4 23 Fall Anticoagulation In-Class Lecture PDF

ANTICOAGULATION: FOCUS ON ORAL THERAPY Deanna McDanel, PharmD, BCPS, BCACP Clinical Pharmacy Specialist, Ambulatory Care Clinical Associate Professor August 2023 OVERVIEW Overview of indications Oral anticoagulant options Warfarin special considerations DOAC special considerations Case discussion...

ANTICOAGULATION: FOCUS ON ORAL THERAPY Deanna McDanel, PharmD, BCPS, BCACP Clinical Pharmacy Specialist, Ambulatory Care Clinical Associate Professor August 2023 OVERVIEW Overview of indications Oral anticoagulant options Warfarin special considerations DOAC special considerations Case discussion 2 OBJECTIVES 1. 2. 3. 4. 5. 6. 7. 8. 9. Understand the various indications for anticoagulation, corresponding preferred anticoagulation, duration and treatment targets. Describe the MOA and pharmacology of warfarin. Recommend the appropriate dose for initiation of warfarin. Recommend appropriate monitoring for follow-up INRs. Know the possible causes for sub- and supra-therapeutic INRs, including factors that affect warfarin. Recommend and modify the maintenance dose of warfarin based on the patient’s INR and assessment parameters. Recommend what to do in excessive anticoagulation for reversal of an INR >5.0 with and without bleeding. Recognize the clinically significant drug interactions with warfarin. Educate patients on warfarin therapy. 3 OBJECTIVES (cont.) 10. Recognize the direct acting oral anticoagulant therapies. 11. Recite the important prescribing information and counseling points about dabigatran, rivaroxaban, and apixaban that would be pertinent when managing or dispensing this therapy for a patient. 12. Recommend the appropriate candidates for a direct acting oral anticoagulant and where they may have a place in anticoagulation therapy. 13. Understand the general dosing considerations for dabigatran, rivaroxaban, and apixaban. 14. Describe the reversal options for DOACs. 15. Recommend what DOACs may be used in an obese patient. 4 INDICATIONS FOR ANTICOAGULATION 5 Overview of Indications TREATMENT or PREVENTION of Thrombus PREVENTION of Arterial Thrombosis and Stroke • Venous Thromboembolism (VTE) • Deep Vein Thrombosis (DVT) • Pulmonary Embolism (PE) • Thrombophilias • Atrial Fibrillation/Flutter • Mechanical Heart Valves (MHV) • Other 6 Venous Thromboembolism (VTE) ◼ ◼ ◼ ~ 2 million people in US per year (1/1000 persons per year) Know risk factors associated with VTE Virchow’s Triad: Physiologic changes in any of 3 factors increase risk for thrombosis  Decreased blood flow (i.e. venous stasis)  Changes in intrinsic properties of blood (i.e. hypercoagulable states)  Vessel injury/inflammation (i.e. surgery, trauma) 7 VTE - Risk Factors Persistent risk factors • Active cancer • Antiphospholipid syndrome Minor risk factors • Present within 2 months of diagnosis • General anesthesia <30 min • Hospital admission <3 days with acute illness • Confinement to bed >3 days with an acute illness • Prolonged car or air travel • Estrogen therapy, pregnancy, or puerperium • Leg injury associated with reduced mobility for at least 3 days Major risk factors • Present within 3 months of diagnosis • Surgery with general anesthesia >30 min • Confinement to bed in hospital (only “bathroom privileges”) for >3 days with an acute illness • Cesarean section • Major trauma CHEST 2021; 160(6): e545-608. 8 Treatment of VTE Treatment • DOACs preferred • Rivaroxaban or apixaban alone • Dabigatran or edoxaban AFTER 5-10 days parenteral agent • Warfarin (goal INR 2.0-3.0) + LMWH/heparin for >5 days Duration • 3 months ONLY • Provoked by major or minor transient risk factors • At least 3 months and then extended-phase • Unprovoked • Provoked by a persistent risk factor 9 CHEST 2021; 160(6): e545-608. FYI Thrombophilias Inherited Thrombophilias (order of most common): Factor V Leiden mutation Prothrombin (Factor II) gene mutation Protein C, Protein S, and Antithrombin deficiency Chon DM et al. Sem Thromb and Hemostasis 2007;33(6):573-81. Thomas RH. Arch Intern Med 2001; 161: 2433-2439. Acquired Hypercoagulability: Antiphospholipid antibody syndrome (APS) Malignancy, infection, chronic inflammatory diseases, pregnancy, nephrotic syndrome, others Bick RL.Clin Appl Thrombosis/Hemostasis 2006;12(2);125-35. Seligsohn U et al. NEJM 2001; 344:1222-31. 10 Treatment – Thrombophilias ◼ FYI No concrete recommendations for duration of anticoagulation  Typical duration for specific thrombosis Warfarin DOACs • Numerous Guidelines: Preferred over DOACs for Antiphospholipid Antibody Syndrome • May be an option for all thrombophilias • INR goal is indication specific (usually 2.0-3.0) • No official guideline recommendations on use in TP • TP represented in VTE trials (low numbers) • May have a role in treatment and clinically not a contraindication for most TP • NOT RECOMMENDED for APS Thomas RH. Arch Int Med 2001; 161:2433-39. Pengo et al. Blood 2018; doi: 10.1182/blood-2018-04-848333 CHEST 2021; 160(6):2247-2259 11 Atrial Fibrillation/Flutter (AF) ◼ ◼ ◼ Irregular contraction of atria → blood pooling → clot formation → embolism→ stroke Most common cardiac rhythm disorder AF increases with age  Increases > 60 yo –   ◼ ◼ ~10% prevalence >80 yo Mean age 72 yo Uncommon if < 50 yo Men > women Stroke risk increases with age and other factors 12 Stroke Risk Stratification FYI Score CHA2DS2-VASc Score Adjusted Stroke Rate (%/Year) - FYI C = Congestive Heart Failure (or LV systolic dysfunction) 1 0 0 1 1.3 H = Hypertension 1 2 2.2 A = Age > 75 years old 2 3 3.2 D = Diabetes mellitus 1 4 4.0 S = Stroke/TIA/Thromboembolism 2 5 6.7 Disease# 1 6 9.8 7 9.6 CHA2DS2-VASc Risk* V = Vascular A = Age 65 - 74 1 8 6.7 Sc = Sex category (Female) 1 9 15.2 #Vascular: prior MI, angina, PCI, CABG; presence of intermittent claudication, prior surgery to abdominal aorta, lower extremity vessels, or abdominal/thoracic surgery; arterial or venous thrombosis Lip GY, et al. Chest. 2010;137(2):263-72 13 Treatment - Atrial Fib/Flutter ◼ ◼ ◼ Atrial fibrillation/flutter increases the risk for stroke CHA2DS2-VASc is used to score risk of stroke Oral anticoagulation for stroke prevention typically indefinitely  Use if CHA2DS2-VASc is >1 for men or >2 for women 0 • No anticoagulation 1 • Men ≥ 1 Anticoagulation • Women = 1 No anticoagulation ≥2   • Recommend anticoagulation for all patients DOACs preferred If warfarin used, maintain TTR >70% in range 2.0-3.0 Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report. Chest 2018;Aug 21. Circulation 2019;140(2):e125-e151. 