice Guidelines. CHEST 2016;149(2):315–352. 8 ADDITIONAL ACCP RECOMMENDATIONS  In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually) week everymonthevery  In patients with DVT of the leg or PE who receive extended therapy, there is no need to change the choice of anticoagulant after the first 3 months unless patient circumstances dictate a change in therapy (Grade 2C)  In patients with acute DVT of the leg, we suggest not using compression stockings routinely to prevent PTS (Grade 2B) Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report, 10th ed: American College of Chest Physicians Evidence-Based Clincal Practice Guidelines. CHEST 2016;149(2):315–352. 10 it understand RECURRENT VTE  In patients with recurrent VTE while on warfarin __ therapy (in the therapeutic range) or on DOAC (and believed to be compliant), switching to treatment with LMWH at least temporarily is suggested (Grade 2C) Ingnth  In patients who have recurrent VTE while on long-term LMWH (and are believed to be compliant), increasing the LMWH dose by about one-quarter to one-third is suggested (Grade 2C) Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report, 10th ed: American College of Chest Physicians Evidence-Based Clincal Practice Guidelines. CHEST 2016;149(2):315–352. 11 QUESTION In patients with acute DVT of the leg or PE and no cancer, DOAC is suggested over warfarin therapy. First coamadin  True X tenpoffepy  False whenstop 0 Aftersdays 12 QUESTION – ASSIGNMENT CHECK By what routes of administration can UFH be given? a. b. c. d. e. IV and buccal administration IV and IM administration IV, IM, and oral administration IV, IM, and SQ administration IV and SQ administration I Treatmat To prophlyaxis ta 13 Parenteral Anticoagulants factor za andbox molecule Bigger y no • Unfractionated Heparin • LMWH (Lovenox®)to WBShalerweight factorNot • Fondaparinux (Arixtra®) • Direct Thrombin Inhibitors 14 Unfractionated Heparin (UFH) r  Mechanism of Action (MOA)  Potentiates action of antithrombin III thereby inactivating thrombin and factor Xa  Indications soFyi  Prophylaxis and treatment of thromboembolic disorders  Acute Coronary Syndrome (UA/NSTEMI, STEMI)  Percutaneous coronary intervention (PCI)  Dosing us  Thromboprophylaxis: 5000 units SC every 8 – 12 hours  Treatment of VTE: 80 units/kg IV bolus (max 10,000 units), followed by continuous infusion of 18 units/kg/hour (max initial infusion: 2,000 units/hour) (Use Actual Body Weight- ABW for Dosing)  Dose adjustments as required to obtain 1.5 – 2.5 x pt’s baseline aPTT Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. Pharmacotherapy: A Pathophysiologic Approach, 10e., Ch19: Venous Thromboembolism. 15 New York: McGraw-Hill Education, 2017. Unfractionated Heparin (UFH)  PK  Onset: IV – Immediate; SC – 20 to 30 minutes  Does not cross placenta or enter breast milk the  Renal dosing not required  Adverse effects  Bleeding, heparin induced thrombocytopenia (HIT) t  Hyperkalemia and osteoporosis (with long-term use)  Antidote/Reversal agent  Protamine sulfate  ~ 1mg:100units of heparin Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 16 Unfractionated Heparin (UFH)  Contraindications: uncontrolled active bleed, history of HIT, severe thrombocytopenia  Monitoring parameters aPTT every 6 hours after initiation and dosage change t Ms 2 Staph After reaching therapeutic range, monitor aPTT every 24 hours Platelets, Hgb, Hct at baseline and daily  UFH is recommended for patients with renal insufficiency  Often used upon admission per pharmacy protocol Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 17 Norenaladj UFH – CALCULATION t  MD orders heparin pharmacy to dose for patient MZ who is 45 t years old and weighs 60 kg.  Diagnosis: DVT; PMH: none; NKDA  Baseline pertinent labs  aPTT: 32.5  H/H: 14/42  Plt: 200 x 10 9 /L 80 N't Calculate the initial heparin bolus dose (in units) and infusion rate (in mL/hr). Premixed heparin bags contain 25000 units in 250 mL D5W. Round to the nearest 100 units for all calculations. twounits thy gifts MDI 25000 loounits foul Isola ont 18 NBones gadgets 2Sxptbaselineaptt UFH – CALCULATION ptwagut 60kg  You informed patient MZ’s nurse of the heparin bolus dose and infusion rate. You also ordered aPTT in 6 hours.  Six hours later, the value comes back at 43. Utilizing the O for the patient. protocol below, decide the heparin regimen Round to the nearest 100 units for all calculations.  PTT = less than 35; Bolus = 80 units/kg (max 5000 units); Infusion Rate = Increase by 4 units/kg /hr  PTT = 35-42; Bolus = 40 units/kg (max 5000 units); Infusion Rate = Increase by 2 units/kg /hr  PTT = 43-49; Bolus = 20 units/kg (max 3000 units); Infusion Rate = Increase by 2 units/kg /hr  PTT = 50-70; Bolus = 0; Infusion Rate = Continue same rate  PTT = 71-90; Bolus = 0; Infusion Rate = Reduce by 2 units/kg /hr  PTT = 90-140; Bolus = 0; Infusion Rate = Hold heparin for 1 hour, then reduce by 3 units/kg /hr  PTT = greater than 140; Bolus = 0; Infusion Rate = Hold heparin for 2 hours, then reduce by 3 units/kg /hr o 19 Wendt this UFH – CALCULATION  You informed patient MZ’s nurse of the heparin bolus dose and infusion rate. You also ordered aPTT in 6 hours.  