14 Heart Valve Replacement ◼ ◼ Prosthetic heart valves: mechanical and bioprosthetic Mechanical: increased risk of stroke (0.5 – 2.5% per year)  Clotting dependent on the position of the valve and type of valve MECHANICAL BIOPROSTHETIC All require lifelong warfarin 3-6 months*: Aspirin 75-100 mg/d OR Warfarin (INR 2.5) *If atrial fib also - lifelong AND must use warfarin or DOACs (only when >3 mo from insertion) based on CHA2DS2-VASc Thrombogenic Low thrombogenicity Durable Limited life span Valves last 20-30 yrs 10%-30% fail within 10-15 yrs Preferred in younger patients AND if can take lifelong warfarin Preferred in older patients OR can not take lifelong anticoagulants Otto et al. 2020 ACC/AHA Guideline for the Management of Valvular Heart Disease. JACC 2021;77(4):e25-197 15 Position of Heart Valve Mitral valves have an increased risk of thrombosis versus aortic valves 16 Treatment - Heart Valves MECHANICAL Heart Valves Duration of Warfarin INR Range Aortic mechanical valve no other risk factors Indefinite 2.0 to 3.0 Aortic mechanical valve with risk factors Indefinite 2.5 to 3.5 Mitral mechanical valve Indefinite 2.5 to 3.5 On-X aortic mechanical valve Indefinite 3 months: 2.0-3.0 + ASA 81 mg Ongoing: 1.5-2.0 + ASA 81 mg (if no other risk factors) Mechanical valve at low bleeding ADD Aspirin 50-100 mg/d to indefinite warfarin risk *Direct acting anticoagulants should never be used for anticoagulation of mechanical heart valves 17 J Am Coll Cardiol. 2021;77:e25–197. Summary – Indications TREATMENT of Thrombus – DVT and PEs PREVENTION of Stroke – AF and Heart Valves • All oral agents approved; DOACs preferred • If use of warfarin INR target 2.0-3.0 • Duration: All at least 3 months; extended-phase for some • Depending on unprovoked or provoked by persistent or transient risk factor • AFib/Flutter: if CHA2DS2-VASc >1 men or >2 women → all oral agents approved • DOACs preferred • Warfarin (INR goal 2.0-3.0 - maintain TTR >70%) • Mechanical valves: warfarin ONLY with INR range depending on position of valve • INR 2.0-3.0 if aortic valve without risk factors • INR 2.5-3.5 if mitral valve or aortic valve with risk factors • Duration: indefinitely (all valves and most AF) 18 19 Direct Acting Oral Anticoagulants (DOACs) Warfarin OVERVIEW Initiation, Dosing and Management • • • • Dabigatran (Pradaxa®) Apixaban (Eliquis®) Edoxaban (Savaysa®) Rivaroxaban (Xarelto®) Summary of Use 20 Oral Anticoagulants Mechanism of Action APIXABAN EDOXABAN RIVAROXABAN WARFARIN DABIGATRAN 21 Oral Anticoagulants: Properties Properties Dabigatran Apixaban Edoxaban Rivaroxaban Warfarin 3-7%* 50% 62% 80-100% ~100% 35% 87% 55% 92-95% 99% T1/2 12-17 hrs ~12 hrs 10-14 hrs 5-9 hrs 20-60 hrs Steady state 2-2.5 days 2-3 days 2.5-3 days 1-2 days 10-14 days Hepatic Elimination Conjugation; No CYP450 CYP3A4; non-CYP Hydrolysis; non-CYP CYP3A4; non-CYP CYP 2C9, 3A4, 1A2 Renal Elimination 80%^ 27% 50% 66% 92% Bioavailability Protein Binding *Requires acidic environment; ^80% of the 3-7% absorbed orally is renally eliminated 22 Warfarin VII II X X Protein C&S Interferes with conversion of vitamin K to antagonize the production of vitamin K dependent clotting factors • Universal anticoagulant • Established effectiveness in numerous indications • CHALLENGING medication to manage Indications* Mechanism 50+ Dabigatran Package Insert: 06/2021 Years 1 mg (pink) 2 mg (purple) 2.5 mg (light green) 3 mg (brown) 4 mg (blue) 5 mg (peach) 6 mg (dark green) 7.5 mg (yellow) 10 mg (white) Formulations Mainstay Anticoagulant 23 Warfarin – Vitamin K Antagonist Decreased clotting factor synthesis 24 Warfarin - Pharmacology • Warfarin is racemic mixture of 2 enantiomers • (S)-warfarin is ~3 times more potent than (R)warfarin • • Nearly 100% oral bioavailability 99% protein bound • Metabolized by the CYP450 • (S)-warfarin→ 2C9 & 3A4 • Drug interactions • (R)-warfarin→ 1A2 & 3A4 • Elimination by urinary excretion 25 Dabigatran IIa Inhibitor Inhibits both clotbound & circulating thrombin (Factor II) Prodrug: dabigatran etexilate → dabigatran Conversion by plasma esterase • Risk reduction of stroke and systemic embolism in non-valvular atrial fibrillation • Treatment and risk reduction of recurrence of DVT and PE – ADULT and PEDS (8-17 yo) • Prevention of VTE in total hip replacement surgery Mechanism Indications* 1st new anticoagulant in U.S. in >50 years Dabigatran Package Insert: 06/2021 Capsules: 75 mg 110 mg 150 mg Formulations *Generic approved 26 Apixaban X a Inhibitor Oral, direct, selective Factor Xa inhibitor Mechanism Apixaban Package Insert: 4/2021 • Risk reduction of stroke and systemic embolism in non-valvular atrial fibrillation • Treatment of DVT and PE • Risk reduction of recurrence of DVT and PE following >6 mo of therapy • Prevention of VTE in total hip and knee replacement surgery Indications* Tablets: 2.5 mg 5 mg Formulations 27 Rivaroxaban X a Inhibitor Oral, direct, selective Factor Xa inhibitor First approved • • • • • • Mechanism Rivaroxaban Package Insert: 01/2022 Decreased stroke/systemic embolism risk in non-valvular atrial fibrillation Treatment and recurrence risk reduction after 6 months of DVT and PE – ADULTS and PEDS (birth to <18) Prevention of VTE in total hip and knee replacement surgery Reduce risk of major cardiovascular event in patients with chronic CAD or PAD IN ADDITION to aspirin Prophylaxis of VTE in acutely ill medical patients at mod- to high risk VTE Prophylaxis in PEDS - fontan procedure Indications* Tablets: 2.5 mg 10 mg 15 mg 20 mg Oral Suspension 1 mg/ml Formulations 28 Edoxaban FYI X a Inhibitor Oral, direct, selective Factor Xa inhibitor Mechanism Edoxaban Package Insert: 3/2021 • Risk reduction of stroke and systemic embolism in non-valvular atrial fibrillation • Treatment of DVT and PE Indications* Tablets: 15 mg 30 mg 60 mg Formulations 29 Comparison: Oral Anticoagulants Property Warfarin Dabigatran (Pradaxa®) Apixaban (Eliquis®) Rivaroxaban (Xarelto®) Edoxaban - FYI (Savaysa®) Factor Inhibition II, VII, IX, X; Proteins C and S IIa (Thrombin) Xa Xa Xa FDA-Labeled Indications Normal Dosing Renal Dosing • • • • AFib VTE treatment AVR/MVR Post-MI systemic embolism prevention AFib VTE treatment VTE recurrence PEDS VTE treatment & recurrence 8 to 17 yo • Post-op THR • • • • AFib VTE treatment VTE recurrence Post-op THR/TKR • • • • • • • • AFib VTE treatment VTE recurrence PEDS VTE treatment & recurrence birth to 17 yo Post-op THR/TKR CAD/PAD Medically ill PEDS Fontan procedure • AFib • VTE treatment 20 mg Daily (BID some) Daily 150 mg BID 5 mg BID VTE: PLUS >5 days LMWH VTE: After >5 days LMWH Peds: Weight-based see PI VTE: 10 mg BID x 7 days No Reversibility* Pregnancy • • • • AF: CrCl 15 – 30 → Decrease 50% VTE: CrCl <30 → AVOID CrCl <15, Dialysis, <50 for Peds: AVOID VTE: 15 mg BID x 3 wks CAD/PAD: 2.5 mg BID + ASA 81 mg/d Med Ill: 10 mg/d x31-39 d Peds: Weight-based see PI AF: ABCs >2 → Decrease 50% AF: CrCl <50 → Decrease 25% A: Age >80 years B: Body weight <60 kg C: SCr >1.5 mg/dL CrCl <15, <50 for Peds: AVOID VTE: No 60 mg Daily VTE: After >5 days LMWH AF & VTE: CrCl 15 – 50 → Decrease 50% CrCl <15 or >95: AVOID Vitamin K, Kcentra® Praxbind® (Idarucizumab) Andexxa® (Recombinant Factor Xa) Andexxa® (Recombinant Factor Xa) Maybe Andexxa® (Not FDA approved) X C B C C Comparison: Oral Anticoagulants (cont.) Dabigatran (Pradaxa®) Apixaban (Eliquis®) Rivaroxaban (Xarelto®) Edoxaban - FYI (Savaysa®) Labeling Warfarin Administration Specifics • With or without food • Crushing: allowed • Generally in evening for adjusting for INR • With or without food • Swallow WHOLE • MUST be in original bottle/blister pack • Not in MED BOXES • With or without food • Afib: Evening meal • VTE: With food • Crushing: allowed • With or without food • Crushing: allowed • Coagulation: INRs • CBC • Renal function • CBC/LFTs • Renal function • CBC/LFTs • Renal function • CBC/LFTs • Renal function • CBC/LFTs Adverse Effects • Bleeding • Bleeding • DYSPEPSIA • Bleeding • Bleeding • Bleeding Boxed Warnings and Contraindications • Spinal hematoma • • • • • Premature stop • Spinal hematoma • Active bleeding • Premature stop • Spinal hematoma • Active bleeding • Premature stop • Spinal hematoma • CrCl >95 ml/min = ↓ efficacy in Afib • Serious/fatal bleeding • Prosthetic heart valves • Pregnancy: not recommended • Triple-positive APS • Severe hepatic impairment • Serious/ fatal bleeding • Prosthetic heart valves • Pregnancy-related hemorrhage • Triple-positive APS • Hepatic impairment (Child Pugh B and C or any degree of hepatic disease w/ coagulopathy) • Serious/fatal bleeding • Mechanical heart valves or moderate to severe mitral stenosis • Triple-positive APS • Moderate/severe hepatic impairment Monitoring Warnings, Precautions Premature stop Spinal hematoma Active bleeding Mechanical prosthetic heart valves • Serious/fatal bleeding • Bioprosthetic heart valves • Geriatrics: bleeding risk increases with age • Triple-positive APS Choice of Anticoagulant - Considerations Indication Baseline SCr/BUN, CBC Age (Peds) Weight/BMI (Obesity) Coexisting Medications Dietary Intake Pill Box Use Adherence Once vs Twice Daily Dosing INR Control (if on warfarin) Cost/Insurance 32 Anticoagulation Initiation ◼ ◼ Initiate immediately after diagnosis of indication Acute VTE Warfarin Parenteral agent (LMWH or Heparin) ◼ >5 days AND for warfarin INR >2.0 for 24 hrs Dabigatran 150 mg BID Edoxaban 60 mg Daily Referral for warfarin management; DOACs maybe 33 34 35 36 37 WARFARIN SPECIAL CONSIDERATIONS 38 Warfarin Dosing Initial Dosing Considerations • • • • • • Previous stable dose if on warfarin before Age, weight, diet and alcohol consumption Baseline interacting medications Baseline INR (usual INR 0.9-1.1) Ethnic background Pharmacogenetic-based dosing CHALLENGING • Narrow therapeutic window • Considerable variability in dose response • No standardized dosing • Multiple factors affect warfarin therapy 39 Onset of Action II ◼ VII IX X Protein C&S Depends on vitamin K-dependent clotting factors t½    Protein C and factor VII decline rapidly (12-24 hrs) Factors IX and X do not occur for 4-6 days Reduction in factor II is the most delayed, >6 days 2-7 Days Initial effects on INR 10-14 Days Steady state depletion of formed clotting factors 40 Clotting Factor Half-Lives FYI Vitamin K-Dependent Proteins Half-Life (Hrs) Factor VII 6 Protein C 8 Factor IX 24 Protein S 30 Factor X 36 Factor II 60 41 Warfarin Dosing 5 mg • 10 mg x 2 days may be used for healthy outpatients • 10 mg or loading doses generally NOT preferred: • Heparin/LMWH discontinued prematurely • Decreased protein C and S levels → procoagulant effect Chest 2012; 141(2 Suppl): e152S-e184S. < 5 mg Consider if: • Elderly (>60 yo) • Debilitated or malnourished • Heart failure or liver disease • Recent major surgery • Interacting medications (e.g. amiodarone) • Asian ethnicity? 42 Pharmacogenomics ◼ FYI 1/3rd of patients on warfarin have genetic metabolic variations    CYP2C9 (require lower doses) VKORC1 (may require lower or higher doses) May be responsible to 40% of warfarin dose variability ◼ Labeling: pharmacogenomically guided initial dosing ranges based on CYP2C9 and VKORC1 status ◼ Pharmacogenomics based dosing could lead to:   ◼ ◼ More rapid achievement of stable dose Lower risk for high INRs and bleeding Disadvantages: cost, delay in therapy Guidelines suggest against routine testing for this http://www.pharmacistsletter.com/pl/detaildocuments/231002GENETIC.pdf, Chest 2012; 141(2 Suppl): e152S-e184S; Clin Pharmacol Ther. 2005; 77: 1-16; Clin Pharmacokinet. 