Six hours later, the value comes back at 43. Utilizing the protocol below, decide the heparin regimen for the patient. Round to the nearest 100 units for all calculations. Imus Gonzo 1200units in fusion m 2 60 Rgonit1hr Additional Amur concentrationin love newreport PA a skiff 20 Low Molecular Weight Heparin (LMWH) enoxaparin (Lovenox®) MOA Anti-Xa by binding to anti-thrombin Indication: Fyi VTE prophylaxis and treatment ACS Boxed Warning epiduralorintrathecal Patient receiving neuraxial anesthesia or undergoing spinal puncture at risk of hematomas and subsequent paralysis Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 21 needreal dosing imported ENOXAPARIN (LOVENOX®) DOSING Indication and Renal function Acute DVT/PE treatment: CrCl ≥ 30 ml/min sa Dose Knowallofthist 1 mg/kg ABWySC q12h OR 1.5mg/kg ABW SC once daily- only for inpatient VTE treatment Acute DVT/PE treatment: CrCl < 30 ml/min 1 mg/kg ABW SC once daily DVT prophylaxis: CrCl ≥ 30 ml/min 40 mg SC once daily DVT prophylaxis: CrCl ≥ 30 ml/min (THA) 30 mg SC q12h (initiate ≥ 12 hours preop or ≥ 12 hours post-op) OR 40 mg SC once daily FoxalHip 30 mg SC q12h (initiate ≥ 12 hours preFalknerop or ≥ 12 hours post-op) DVT prophylaxis: CrCl ≥ 30 ml/min (TKA) DVT prophylaxis: CrCl < 30 ml/min 30 mg SC once daily Antithrombotic Therapy and Prevention of Thrombosis, 9th ED: ACC Guidelines. CHEST 2012;141(2)(Suppl):7S-47S. Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 22 LMWH  Contraindications: active major bleeding, history of immune-mediated HIT in past 100 days or in presence of circulating antibodies  Monitoring  Anti-Xa level monitoring not required in most cases  Anti-Xa levels recommended in pregnancy  Obtain peak anti-Xa levels four hours post dose (after 3rd dose)  Therapeutic range for anti-Xa levels for VTE Fyi  Prophylaxis dosing (in pregnancy): 0.2 – 0.6 anti-Xa units/mL  Treatment dosing (twice daily): 0.6 – 1 anti-Xa units/mL  Monitor platelets, Hgb, Hct, SCr Note: Do not expel air bubble from syringe prior to injection Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 23 Indirect Factor Xa Inhibitor  Fondaparinux (Arixtra®)  MOA  Inhibits Factor Xa via anti-thrombin  indirectly inhibits Factor Xa  Indications  VTE prophylaxis and treatment  Dosing Indication / Weight IEProphylaxis of VTE: ≥ 50 kg < 50 kg t Treatment of VTE: < 50 kg 50 – 100 kg > 100 kg Dose Important 2.5 mg SC daily Contraindicated 5 mg SC daily 7.5 mg SC daily 10 mg SC daily Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 24 Indirect Factor Xa Inhibitor Fondaparinux (Arixtra®)  Boxed Warning  Patient receiving neuraxial anesthesia or undergoing spinal puncture at risk of hematomas and subsequent paralysis  Contraindications  Severe renal impairment (CrCl < 30mL/min)  Body weight < 50 kg (for VTE prophylaxis)  Active major bleed  Bacterial endocarditis Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 25 Indirect Factor Xa Inhibitor  Monitoring  Anti-Xa levels, platelets, Hgb, Hct, SCr  Anti-Xa levels should be obtained 3 hours post dose (not recommended routinely)  Side effects  Bleeding  Local injection site reactions  Hypokalemia  Hypotension a  No antidote  Note: Do not expel air bubble from syringe prior to injection Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 26 DIRECT THROMBIN INHIBITORS  Argatroban  Bivalirudin (Angiomax®)  Will be discussed in HIT lecture 27 SUMMARY OF PARENTERALagent Apatow ANTICOAGULANTS Knows Pharmacological Options Drug Class/Mechanism of Action Unfractionated heparin Potentiates action of antithrombin III thereby inactivating thrombin and factor Xa Low molecular weight heparin (LMWH) (Lovenox®, Fragmin®) Anti-Xa by binding to antithrombin Fondaparinux (Arixtra®) Indirect factor Xa inhibitor Argatroban Bivalirudin (Angiomax®) Direct thrombin inhibitors I Route of Administration I 28 Bad COME SUMMARY OF PARENTERAL ANTICOAGULANTS Unfractionated Heparin  aPTT monitoring (all patients)  No adjustment for renal impairment  Active for Xa and IIa (thrombin)  Less $, not favored in guidelines Low-Molecular-Weight Heparinsor pregnancy  Anti-Xa monitoring (some patients)  Must be renally dosed  Mostly active for Xa Fondaparinux (Arixtra®)  Anti-Xa monitoring (rare)  Contraindicated in severe renal impairment (CrCl < 30 mL/min)  Only active for Xa 29 Oral Anticoagulants • Vitamin K antagonist (VKA) • Warfarin • New/Direct Oral Anticoagulants: • Dabigatran • Rivaroxaban • Apixaban • Edoxaban (VTE treatment only) • Betrixaban (VTE prophylaxis only) – Discontinued 30 VITAMIN K ANTAGONIST  VKA  Warfarin (Coumadin®)  MOA: Prevents vitamin K dependent synthesis for clotting factors II, 1972 7 VII, IX, X and proteins C and S by inhibiting epoxide reductase  Half-lives       Factor VII : 4 – 6 hours Factor IX : 21 – 30 hours Factor X : 27 – 48 hours Factor II : 42 – 72 hours t longest Protein C : 8 hours Protein S : 60 hours  Indicationsor Fy  Prophylaxis and treatment of stroke and systemic embolism in atrial fibrillation and cardiac valve replacement  Prophylaxis and treatment of DVT and PE  Reduction in risk of death, recurrent