2006; 45: 1189-1200; Clin Pharmacol Ther. 2006;80(2):169-78 43 Formulations          1 mg (pink) 2 mg (purple) 2.5 mg (light green) 3 mg (brown) 4 mg (blue) 5 mg (peach) 6 mg (dark green) 7.5 mg (yellow) 10 mg (white) 44 Monitoring INRs Initial monitoring: 2 to 3 days after starting 0.1-0.2 per INR Increase day FIRST WEEK after initiation 10-14 Days Steady State Chest 2012; 141(2 Suppl): e152S-e184S. 2 to 3 times per week x 1 to 2 weeks <2 Weeks 4 Weeks Periodically thereafter NOT Stable Dose changes, low/high INRs, other factors STABLE Up to 12 wks may be considered over 4 wks if consistently stable x 3 months 45 Adverse Effects ◼ 2nd most common drug implicated in ER visits Most common: BLEEDING ◼ Annual frequencies of bleeding: ◼    ◼ Minor: 6% - 29% Major: 3.0% Fatal: 0.6% Common sites of bleeds:       Nose or pharynx Soft tissue GI tract Urinary tract Intracranial Thoracic 35% 21% 15% 15% 4% 3% 46 CASE 1: Warfarin ◼ ◼ ◼ AW again is a 35 yo female diagnosed with an acute DVT of femoral vein on Doppler After discussion of her options she elected to start warfarin She was started also on enoxaparin 120 mg daily (weight 82 kg)  Dosing 1.5 mg/kg daily OR 1 mg/kg BID (80 mg BID an option) 47 48 49 Assessing Warfarin Therapy Parameters to assess Change • • • • • • Current warfarin dose Non-adherence (missing or extra doses) Changes in vitamin K intake Alcohol use: 1 per day women, 2 per day men Drug interactions Changes in health (fever, diarrhea, nausea, vomiting) • Bleeding or thromboembolism signs or symptoms • Consistent or transient • When (i.e. within last 2 wks) 50 Dietary Vitamin K ◼ ◼ Educate on vit K in common foods Most common high in vit K are green, leafy vegetables  ◼ Liquid dietary supplements have a high vitamin K content   ◼ CONSISTENCY IS KEY! ◼ Others: green tea, vegetable oils (canola, soybean) SlimFast, Boost, Ensure Enteral nutrition Multivitamin products and Viactiv calcium chews Consider seasonal variation in produce availability FYI Spectrum of Green Kale 1100 mcg* Brussels Sprouts 300 mcg Asparagus 150 mcg Celery 55 mcg Spinach 900 mcg* Broccoli 200 mcg Vitamin K content per 1 cup *Boiled USDA National Nutrient Database for Standard Reference https://www.nal.usda.gov/sites/www.nal.usda.gov/files/vitamin_k.pdf Cucumber (peeled) 8 mcg Romaine Lettuce 60 mcg Iceberg Lettuce 13 mcg • Alcohol binge • Medication changes • Decreased dietary vitamin K • Acute illness, persistent fever, and/or diarrhea • Signs of bleeding • Significant weight loss (i.e. bariatric surgery) • Missed doses • Medication changes • Increased dietary vitamin K • New vitamins, Slim Fast/Boost/Ensure, Viactiv calcium • Signs of clotting/stroke • Weight gain DECREASED INR INCREASED INR INR Changes 53 Managing Out of Range INRs Consider Indication HIGH INR If NOT bleeding: • One time decrease OR • Decrease dose 5-15% and/or • Hold doses: • > 1 pt above → hold 1 dose • > 2 pts above → hold 2 doses • 3-5 held doses reverses INR Excessive INRs >4.5 or BLEEDING see reversal of warfarin LOW INR If missed dose: • Give boost and/or resume normal dose If consistent change/unknown etiology: • Increase dose by 5-15% and/or • Give extra one-half to full dose <1.8 may be at risk for thrombus, bridging not generally advised Recheck INR < 2 weeks CHEST 2012: If previously stable and < 0.5 below or above range, continue current dose and check in 1-2 weeks 54 Excessive Anticoagulation INR NO BLEEDING Recommendations for Reversal of INR (all monitor INR more frequently) < 4.5 Omit or lower dose No dose change if minimally above range (see algorithms) 4.5 to 10 Omit 1-2 doses + resume at lower dose when INR in range *Suggest AGAINST routine use of vitamin K > 10.0 #Vitamin Hold warfarin therapy AND give oral vitamin K# *Dose of vitamin K not defined in the guidelines, most likely oral vitamin K 2.5 – 5 mg per past recommendations K is otherwise known as phytonadione (Mephyton®) ANY BLEEDING Evaluate and Admit for Reversal if Necessary MAJOR Bleeding Hold warfarin therapy AND rapid reversal with four-factor prothrombin complex concentrate (PCC) [i.e. Kcentra®] instead of FFP ADD vitamin K 5 to 10 mg IV suggested over PCC use alone Chest 2012; 141(2 Suppl): e152S-e184S. 55 Perioperative Management – Warfarin FYI 56 Douketis JD, et al. CHEST 2022 162(5):e207-e243. Example Dose Change (cont.) ◼ Dose: 5 mg Mon, Wed, Fri; 7.5 mg 4 days/wk (using 5 mg tabs), INR 3.3 (range 2.0-3.0)    Determine weekly dose = 45 mg/wk Keep in mind TABLET SIZE of 5 mg Percent change: change divided by weekly dose – –   Decrease of ½ tab is 2.5/45 mg = 5.5% per week Decease of 1 tab is 5/45 mg = 11% per week ~5% change thus would be decrease of 2.5 mg to 5 mg 4 d/wk and 7.5 mg 3 d/wk (42.5 mg/week) Could argue to do one time decrease or nothing and recheck in 2 weeks 57 CASE 2: Warfarin Therapy ◼ 60 yo male with mitral valve replacement (2004 – St. Judes bileaflet valve), HTN, hyperlipidemia, and depression ◼ Warfarin dose: 10 mg Mon, Wed, Fri; 7.5 mg 4 d/wk (5 mg tabs) ◼ Denies symptoms of bleeding or stroke, non-adherence, or alcohol use ◼ He replaced his daily iceberg lettuce salad with a spinach salad daily last week, which he would like to continue this ◼ INR today = 2.1 58 CASE 2: Warfarin Therapy ◼ What goal INR range does he have? ◼ What is your assessment of his INR? 59 60 61 CASE 2: Warfarin ◼ Recommended dose and follow-up?      Subtherapeutic due to consistent change Increase dose 5-15% – Likely closer to 10% increase (2% may not be enough, 20% may be too aggressive) Current dose = 60 mg/wk (10 mg MWF; 7.5 mg 4 d/wk) 2.5 mg increase is 4% per week (2.5 / 60 mg = 4%) If increase dose 5 mg = 8% increase – Example dose: 7.5 mg Mon, Fri; 10 mg 5 d/wk  Follow-up INR in 2 weeks 62 Warfarin Drug Interactions Pharmacokinetic Pharmacodynamic Other Absorption: not common (ex. bile acid sequestrants) Clotting factor synthesis and degradation Antibiotics Plasma protein binding (ex. valproic acid, phenytoin) Platelet inhibition Herbal and natural product interactions Metabolism: Induction and Inhibition of CYP450 system 63 Induction of Metabolism INR Induction of CYP2C9 that metabolizes (S)warfarin Synthesis of new drug-metabolizing enzymes Decreases INR Upon discontinuation INR increases Onset: GRADUAL Few days to 1-2 weeks Dissipation: 1-2 weeks Examples: - Rifampin - Nafcillin - Dicloxacillin - Carbamazepine - Phenytoin - Barbiturates 64 Inhibition of Metabolism INR Variability in the potency of inhibition Increases INR Upon discontinuation INR decreases CYP2C9: POTENT effect CYP1A2 & CYP3A4: less potent effect Onset: Immediate after sufficient drug levels Dissipation: Based on half-life of inhibiting drug Examples: - Sulfamethoxazole/ trimethoprim - Metronidazole - Azole antifungals - Amiodarone **All would require EMPIRIC dose decrease Inhibition interactions more common than induction 65 Clotting Factor Synthesis/Catabolism Levothyroxine: • Increases catabolism of clotting factors Salicylates (i.e. Pepto-Bismol, aspirin >2 g/d) and Quinidine • Decreases production of clotting factors INR Propylthiouracil/methimazole: • Reduces circulating thyroid hormone concentrations → decrease catabolism of clotting factors 66 Platelet Inhibition Drugs that impair platelet function increase bleeding, especially GI bleeds • • • NSAIDs Aspirin Clopidogrel, ticlopidine, ticagrelor, prasugrel Salsalate (an nonacetylated salicylate) has minimal effects on platelets and is less likely to cause gastric erosions NO effect on INR Acetaminophen preferred analgesic (>2 g/d may affect INR) 67 Antibiotics Almost all interfere, some inhibition and induction Safe: MOST penicillins & cephalosporins INR Increase INR – Unknown: Moxifloxacin, tetracycline Inhibition: Ciprofloxacin, metronidazole, sulfamethoxazole/trimethoprim May increase INR – more common in elderly Azithromycin, clarithromycin, doxycycline, erythromycin, levofloxacin INR Decrease INR – Induction: Dicloxacillin, nafcillin, rifampin 68 Herbal and Natural Products 1 out of 5 people take herbal/natural products, supplements, or other vitamins >70% Patients don’t tell healthcare providers about nontraditional treatments Most common: • Increase INR: CBD • Decrease INR: Coenzyme Q-10, St. John’s Wort, Green tea • Increased bleeding: Garlic, Ginkgo, Ginseng Make sure to ASK and investigate! 69 70 71 Managing Drug Interactions Educate patients to call when starting/stopping high risk medications Thorough medication history (prescription, OTC and herbals) Avoid interacting drugs if possible Anticipate effects on the INR and make appropriate dosing adjustments Monitor INRs frequently Refer to drug interaction sources if ever in doubt 72 Patient Education ▪ ▪ ▪ ▪ ▪ Dosing (INR range for warfarin) Adherence to therapy (12 hour rule) Drug-drug interactions Diet: taking with food (rivaroxaban), consistency is key with vitamin K (warfarin) Alcohol: 1/day women, 2/day men ▪ ▪ ▪ ▪ ▪ ▪ ▪ 1 = 12-ounce beer, 4-ounce wine, 1 shot of liquor Laboratory monitoring Ongoing assessment Pregnancy risk with warfarin Other: activity, illness, weight Signs/symptoms of bleeding or thrombosis Communication with all health care providers 73 Summary of Warfarin Therapy Multiple indications for prevention and treatment of thrombosis Each indication has INR range and duration for warfarin Narrow therapeutic window requiring close monitoring Life-saving medication, but dangerous if not monitored Many factors affect the INR and dosage requirements Patient education on these factors is KEY! 74 DOACs SPECIAL CONSIDERATIONS 75 DOAC: Adult ACUTE VTE Treatment 21 Days 21 Days to 6 Mo Rivaroxaban 15 mg BID 20 mg daily >6 Months/Ongoing 10 mg daily (optional*) 7 Days Apixaban 10 mg BID 7 Days to 6 Months 5 mg BID >6 Months/Ongoing 2.5 mg BID (optional*) *For both rivaroxaban and apixaban, recurrent VTE patients not represented in ongoing trials Parenteral Anticoagulant 5-10 days FIRST Dabigatran 150 mg BID Parenteral Anticoagulant 5-10 days FIRST Edoxaban 60 mg daily DOAC: Adult VTE Treatment Dosing VTE Treatment Dabigatran Apixaban Edoxaban Initial Treatment Dose 150 mg BID AFTER 5-10 days of parenteral anticoagulation (i.e. heparin or LMWH) 10 mg BID for 7 days 60 mg daily AFTER 510 days of parenteral → 5 mg BID anticoagulation (i.e. heparin or LMWH) Risk of Recurrence Reduction 150 mg BID 2.5 mg BID (if CrCl >30 ml/min) *After previous treatment *After >6 months Not in labeling Other Dosing 75 mg BID: • P-gp inhibitor AND CrCl 30-50 ml/min AVOID: • P-gp inhibitor AND CrCl <30 ml/min 2.5 mg BID: • Strong dual Pgp/CYP3A4 inhibitors AVOID if taking 2.5 mg BID already 30 mg daily: • <60 kg • On certain P-gp inhibitors Renal Dosing (ml/min) CrCl <30: DO NOT USE No dose adjustment CrCl 15 – 50: 30 mg CrCl <15: AVOID (CrCl <25 not studied) Rivaroxaban 15 mg BID for 21 days → 20 mg daily with food 10 mg daily (with/without food) *After >6 months CrCl <15: AVOID DOAC: AFib Dosing Dosing Dabigatran Apixaban Edoxaban Rivaroxaban 150 mg BID Normal AFib Dosing 5 mg BID 60 mg daily 20 mg daily with evening meal CrCl 15 – 30: Renal AFib Dosing 75 mg BID (CrCl in ml/min) CrCl <15 or Dialysis: AVOID 2.5 mg BID ONLY if >2 of the following: A: Age >80 years B: Body weight <60 kg C: Serum Creatinine >1.5 mg/dL CrCl 15 – 50: 30 mg daily CrCl <50: 15 mg with pm meal Renal Elimination 80% 27% CrCl <15 or >95: AVOID 50% 66% DOACs: Dosing in Obesity BMI >40 kg/m2 OR Weight >120 kg ◼ Apixaban and rivaroxaban proved to be at least as safe and effective as warfarin for obesity for both VTE treatment and prevention  No guideline directed recommendation for AFib ◼ An increased BMI is not associated with an increased risk of recurrent VTE or bleeding ◼ Betrixaban, edoxaban, and dabigatran should be avoided for VTE treatment and prevention due to lack of clinical and pharmacokinetic data ◼ DOACs should not be used in the postsurgical phase after bariatric surgery, but may be considered after 4 weeks Martin KA, et al. J Thromb Haemost. 2021;19(8):1874-1882. 79 DOACs – Mechanical Valves AHA/ACC 2020 • In patients with mechanical heart valves with or without AF who require long term anticoagulation with VKA to prevent thrombosis, NOACs are not recommended ESC/EACTS 2021 • OAC using VKA is recommended lifelong for all patients with a mechanical valve prosthesis • NOACs are not recommended in patients with a mechanical valve prosthesis RE-ALIGN Trial TERMINATED EARLY - Significantly more thromboembolic events (valve thrombosis, stroke, transient ischemic attack, and myocardial infarction) in dabigatran vs warfarin - Excess of any and major bleeding Otto CM, et al. Circulation. 2021;143:e72-e227 Vahanian A, et al. European Heart Journal. 