MI, and thromboembolic events status post MI Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 31 imported WARFARIN (COUMADIN®) Dosing Individualized oral daily dosing to achieve target INR  Rule of thumb  Low Dose: 2.5 mg PO daily; Elderly ≥ 60 years old, high bleeding risk, DDI, comorbidities (heart failure, liver disease, hyperthyroidism)  Standard: 5 mg PO daily; Most patients  High dose: 7.5 – 10 mg daily; Younger < 60 years old, healthier, ability to obtain daily INR, low bleeding risk Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 32 INR GOALS FOR ANTICOAGULATION TREATMENT Indication INR Goal Range VTE 2.0 – 3.0 Atrial fibrillation/atrial flutter 2.0 – 3.0 Prosthetic heart valve recomendati 2.0 – 3.0 only * Mechanical mitral valve warfarin 2.5 – 3.5 t Cerebrovascular disease 2.0 – 3.0 Left ventricular dysfunction 2.0 – 3.0 Myocardial infarction 2.0 – 3.0 Hypercoagulable condition, antiphospholipid antibody syndrome 2.0 – 3.0 Antithrombotic Therapy and Prevention of Thrombosis, 9th ED: ACC Guidelines. CHEST 2012;141(2)(Suppl):7S-47S. 33 WARFARIN (COUMADIN®) Allow sufficient time for changes in INR to occur when adjusting the dose. Maintenance dose changes should not be made more frequently than every 3 days. To adjust maintenance doses, weekly dose should be reduced or increased by 5% to 25%. Full effect of dose changes may not become evident for 5 to 7 days or longer. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. Pharmacotherapy: A Pathophysiologic Approach, 10e., Ch19: Venous Thromboembolism. New York: McGraw-Hill Education, 2017. 34 MAINTENANCE DOSAGE ADJUSTMENT ALGORITHM FOR TARGET INR OF 2.0 TO 3.0, NO BLEEDING goal INR < 1.5 1.5 to 1.9 2.0 to 3.0 weeks 3.1 to 3.9 4.0 to 4.5 Adjustment Increase Increase dose by 10– dose by 5– 20%; 10%* consider extra dose No change Decrease dose by 5– 10%* Hold for 0–1 day; then, decrease dose by 10% Next INR 4–8 days 1 week x the number of consecutive inrange INRs (max: 12 wks)^ 7–10 days 4–8 days 7–10 days *If INR is 1.8–1.9 or 3.1–3.2, consider no change with a repeat INR in 7–10 days. ^Example: If a patient has had 3 consecutive INRs within therapeutic range, schedule a return visit for 3 weeks. Federal Bureau of Prisons. Anticoagulation Protocol. https://www.bop.gov/resources/pdfs/anticoagulationprotocol2018.pdf 35 WARFARIN (COUMADIN®) PK two  Racemic mixture: R&S enantiomers  S enantiomer more potent at  Peak response: Full therapeutic effect 5-7 days  Duration: 2 – 5 days  Protein binding: 99%  Metabolism: S-enantiomer: CYP2C9, 3A4; Renantiomer: CYP3A4, 1A2, 2C19  Excretion: Urine (primarily as metabolites, 92%) Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 36 Netforprogestogen WARFARIN (COUMADIN®)  Adverse effects  Bleeding  Tissue necrosis (rare)  Antidotes/Reversal Agents  Vitamin K  Prothrombin complex concentrate  Fresh frozen plasma  Monitoring Festa to af  INR (daily to q3 days for 1 st week, then q7-14 days, then q4-12 weeks)  Hct, Hgb, signs/symptoms of bleeding  Pregnancy category X  Pregnancy category D for women with mechanical heart valves Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 37 APTT VS. PT/INR PT/INRas aPTT  Stands for activated partial thromboplastin time  Measure clotting time from the activation of factor XII 12 through the formation of fibrin clot (i.e. measuring integrity of intrinsic and common pathways of coagulation)  PTT prolongations are caused by factor deficiencies (factors VIII, IX, XI, and/or XII) or inhibitors (such as unfractionated heparin or argatroban) warfarin  Stands for prothrombin time/International Normalized Ratio  Measure clotting time from the activation of factor VII through the formation of fibrin clot (i.e. measuring integrity of extrinsic and common pathways of coagulation)  Due to variability of reagents and analyzers leading to variable PT levels, INR calculation was developed to help standardize PT values  One of the uses is for monitoring warfarin therapy my 38 WARFARIN (COUMADIN®) Fist Please Let Greg Brown Bring Peaches To Your Wedding Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 39 QUESTION – VKA (DOSAGE FORM COLOR) A pharmacy receives a prescription for warfarin 5 mg PO daily. What is the color of the warfarin tablet? a. b. c. d. e. Peach Green Yellow Pink Blue 40 WARFARIN (COUMADIN®) Drug-Drug Interactions INR INR 2C9 inhibitors 2C9 inducers Amiodarone Rifampin Antibiotic (Azoles antifungalfluconazole) Phenobarbital Bactrim safe Metronidazole Carbamazepine Phenytoin •When starting amiodarone, reduce warfarin dose by 30-50% •Pharmacodynamic drug interactions point •NSAIDs, antiplatelet agents, other anticoagulants, SSRI, SNRI e •Increase bleeding risk without increasing INR f off Bleeds Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 41 Diet and VKA Broccoli Spinach Green tea Kale Lettuce Avocado •Dietary vitamin K will help produce vitamin K-dependent clotting factors  Overcomes effect of warfarin •Patients must maintain a consistent vitamin K diet Lexi-Comp, Inc. (LexiDrugs® ) Mobile application. LexiComp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 42 VKA AND HERBAL SUPPLEMENTS Increase effects of warfarin: 5 G’s Garlic, ginger, gingko, ginseng (other types), glucosamine Decrease effects of warfarin: St. John’s wort (2C9 inducer), ginseng (American) Ge, B, Zhang, Z, Zuo, Z. Updates on the clinical evidenced herb-warfarin interactions. Evid Based Complement Alternat Med. 2014;2014:957362. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 43 VITAMIN K ANTAGONIST AND GENETICS Pharmacogenomic testing Haplotypes  CYP2C9  Presence of variant alleles CYP2C9*2 and CYP2C9*3 results in slower clearance of warfarin  lower doses  VKORC1 (Vitamin K Epoxide Reductase Complex 1)  AA genotype – sensitive to warfarin, requiring lower warfarin doses  Not routinely recommended  Delayed results  Useful information in guiding initial therapy if available 2 – 3 days Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. Dean L. Warfarin Therapy and the Genotypes CYP2C9 and VKORC1. 2012 Mar 8 [Updated 2016 Jun 8]. 44  Advantages  Once daily dosing  Oral treatment  Inexpensive  Antidote available WARFARIN (COUMADIN®)  Disadvantages  INR monitoring  Diet restrictions  Counseling Points  Treatment indication and duration of treatment  Self monitoring for s/sx’s of bleeding  DDIs  Contraception information in females of child bearing age  Maintain a consistent Vitamin K dietary intake  Coumadin medical ID alert options Lexi-Comp, Inc. (LexiDrugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Sh apiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 45 SIGNS AND SYMPTOMS OF BLEEDING  Unexpected bleeding or bleeding that lasts a long time  Red or black, tarry stool  Pink or brown urine  Unusual bruising  Coughing up blood  Vomiting blood or vomit that looks like coffee grounds  Unexplained pain, swelling, or joint pain  Unusual headaches, dizziness, or weakness  Recurring nose bleeds Warfarin Considerations for Use. https://www.acc.org/tools-and-practice-support/clinical-toolkits/atrial-fibrillationafib/anticoagulant-dosing-table/warfarin. Accessed 2/24/19. 46 QUESTION – VKA (INITIAL DOSING) YN, a 55-year-old male patient with DVT and a baseline INR of 1.1, is started on warfarin 5 mg daily on day 1 and day 2 as well as enoxaparin 80 mg SC BID. He has no history of malignancy, malnutrition, heart failure, alcohol abuse, or liver dysfunction. His INR today (Day 3) is 1.5. Select the best warfarin dose for Day 3. of ME Tay A. 10 mg standarddose so B. 5 mg C. 1 mg D. HOLD warfarin today 47 QUESTION – VKA (MAINTENANCE DOSING) Since hospital discharge, YN has been on warfarin 5 mg PO daily (INR target 2-3). INR for week 1 post discharge was 2.4. INR for week 2 post discharge was 2.6. He comes to clinic today for a third follow up visit (two weeks from the last appointment). INR today is 1.7. There is no s/ sx’s of bleeding. Pt states that he has started to eat green leafy vegetables consistently for a week to be healthier. He plans to continue doing this. He is not on any other medications. What recommendations would you make regarding YN’s warfarin regimen? A. Continue the current maintenance dose (5 mg PO daily) B. Recommend 5 mg PO daily M-Sat and 7.5 mg PO daily Sun C. Advise patient to stop eating green leafy vegetables 48 MAINTENANCE DOSAGE ADJUSTMENT ALGORITHM FOR TARGET INR OF 2.0 TO 3.0, NO BLEEDING INR < 1.5 1.5 to 1.9 2.0 to 3.0 3.1 to 3.9 4.0 to 4.5 Adjustment Increase Increase dose by 10– dose by 5– 20%; 10%* consider extra dose No change Decrease dose by 5– 10%* Hold for 0–1 day; then, decrease dose by 10% Next INR 4–8 days 1 week x the number of consecutive inrange INRs (max: 12 wks)^ 7–10 days 4–8 days 7–10 days *If INR is 1.8–1.9 or 3.1–3.2, consider no change with a repeat INR in 7–10 days. ^Example: If a patient has had 3 consecutive INRs within therapeutic range, schedule a return visit for 3 weeks. Federal Bureau of Prisons. Anticoagulation Protocol. https://www.bop.gov/resources/pdfs/anticoagulationprotocol2018.pdf 49 QUESTION – VKA INTERACTIONS Which effect would be predicted if a patient on warfarin with a stable INR is started on amiodarone? if Both oniodateret warfarinorimpaired reduction a. The INR would decrease and the patient may by so so experience bleeding b. The INR would increase and the patient may clot c. The INR would increase and the patient may experience bleeding d. The INR would decrease and the patient may clot e. The INR would not change 50 Direct Thrombin Inhibitor  Dabigatran (Pradaxa®)  MOA:  Direct thrombin inhibitor  Indications: Fist  Prophylaxis and treatment of DVT and PE and prevention of VTE recurrence  Non-valvular atrial fibrillation (AF) (to  risk of stroke and systemic embolism)  Postoperative thromboprophylaxis for hip replacement surgery Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 51 DABIGATRAN (PRADAXA®)  Dosing Indication and Renal Function Dose DVT/PE treatment and prevention and CrCl ≥ 30 mL/min 150 mg by mouth twice daily (after 5 – 10 days parenteral anticoagulation) DVT/PE treatment and prevention and CrCl < 30 mL/min Avoid use Postoperative 110 mg on day 1 then 220 mg PO daily up to 35 days Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 52 DABIGATRAN (PRADAXA®)  Boxed Warning  Patient receiving neuraxial anesthesia or undergoing spinal puncture at risk of hematomas and subsequent paralysis  Upon premature discontinuation, the risk of thrombotic events is increased  Contraindications  Active pathological bleeding  Patients with mechanical prosthetic heart valve(s) Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 53 DABIGATRAN (PRADAXA®)  PK:  t1/2 = 12 – 17 hours  Substrate of efflux P-gp transporters  Prodrug  Adverse effects  Bleeding, dyspepsia, gastritis like symptoms  Drug interactions  P-gp inhibitors and CrCl < 50  Avoid concurrent use  P-gp inducers  Avoid concurrent use  Antidotes/Reversal agents  Idarucizumab (Praxbind®) Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 2/24/2019. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 54 comebookototsts voyotat INHIBITORS AND INDUCERS P-gp Inhibitors Amiodarone Carvedilol Dronedarone Verapamil Dual P-gp and Strong CYP3A4 Inhibitors Dual P-gp and Strong CYP3A4 Inducers Is Ketoconazole Carbamazepine Itraconazole gasifiedPhenytoin Rifampin St. John’s wort Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 2/24/2019. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 55 MrPhys DABIGATRAN (PRADAXA®)  Counseling points  Administer with a full glass of water without regard to meals  Do not break, chew, or open capsules  Store in original container and discard 4 months after opening  Missed dose: take immediately unless it is within 6 hours of next dose  Interrupting treatment risk of thrombotic events  Pros  Lack of monitoring  No diet restrictions  Cons  GI irritation  Twice daily dosing  Renally dosed  DDI so Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 56 Direct Factor Xa Inhibitors  Rivaroxaban (Xarelto®)  MOA:  Factor Xa inhibitor  Indications:  DVT and PE treatment and prevention of VTE recurrence  Non-valvular atrial fibrillation (AF) (to  risk of stroke and systemic embolism)  Postoperative thromboprophylaxis for hip/knee replacement surgeries Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 57 RIVAROXABAN (XARELTO®)  Boxed warning  Patient receiving neuraxial anesthesia or undergoing spinal puncture at risk of hematomas and subsequent paralysis  Upon premature discontinuation, the risk of thrombotic events is increased  Contraindications  Active pathological bleeding Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 58 RIVAROXABAN (XARELTO®)  Dosing Indication and Renal function Dose DVT/PE treatment: CrCl ≥ 30mL/min 15 mg PO twice daily with food for 3 weeks, then 20 mg PO daily with food DVT/PE treatment: CrCl < 30mL/min Avoid use to Reduction in risk of recurrent DVT/PE after initial treatment 10 mg PO daily; following ≥6 months of therapeutic anticoagulation Postoperative DVT thromboprophylaxis 10 mg PO daily (start 6-10 hours after sx) for 12 – 14 days knee and 35 days for hip Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 59 RIVAROXABAN (XARELTO®)  PK:  t1/2 = 5 – 9 hours, 11 – 13 hours in elderly  Substrate of of CYP450 (3A4 - major) and efflux P-gp transporters  Adverse effects  Bleeding  Drug interactions: CYP3A4 and P-gp inhibitors and inducers  Dual P-gp and strong CYP3A4 inhibitors  Avoid concomitant use  Dual P-gp and strong CYP3A4 inducers  Avoid concomitant use  Antidotes/Reversal agents  Andexxa® Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 2/24/2019. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 60 RIVAROXABAN (XARELTO®)  Counseling points  Take with food at the same time each day (doses ≥ 15 mg)  Interrupting treatment risk of thrombotic events  Missed dose: 3 0  Twice daily dosing- take as soon as remember on same day, may take 2 doses at the same time to make up  Once daily dosing- take as soon as remember on same day  Pros  Dosed once daily (after 3 weeks)  No monitoring required  Cons  Not recommended for renal dysfunction  DDI Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 61 Direct Factor Xa Inhibitors  Apixaban (Eliquis®)  MOA  Factor Xa inhibitor  Indications  DVT and PE treatment and prevention of VTE recurrence  Non-valvular atrial fibrillation (AF) (to  risk of stroke and systemic embolism)  Postoperative thromboprophylaxis for hip/knee replacement surgeries Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 62 APIXABAN (ELIQUIS®)  Boxed warning  Patient receiving neuraxial anesthesia or undergoing spinal puncture at risk of hematomas and subsequent paralysis  Upon premature discontinuation, the risk of thrombotic events is increased  Contraindications  Active pathological bleeding Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 63 APIXABAN (ELIQUIS®)  Dosing Indication I Dose DVT/PE treatment and CrCl ≥ 25 mL/min 10 mg PO twice daily for 7 days followed by 5 mg twice daily DVT/PE treatment and CrCl < 25 mL/min Avoid use Reduction in risk of recurrence 2.5 mg twice daily; after at least 6 months of treatment for DVT/PE Postoperative 2.5 mg PO twice daily (start 12 – 24 hrs after surgery) x 10 – 12 days for knee and 35 days for hip Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 64 APIXABAN (ELIQUIS®)  PK:  t 1/2 = 8 hours (2.5mg), 15 hours (5mg)  Substrate of of CYP450 (3A4 – major) and efflux P-gp transporters  Adverse effects  Bleeding  Drug interactions: P-gp and 3A4 inhibitors and inducers  Dual P-gp and strong CYP3A4 inhibitors:  Apixaban dose > 2.5 mg BID  Reduce dose by 50%  Apixaban dose of 2.5 mg BID  Avoid concomitant use  Dual P-gp and strong CYP3A4 inducers  Avoid concomitant use  Antidotes/Reversal agents  Andexxa® Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 2/24/2019. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 65 APIXABAN (ELIQUIS®)  Counseling points  Interrupting treatment risk of thrombotic events  Avoid missed doses in treatment to minimize stroke risk  Pros  Lack of monitoring  No diet restrictions  Cons  Twice daily dosing  Renally dosed  DDI Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 66 DOSING ACTIVIT Y – COMPARE & Eyo CONTRAST Medication VTE Treatment Nonvalvular Atrial Fibrillation Rivaroxaban CrCl ≥ 30 mL/min: 15 mg PO twice daily with food for 3 weeks, then 20 mg PO daily with food CrCl < 30 mL/min: avoid use Apixaban CrCl ≥ 25 mL/min: 10 mg PO twice daily for 7 days followed by 5 mg twice daily CrCl < 25 mL/min: avoid use 67 Factor Xa Inhibitors  Edoxaban (Savaysa®) AFB  Carries a BBW not to use for atrial fibrillation if CrCl > 95mL/min due to reduced efficacy  Not applicable to DVT/PE treatment, but warrants consideration  Not used as frequently as the other oral anticoagulants Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 68 Factor Xa Inhibitors  Edoxaban (Savaysa®) MOA  Factor Xa inhibitor Indications  VTE treatment  Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism) Boxed Warnings for VTE: similar to previous Factor Xa inhibitors Contraindication: active pathological bleeding Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 69 EDOXABAN (SAVAYSA®)  Dosing Indication Dose 000 DVT/PE treatment 60 mg PO once daily (start after 5-10 days of and CrCl > 50 mL/min parenteral anticoagulation) µ DVT/PE treatment and CrCl 15-50 mL/min or weight ≤ 60 kg 30 mg PO once daily DVT/PE treatment Contraindicated and CrCl ≤ 15 mL/min Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 70 EDOXABAN (SAVAYSA®)  PK:  t 1/2 = 10 – 14 hours  Substrate of efflux P-gp transporters  Adverse effects  Bleeding  Drug interactions  P-gp inhibitors  30 mg once daily  P-gp inducers (rifampin)  Avoid concurrent use  No Antidotes/Reversal agents Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 2/24/2019. 71 BETRIXABAN (BEVYXXA®) Fye  MOA  Factor Xa inhibitor  Indications  VTE prophylaxis in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE  Discontinued Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 2/24/2019. 72 DOAC INTERACTIONS - SUMMARY Medication Dabigatran (Pradaxa®) Prodrug Drug Interactions P-gp inhibitors and CrCl < 50 (CrCl < 30 for Afib)  Avoid concurrent use For afib, dronedarone or PO ketoconazole with CrCl 30-50: 75 mg BID P-gp inducers  Avoid concurrent use Rivaroxaban Dual P-gp and strong CYP3A4 inhibitors  Avoid concomitant use (Xarelto®) Dual P-gp and strong CYP3A4 inducers  Avoid concomitant use Apixaban (Eliquis®) Dual P-gp and strong CYP3A4 inhibitors: Apixaban dose > 2.5 mg BID  Reduce dose by 50% Apixaban dose of 2.5 mg BID  Avoid concomitant use Dual P-gp and strong CYP3A4 inducers  Avoid concomitant use Edoxaban (Savaysa®) P-gp inhibitors  30 mg once daily (for afib, no dosage adjustments) P-gp inducers (rifampin)  Avoid concurrent use 73 DOAC - PATIENT COUNSELING - SUMMARY Medication Counseling Points Dabigatran (Pradaxa®) • • • • • Administer with a full glass of water without regard to meals Do not break, chew, or open capsules Store in original container and discard 4 months after opening Missed dose: take immediately unless it is within 6 hours of next dose Interrupting treatment risk of thrombotic events Rivaroxaban (Xarelto®) • • • Apixaban (Eliquis®) Edoxaban (Savaysa®) Interrupting treatment risk of thrombotic events Take with food at the same time each day (doses ≥ 15 mg) Interrupting treatment risk of thrombotic events Missed dose:  Twice daily dosing- take as soon as remember on same day, may take 2 doses at the same time to make up  Once daily dosing- take as soon as remember on same day Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 74 SUMMARY OF ORAL ANTICOAGULANTS Pharmacological Options Drug Route of Class/Mechanism of Administration Action Warfarin (Coumadin®) Vitamin K antagonist PO Dabigatran (Pradaxa®) Direct thrombin inhibitor PO Rivaroxaban (Xarelto®) Factor Xa inhibitor PO Apixaban (Eliquis®) Factor Xa inhibitor PO Edoxaban (Savaysa®) Factor Xa inhibitor PO 75 SUMMARY OF ORAL ANTICOAGULANTS  VKA (Warfarin)  Effective clotting factor synthesis inhibitor  Delayed onset of action  Many DDI  Dietary restrictions  Frequent monitoring (INR)  NOAC/DOAC  Direct inhibitor of clotting factors (Xa or IIa)  Immediate onset of action  Few DDI  No routine monitoring  Not recommended in renal impairment 76 QUESTION – KNOWLEDGE CHECK Which boxed warning do LMWHs, factor Xa inhibitors, and dabigatran all carry? a. Stevens Johnson syndrome b. Spinal or epidural hematoma formation when receiving neuraxial anesthesia or undergoing spinal puncture