2022;43:561-632 Eikelboom et al. NEJM 2013; 369:13:1206-14 DOACs – Valvular Heart Disease with Atrial Fibrillation Valvular AF VHD USE Aortic Regurgitation Aortic Stenosis Mitral Regurgitation Mitral Stenosis Tricuspid Regurgitation Transcatheter Aortic Valve Replacement Surgical Bioprosthetic Valve <3 months Surgical Bioprosthetic Valve >3 months Mechanical Valve On-X Mechanical Valve ? Antiphospholipid Antibody Syndrome (APS) • Acquired thrombophilia • Significant increased risk of both venous and arterial thrombosis, recurrent pregnancy loss and/or thrombocytopenia Antiphospholipid Antibodies ALL 3 Antibodies = TRIPLE POSITIVE APS • Anticardiolipin antibodies (ACA) Most common • Lupus anticoagulant (LA) 60% LA patients have ACA • Beta-2 glycoprotein I antibody (β2-GPI) Labeling Warnings, Precautions Dabigatran (Pradaxa®) • Serious/fatal bleeding • Bioprosthetic heart valves • Geriatrics: bleeding risk increases with age • Triple-positive APS Apixaban (Eliquis®) • Serious/fatal bleeding • Prosthetic heart valves • Pregnancy: not recommended • Triple-positive APS Rivaroxaban (Xarelto®) • Serious/ fatal bleeding • Mechanical heart valves or moderate to severe mitral stenosis • Triple-positive APS Edoxaban - FYI (Savaysa®) • Serious/fatal bleeding • Prosthetic heart valves • Pregnancy-related hemorrhage • Triple-positive APS Meta-Analysis 2023 FYI DOACs and APS - Key Points Warfarin is ONLY option for thrombosis treatment and prevention in triple positive APS, especially arterial thrombosis Strongly consider avoidance of DOACs in any patient with APS Likely will see package labeling and guidelines to reflect avoidance of DOACs in ALL APS patients For reference, see this Rapid Resource on APS by the Anticoagulation Forum DOACs: Drug Interactions Medication Dabigatran Apixaban Edoxaban Rivaroxaban Drugs that Increase Levels Drugs that Decrease Levels P-gp inhibitors (↓ dose or AVOID)* • Dronedarone • Ketoconazole (oral) P-gp inducers (AVOID) • Rifampin Dual P-gp/CYP3A4 inhibitors (↓ dose or AVOID)# • Clarithromycin • Itraconazole • Ketoconazole • Ritonavir Dual P-gp and/or CYP3A4 inducers (AVOID) • Carbamazepine, phenytoin, rifampin • St. John’s wort P-gp inhibitors (↓ dose to 30 mg) • VTE: azithromycin, clarithromycin, erythromycin, itraconazole, ketoconazole, quinidine, verapamil (No dose reduction in Afib) • AVOID with antiretrovirals and cyclosporine P-gp inducers (AVOID) • Rifampin Dual P-gp/CYP3A4 inhibitors (AVOID) • Conivaptan • Itraconazole • Indinavir • Ketoconazole • Lopinavir/ritonavir • Ritonavir Dual P-gp/CYP3A4 inducers (AVOID) • Carbamazepine, phenytoin, rifampin • St. John’s wort *Theoretical other inducers i.e. carbamazepine, phenytoin, St. John’s wort *Theoretical other inducers i.e. carbamazepine, phenytoin, St. John’s wort ALL: Increased risk of bleeding with other anticoagulants, antiplatelet agents and NSAIDs *AFib - Decrease to 75mg BID if P-gp inhibitors AND CrCl 30-50 ml/min; AVOID if P-gp inhibitor and CrCl < 30 ml/min; DVT/PE or VTE prevention 85 in THR – Avoid if P-gp inhibitor and CrCl <50 ml/min #Decrease dose to 2.5mg BID if on strong dual P-gp/CYP3A4 inhibitors (AVOID if taking 2.5mg BID already) Warfarin Conversion → DOACs DOAC Conversion FROM Warfarin TO a DOAC Rivaroxaban STOP warfarin and START rivaroxaban when INR <3.0 Edoxaban STOP warfarin and START edoxaban when INR <2.5 Apixaban STOP warfarin and START apixaban when INR <2.0 Dabigatran STOP warfarin and START dabigatran when INR <2.0 DOACs: Managing Bleeding ◼ ◼ Antidote if available and meets criteria for use Other:     SUPPORTIVE CARE and other potential options if antidotes not readily available    Maintain adequate diuresis → renal elimination Activated charcoal if within 2-4 hrs since last dose Prothrombin complex concentrate (PCC) – Contains factors II, VII, IX and X – Activated (i.e. Feiba®) or inactivated (i.e. Kcentra®) – Effectiveness unknown, limited data, theoretical speculation, cost $$$ Tranexamic acid given with PCC (does not work alone) Hemodialysis: *DABIGATRAN ONLY* increase clearance 60% over 2-3 hrs Hemodynamic stability: RBCs and/or platelet concentrates in thrombocytopenia Other: fresh frozen plasma (FFP), cryoprecipitate, and recombinant factor VIIa should not be utilized as will not reverse anticoagulation Crowther MA, Warkentin TE. J Thromb Haemost. Jul 2009;7 Suppl 1:107-110 van Ryn J, et al. Thromb Haemost. Jun 2010;103(6):1116-1127 87 DOACs: Reversibility Property Idarucizumab (Praxbind®) Andexxa® Mechanism of Action Humanized monoclonal antibody fragment to bind dabigatran Recombinant modified human factor Xa protein FDA-Labeled Indications Reversal of dabigatran for: • Emergency surgery/urgent procedures • Life-threatening or uncontrolled bleeding Reversal of apixaban and rivaroxaban for: • Life-threatening or uncontrolled bleeding Not shown effective/not indicated for edoxaban Normal Dosing 5 g IV (2 vials of 2.5 g/50 mL) Limited data to support additional 5 g See package labeling; Based on specific FXa inhibitor being reversed, the dose of FXa inhibitor and time since the last dose Warnings and Precautions • • • • • • Adverse Effects Headache, hypokalemia, delirium, constipation, pyrexia, and pneumonia Thromboembolic risk Re-elevation of coagulation parameters Hypersensitivity reactions Hereditary fructose intolerance Praxbind® Package Insert: 2015 October Andexxa® Package Insert: 2020 September Thromboembolic risk Re-elevation of coagulation parameters UTIs and pneumonia (>5%) Infusion-related reactions (>3%) 88 DOACs: Peri-Procedural Management FYI 89 Douketis JD, et al. CHEST 2022 162(5):e207-e243. DOAC Ongoing Management • • • • • • • Initial Education Follow-up Monitoring Adherence Bleeding Diet (Rivaroxaban) Stroke or VTE Reversibility Cost Procedures • 2-4 weeks • 3 months • Every 6-12 months • Baseline renal function • Periodic/annually: • Renal function • CBC • LFTs? 90 91 92 93 DOACs: Summary Assess each patient to determine if candidate for DOAC Some advantages and disadvantages to warfarin Role of monitoring and appropriate tests Use in special populations Role of Anticoagulation Clinics in managing these patients 94 Questions? ◼ Optional Office Hours  Thurs 1/31 3:00-4:00 pm [email protected] 95 Case Discussion 96 Warfarin Case ◼ ◼ ◼ ◼ DM is a 62 yo male with a mitral MVR His dose is 7.5 mg Mon, Fri; 10 mg 5 d/wk He started ibuprofen 400 mg every 6-8 hours prn for pain after twisting his ankle. He is not able to exercise normally. Last INR = 3.2 (1 week ago). F/U planned in 3 more weeks.  How will this affect his warfarin therapy?  How would you educate HM?  Recommendation for follow-up? 97 Warfarin Case (cont.) ◼ DM returns to clinic for a routine follow-up and his INR is 4.1 and his dose is 7.5 mg Mon, Fri; 10 mg 5 d/wk (range 2.5-3.5). DOACs: Case 1 (cont.)  What questions would you ask to assess this INR?  Based on his assessment, what dose and recommended follow-up would you have? 98 DOACs: Case 1 ◼ ◼ 62 year old female with a past medical history for atrial fibrillation diagnosed 3/2014, pontine stroke (6/2010), type 2 diabetes, HFrEF (EF 35%), dyslipidemia, and hypertension. What is her CHA2DS2VASc score? 99 DOACs: Case 1 ◼ 62 year old female with a past medical history for atrial fibrillation diagnosed 3/2014, pontine stroke (6/2010), type 2 diabetes, HFrEF (EF 35%), dyslipidemia, hypertension, and obesity. ◼ What is her CHA2DS2-VASc score? 100 DOACs: Case 1 (cont.) ◼ Is an anticoagulant warranted? ◼ What is her INR goal if warfarin is chosen? ◼ What should her duration of anticoagulation be? 101 DOACs: Case 1 (cont.) ◼ ◼ She presents to the ACMS clinic today for an INR, which was 2.6. She has been on 7.5 mg daily for about 4 months (using 5 mg tab). She was inquiring about switching off warfarin to another anticoagulant as she doesn’t like having to get monitored so often.    What are some things for you to consider in this decision? After discussion and review of her chart, which agent do you recommend? How do you convert her? 102 103 DOACs: Case 1 (cont.) ◼ She is now ready to switch to a DOAC. Her dose of warfarin is 7.5 mg daily, using 5 mg tablets. ◼ How would we convert her based on the DOAC you chose? 104 DOACs: Case 2 ◼ ◼ ◼ PL is an 79 year old female with a history of new onset atrial fibrillation, hypertension, and diabetes mellitus. Her physician would like to start antithrombotic therapy. Pertinent information: SCr is 1.3 mg/dL, CrCl 35 mL/min, weight is 63 kg (BMI 21 kg/m2) She is asking you which therapy would be best? 105 106 DOACs: Case 3 ◼ ◼ ◼ DJ is a 34 year old female with a history of a DVT diagnosed today. The clot was thought to be unprovoked. She needs to start antithrombotic therapy. Pertinent information: SCr is 0.9 mg/dL, CrCl >90 mL/min, Weight 80 kg (BMI 29 kg/m2) Which therapy would be best? 107 108 AT HOME CASES 109 DOAC: Case A ◼ ◼ 83-year-old female presents to the Cardiology Clinic for evaluation of her anticoagulation regimen Past Medical History:  Paroxysmal atrial fibrillation (diagnosed October of last year, cardioversion January last year and June last year) –   Hypertension Chronic kidney disease, stage III – –  CHA2DS2-VASc Score = 4 (Age >75 yo = 2, HTN, Female) SCr has ranged from 1.1 to 1.9 mg/dL (GFR 25 to 48 ml/min/1.73 m2) Most recent SCr 1.4 mg/dL (CrCl 31.6 ml/min) Glaucoma DOAC: Case A – cont. ◼ Medications Indication Amlodipine 2.5 mg daily HTN Dabigatran 75 mg BID *Started Oct last year Atrial Fibrillation Latanoprost 0.005% 1 drop OS QHS Glaucoma Lisinopril 40 mg daily HTN/CKD Multiple vitamin 1 tablet daily Supplement Vitals:   Blood pressure 135/75 mmHg; pulse 62 bpm Weight 75.9 kg (height 64 in – ideal body weight 54.7 kg) DOAC: Case A – cont. Today (others monthly) 112 DOAC: Case A – cont. Which is an appropriate anticoagulant? Why or why not? A. B. C. D. E. F. Dabigatran 75 mg BID Dabigatran 150 mg BID Rivaroxaban 20 mg daily Apixaban 5 mg BID Edoxaban 60 mg daily Warfarin adjusted to INR of 2.0-3.0 113 DOAC: Case B ◼ ◼ ◼ ◼ DG is a 70 year old female on warfarin extended therapy for atrial fibrillation (INR Goal 2.0-3.0) Past Medical History  Atrial Fibrillation  Osteoporosis  Essential Hypertension  Dyslipidemia Social History  Former Smoker (Quit 20 yrs ago)  Drinks 1-2 alcoholic drinks/week Drug Allergies  Penicillin (rash/hives) DOAC: Case B ◼ Current Medications          Alendronate 70mg – 1 tablet weekly Calcium/Vit. D3 – 1 tablet daily Echinacea – 1 capsule daily Losartan/HCTZ 50/12.5mg- 1 tablet daily Metoprolol tart. 25mg – 0.5 tablets twice daily Potassium 10 mEq XR – 1 tablet twice daily Simvastatin 40mg – 1 tablet every evening Vitamin E – 1 capsule daily Warfarin (has 1mg tablets) – 3mg Tues, Thurs, Sat; 2mg 4 days per week DOAC: Case B ◼ Presents to the ACMS Clinic for INR check   ◼ Current Labs    ◼ Patient has not missed/taken any extra doses; changed her diet, alcohol intake, or medications; and has had no signs/symptoms of bleeding/bruising; no signs of a blood clot Of note, patient uses a med-box to keep track of her medications and money/insurance is no problem Weight: 60.4 kg BMI: 24.5 GFR: 62 mL/min; SCr: 0.9 mg/dL Today’s INR: 1.5 DOAC: Case B ◼ What should we do with her warfarin dosing? ◼ Now let’s say the patient is tired of having to come to clinic to get her INR checked and is interested in starting a direct acting anticoagulation medication:  Is she a good candidate for DOAC’s? – Why or why not?   Which medication would be best for her? Which medication would not be ideal for this patient? SUPPLEMENTAL SLIDES FYI 118 Warfarin Dosing Algorithm: INR 2.0-3.0 INR Goal 2.0-3.0 INR <2.0 Increase Dose by 5-10% OR → Increase ½ Dose OR Do Nothing INR 2.0-3.0 No Change in Warfarin Dose INR 3.1-3.5 Decrease Dose by 5-10% OR → Decrease ½ Dose OR Do Nothing Note: Only used for changing maintenance doses INR 3.6-4.0 INR 4.1-10 Decrease Dose by 515% Hold 1-2 Doses AND Decrease Dose by 5-15% INR >10 Vit K +/Admit based on bleeding 119 Warfarin Dosing Algorithm: INR 2.5-3.5 INR Goal 2.5-3.5 INR <2.5* Increase Dose by 5-10% OR → Increase ½ Dose OR Do Nothing INR 2.5-3.5 No Change in Warfarin Dose INR 3.6-4.0* Decrease Dose by 5-10% OR → Decrease ½ Dose OR Do Nothing Note: Only used for changing maintenance doses INR 4.1-4.5 INR 4.6-10 INR >10 Decrease Dose by 515% Hold 1-2 Doses AND Vit K +/Admit based on bleeding Decrease Dose by 5-15% 120 Dabigatran → Warfarin Renal Function (ml/min) Dabigatran Conversion TO Warfarin CrCl >50 START warfarin 3 days before STOPPING dabigatran CrCl 30-50 START warfarin 2 days before STOPPING dabigatran CrCl 15-30 START warfarin 1 day before STOPPING dabigatran CrCl <15 No recommendations *NOTE: INR not useful for monitoring warfarin until 2 days after stopping dabigatran Factor Xa Inhibitors → Warfarin Factor Xa Inhibitor Apixaban Rivaroxaban Edoxaban Conversion TO Warfarin STOP, begin BOTH warfarin PLUS a parenteral anticoagulant when next dose of factor Xa inhibitor due STOP, begin BOTH warfarin PLUS a parenteral anticoagulant when next dose of edoxaban is due OR Decrease dose in HALF and start warfarin concomitantly, INRs at least weekly before edoxaban dose; STOP when INR >2.0 *NOTE: Initial INRs may not be useful for monitoring warfarin and determining appropriate doses during the transition Dabigatran: Pediatric VTE Dosing ◼ ◼ ◼ ◼ DVT/PE treatment