c. Pancreatitis d. Severe bleeding e. Acute renal failure 77 Important More BRIDGING warfarin  VKA, dabigatran, and edoxaban require initial parenteral therapy  Switching over to one of the aforementioned requires bridging  Patients must receive 5 – 10 days of initial parenteral anticoagulation before starting:  Pradaxa ®  Savaysa ®  Converting from heparin infusion  Give oral NOAC/DOAC at time infusion is stopped  Converting from LMWH or Arixtra ®  Give NOAC/DOAC when next dose is due Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 78 Conversion between Anticoagulants knowthe boldone Oral Factor Xa Inhibitors Oral factor Xa inhibitors Stop factor Xa inhibitor and start parenteral to warfarin anticoagulant and warfarin at next scheduled dose of Factor Xa inhibitor Warfarin to rivaroxaban (R) Stop warfarin and start rivaroxaban when INR < 3 Warfarin to edoxaban (E) Stop warfarin and start edoxaban when INR ≤ 2.5 Warfarin to apixaban (A) Stop warfarin and start apixaban when INR < 2 O 0 O Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 79 Conversion between Anticoagulants Oral Direct Thrombin Inhibitors Dabigatran to warfarin CrCl > 50mL/min: Start warfarin 3 days before stopping dabigatran CrCl 30 – 50mL/min: Start warfarin 2 days before stopping dabigatran CrCl 15 – 30mL/min: Start warfarin 1 day before stopping dabigatran CrCl < 15mL/min: No recommendations can be made Warfarin to dabigatran (D) Stop warfarin and start dabigatran when INR < 2 O Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 80 BACK TO ML  CC: “My right leg is swollen and hurts a lot.”  ML is a 24 year old Asian female that presents to the ER with pain in her right leg. She stated that she has not done anything to hurt it. She just got back from Japan 2 days ago.  PMH: No significant PMH, healthy young female  Medications: Recently started Yaz contraceptive  SH: smoker (1 pack/day), social drinker (3 drinks/weekend) 81 PATIENT CASE comfort  Subjective findings:  Onset of symptoms: 24 hours prior to ER visit  Right leg pain 7/10; no other symptoms  Objective findings:      Ht: 60” Wt: 100 lbs HR, BP, RR, T, O2 saturation: All WNL Allergies: NKDA PE reveals right lower extremity is erythematous, swollen, tender and warm to touch  Imaging: Ultrasound detected occlusive thrombus in right posterior tibial vein  D-dimer: 600 ng/mL  SCr, CrCl, and all other labs WNL 82 PATIENT CASE 1) What are some DVT treatment goals for ML? 2) ML stated that she would like medications that are dosed once a day since she tends to forget the second dose. What are some possible treatment options for ML? 3) What is the recommended duration for ML’s DVT? 4) What recommendations may you give ML the next time she goes to Japan? 5) What type(s) of contraceptive can be recommended for ML? 83 Special Populations • Massive PE • Pregnancy • Cancer (discussed previously) • Renal insufficiency • Extremes of body weight 84 SPECIAL POPULATIONS  Massive PE  Fibrinolytic:     Alteplase (Activase®), “tPa” (tissue plasminogen activator) Must assess CIs for bleeding 100mg IV over 2 hours Anticoagulation post treatment required  Pregnancy  LMWH recommended  Renal insufficiency  Preferred treatments:  Unfractionated heparin  Warfarin DiPiro chapter 85 Extremes of Body Weight F DOAC  Patients at extremes of body weight were underrepresented in DOAC VTE treatment trials  International Society of Thrombosis and Haemostasis suggests:  Standard doses of rivaroxaban or apixaban, without monitoring of peak and trough concentrations: appropriate for VTE treatment or prevention regardless of high BMI and weight  Avoiding dabigatran and edoxaban for VTE treatment and prevention in patients with BMI > 40 kg/m 2 or weight > 120 kg, given that data are either unconvincing (dabigatran) or lacking (edoxaban) Witt DM, Clark NP, Vazquez SR. Venous Thromboembolism. In: DiPiro JT, Yee GC, Haines ST, Nolin TD, Ellingrod VL, Posey L. eds. DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. McGraw Hill; 2023 86 Extremes of Body Weight O UFH  For the obese/morbidly obese patient (> 130% of ideal body weight), either actual body weight or adjusted body weight can be used DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. Pharmacotherapy: A Pathophysiologic Approach, 10e., Ch19: Venous Thromboembolism. New York: McGraw-Hill Education, 2017. Smythe, MA., et al. Guidance for the Practical Management of the Heparin Anticoagulants in the Treatment of VTE. J Thromb Thrombolysis. 2016;41: 165-186 87 Extremes of Body Weight LMWH  In all patients, including underweight and obese, LMWH dosing should be based on actual body weight.  For patients < 40 kg, UFH may be more appropriate.  For enoxaparin treatment dosing in obese patients, 1 mg /kg BID is preferred over 1.5 mg /kg daily.  Obese patients requiring VTE prophylaxis may need higher than normal LMWH doses.  For example, enoxaparin 40 mg subcutaneously twice daily may be more effective than usual VTE prophylaxis doses for patients undergoing bariatric surgery. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. Pharmacotherapy: A Pathophysiologic Approach, 10e., Ch19: Venous Thromboembolism. New York: McGraw-Hill Education, 2017. Smythe, MA., et al. Guidance for the Practical Management of the Heparin Anticoagulants in the Treatment of VTE. J Thromb 88 Thrombolysis. 2016;41: 165-186 Extremes of Body Weight Fondaparinux  Dose should be based on actual body weight.  Including patients with a BMI greater than 30 kg/m 2  Patients weighing more than 100 kg should receive fondaparinux 10 mg SC once daily.  Patients weighing less than 50 kg should receive 5 mg SC once daily. Smythe, MA., et al. Guidance for the Practical Management of the Heparin Anticoagulants in the Treatment of VTE. J Thromb Thrombolysis. 2016;41: 165-186 89 EXTREMES OF BODY WEIGHT Warfarin and obese and morbidly obese patients  Require a longer period to become therapeutic after initiation of warfarin  Have an overall higher average daily dose and mean discharge dose after initiation  Clinicians should anticipate a 40% to 50% higher initial warfarin dose in the obese patient population  For each 1-point increase in BMI, the weekly warfarin dose increased by 0.69 mg  Average warfarin weekly dose in this population can be estimated using the formula: 12.34 + 0.69 × BMI Mueller, JA., et al. Warfarin Dosing and BMI. Annals of Pharmacotherapy. 2014;48(5): 584-588. 90 Antidotes/Reversal Agents 91 92 BE Use of Vitamin K for Over Anticoagulation of Warfarin Symptoms/INR value What to do INR above therapeutic range but < 4.5 Reduce or hold warfarin dose. Monitor INR. Resume treatment when INR therapeutic. Dose reduction may not be needed if only slightly elevated. Supratherapeutic INR of 4.5 – 10 without bleeding Routine use of Vitamin K not recommended if no evidence of bleeding. Hold 1 – 2 doses of warfarin. Monitor INR. Resume warfarin at lower dose when INR therapeutic. Vitamin K used if urgent surgery needed (≤ 5mg, with additional 1 –2 mg in 24 hrs if needed) or bleeding risk is high (1 – 2.5 mg) INR > 10 without bleeding Hold warfarin. Give oral vitamin K 2.5 – 5 mg even if not bleeding. Monitor INR. Resume warfarin at a lower dose when INR is therapeutic. Q Major bleeding from warfarin Hold warfarin. Give vitamin K 5 – 10 mg by slow IV injection and four-factor PCC. PCC suggested over FFP due to risks of allergic reactions, infection transmission, longer prep time, slower onset and higher volume. Antithrombotic Therapy and Prevention of Thrombosis, 9th ED: ACC Guidelines. CHEST 2012;141(2)(Suppl):7S-47S. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 93 VITAMIN K Dose: 1-10 mg 88IV/PO  SC route not recommended due to variable absorption  IM route not recommended due to risk of hematoma  IV: Infuse slowly  Rate of infusion should not exceed 1 mg/minute OR  Dilute dose in minimum of 50 mL, D5W or NS, infused over at least 20 minutes Side effects  Anaphylaxis (boxed warning), flushing, rash, dizziness Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 94 Other Antidotes Antidote Dosing Side effects Protamine sulfate 1 mg will reverse ~100 units of heparin (given w/in last 2 – 2.5 hr); Max Dose 50 mg Bradycardia Hypotension Anaphylaxis 1mg protamine/1mg Lovenox® (given w/in last 8 hr) 0.5mg protamine/1mg Lovenox® (given > 8 hr) Praxbind® Antidote for dabigatran Two 2.5 g doses administered no more than 15 minutes apart (5 g total). May repeat dose per clinical indications. qq Delirium, headache, constipation, nausea Hypokalemia Hypersensitivity reactions Thromboembolic risk Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 3/1/2018. Shapiro, Karen, Sherry A. Brown, and John An. RxPrep course book. San Diego, CA: RxPrep, 2018. Print. 808 – 830. 95 Other Antidotes (Cont.) Antidote Dosing Side effects Kcentra® Four Factor Prothrombin Complex Concentrate (factors II, VII, IX, X, protein C and S) Dose based on pts INR and body weight Do not repeat dose CI: HIT, DIC Made from human blood, risk of carrying infectious disease Side effects: Hypotension, hypokalemia, thromboembolic risk Dosing regimen (low dose or high dose) is based on the specific factor Xa inhibitor given, the factor Xa inhibitor dose, and time since it was last taken. Safety and efficacy of > 1 dose of Andexxa® has not been established. Administer as an IV bolus, with a target rate of 30 mg/min, followed by continuous infusion for up to 120 minutes. Infusion-related reactions Urinary tract infections Pneumonia Thromboembolic risk I Antidote for warfarin Andexxa® Antidote for apixaban or rivaroxaban DIC: disseminated intravascular coagulation Lexi-Comp, Inc. (Lexi-Drugs® ) Mobile application. Lexi-Comp, Inc.; 2/20/2019. 96 QUESTION – ANTIDOTES The pharmacist receives a call from the medical floor. A patient on a heparin drip has been diagnosed with a GI bleed. The drip was started an hour ago, and the patient received 1000 units. What is the best recommendation to reverse UFH in this patient? a. Stop the drip; administer protamine sulfate 10 mg IV over 2 minutes b. Stop the drip; administer protamine sulfate 50 mg IV over 10 minutes c. Stop the drip; administer Praxbind 2.5 g IV over 5 minutes d. Stop the drip; administer Praxbind 2.5 g IV over 5 minutes, repeat x 1 in 15 minutes for a total of 5 g 97 98