for 8 to <18 yo AFTER >5 d of parenteral anticoagulant Reduction in risk of recurrence of VTE Oral pellets are FDA approved, but NOT currently available Weight-based dosing from package insert (CrCl > 50 ml/min – Schwartz)  Adjust the dose according to actual weight as treatment progresses 123 Dabigatran Package Insert: 06/2021 Rivaroxaban: Pediatric VTE Dosing ◼ ◼ ◼ ◼ ◼ DVT/PE treatment for birth to <18 yo after >5 days of parenteral anticoagulant Reduction in risk of recurrence of VTE WITH FOOD Reconstituted oral suspension Weight-based dosing from package insert  Adjust the dose according to actual weight as treatment progresses 124 Rivaroxaban Package Insert: 01/2022 Rivaroxaban: Pediatric Fontan Dosing ◼ ◼ ◼ Thromboprophylaxis in pediatric patients aged >2 years with congenital heart disease who have undergone the Fontan procedure With or without food Weight-based dosing from package insert  Adjust the dose according to actual weight as treatment progresses 125 Dabigatran Package Insert: 06/2021 VTE Studies VTE Studies Study Type Study Arms Primary Efficacy (VTE Recurrence) Major Bleeding Other Dabigatran RE-COVER1 (N=2,564) RCT,DB; Non-inf 6 mo Dabi 150 mg BID vs. Warfarin (INR 2-3); All LMWH or heparin prior Non-Inferior 2.4 vs. 2.1% (p<0.001) Non-Significant 1.6 vs. 1.9% (p=0.38) Sig less: Overall bleeding (16.1% vs. 21.9%) RE-MEDY2: Extension Apixaban AMPLIFY3 (N=5,395) RCT,DB; Non-inf 6 mo Apix 10 mg BID x 7d then 5 mg BID vs. Warfarin (INR 2-3) PLUS enoxaparin Non-Inferior 2.3 vs. 2.7% (p<0.001) Significantly Less AMPLIFY-EXT4: 0.6 vs. 1.8%/yr (p<0.001) 2.5 vs 5mg BID after 6-12 mo; Both doses better than placebo 1.7 vs 8.8%(p<0.001) Edoxaban Hokusai-VTE5 (N=8,240) RCT,DB; Non-inf 3-12 mo Edox 60 mg daily (30 mg if indicated) vs. Warfarin (INR 23); All LMWH or heparin prior Non-Inferior 3.2 vs. 3.4% (p<0.001) Significantly Less Major and clinically nonmajor bleeding Riv 15 mg BID x 3 wks then 20 mg/d vs. Warfarin (INR 23) PLUS enoxaparin Non-Inferior DVT: 2.1 vs. 3% (p<0.001) PE: 2.1 vs. 1.8% (p=0.003) Rivaroxaban EINSTEIN-DVT6 (N=3,449) EINSTEIN-PE7 (N=4,832) Open label; Non-inf 3, 6 ,12 months 1. Schulman S, et al. NEJM 2009;361:2342-52. 2. Schulman S, et al. NEJM 2013;368:709-18 3. Agnelli G, et al. NEJM 2013;369(9):799-808. trial, followed for 6-36 mo. dabi non-inferior (1.8% vs 1.3%) 8.5 vs.10.3%/yr (p=0.004) Non-Significant Major and clinically non-major bleeding DVT: 8.1% both groups PE: 10.3 vs. 11.4% (p=0.23) 4. Agnelli G, et al. NEJM 2013;368(8):699-708. 5. Hokusai-VTE Investigators. NEJM 2013;369(15):1406-15. 6. EINSTEIN-DVT. NEJM 2010;363:2499-510. 7. EINSTEIN-PE. NEJM 2012;10.1056. Atrial Fibrillation Studies AFib Studies Dabigatran RE-LY1 (N=18,133) Study Type RCT, Dabi DB, War OL; Non-inferior Study Arms RCT, DB; Non-inferior Mean f/u = 1.8 yr Edoxaban ENGAGE AFTIMI3 (N=21,105) RCT, DB; Non-inferior Rivaroxaban ROCKET-AF4 (N=14,264) RCT, DB; Non-inferior Mean f/u = 2.8 yr Dabi 150mg Superior Non-Significant 1.11% vs. 1.69%/yr (RR 0.65 [95% CI, 0.52-0.81], p <0.001 Sup) Dabi 150mg: 3.11% vs 3.36% (p=0.32) Sig less: intracranial hemorrhagic (ICH), hemorrhagic stroke (HSt) Sig more: GI bleeds Apix 5 mg BID vs Warfarin (INR 2-3) *2.5 mg BID if >2 of ABCs Apixaban Superior Significantly Less 1.27% vs. 1.6%/yr (HR 0.79 [95% CI, 0.66-0.95]; p=0.01 Sup) 2.13% vs. 3.09% (p<0.001) Sig less: ICH, HSt Edox 30 mg or 60 mg daily vs. Warfarin (INR 2-3) Edox 60mg Non-Inferior Significantly Less 1.61% 30mg, 1.18% 60mg, vs. 1.5%/yr (60mg HR 0.79 [97.5% CI, 0.630.99]; p <0.001 NI) 1.61% 30mg, 2.75% 60mg vs. 3.43% (p<0.001) Sig more: GI bleeds Riv 20 mg daily vs Warfarin (INR 2-3) Rivaroxaban Non-Inferior Non-Significant 1.7% vs. 2.2%/yr (HR 0.88 [95% CI, 0.75-1.03]; p <0.001 NI) 20.7% vs. 20.3% (p=0.44) Sig less: intracranial, critical and fatal bleeds Sig more: GI bleeds Mean f/u = 1.6 yr 1. Connolly SJ, et al. NEJM 2009;361:1139-51. 2. Granger et al. NEJM 2011; 365(10): 981-92. Major Bleeding Dabi 110 mg or 150 mg BID vs. Warfarin (INR 2-3) Mean f/u = 2 yr Apixaban ARISTOTLE2 (N=18,201) Primary Efficacy (Stroke or SE) 3. Giugliano RP, et al. NEJM 2013;369(22); 2093-2104. 4. Patel et al. NEJM 2011; 365(10): 883-891. Other Mean CHADS2 = 2.1 Dyspepsia: 11.3% vs 5.8% (P < 0.001) Discontinuation rates: 1 yr (16% vs. 10%) Mean CHADS2 = 2.1 Drug discontinuation: significantly lower in apixaban group (p = 0.001) Mean CHADS2 = 2.8 (only included if >2) Mean CHADS2 = 3.5 Safety endpoint: major and non-major clinically relevant bleeds DOACs: Orthopedic Dosing VTE Prevention for TKR or THR* Dabigatran Apixaban Normal Dose - Knee 2.5 mg BID for Not approved 12 days Normal Dose - Hip 110 mg day 1 220 mg daily for 28-35 days CrCl ≤30 mL/min or on dialysis: not studies; no dosing provided, AVOID Renal Dosing 2.5 mg BID for 35 days CrCl <30 ml/min: not studied *TKR: Total Knee Replacement; THA: Total Hip Replacement Edoxaban Rivaroxaban 10 mg daily for 12 days, 6-10 hours after surgery once hemostasis established 10 mg daily for 35 days, 6-10 hours after surgery once hemostasis established Not approved CrCl 30-50 ml/min: Observe CrCl <30 ml/min: AVOID Betrixaban X a Inhibitor Oral, direct, selective Factor Xa inhibitor Mechanism Betrixaban Package Insert: 7/2019 Prophylaxis of VTE in adults hospitalized for acute medical illness at risk for thromboembolism due to moderate or severe restricted mobility and other risk factors for VTE Capsules: 40 mg 80 mg Risk factors: • Age >75 • Age 60-74 with D-dimer >2 ULN • Age 40-59 with D-dimer >2 ULN AND history of VTE or cancer Indication Formulations 129 Betrixaban (Bevyxxa®) Dosing: BLACK BOX: Contraindications: • 160 mg day 1 → 80 mg daily until day 35-42 • CrCl 15-30 ml/min OR on P-gp inhibitors: 80 mg day 1 → 40 mg daily until day 35-42 Spinal/epidural hematomas Active pathological bleeding and severe hypersensitivity Warnings: • Risk of bleeding • Reduced dose: severe renal impairment or on P-gp inhibitor (e.g. amiodarone, azithromycin, verapamil, ketoconazole, clarithromycin) • Avoid use in hepatic impairment Pregnancy • Only if benefit outweighs risk 130 Betrixaban (Bevyxxa®) ◼ ◼ APEX trial: randomized, double blind, controlled N=7,513: Adults >40 years, hospitalized for acute illness (i.e. CHF, respiratory failure, infection, rheumatic disease, or stroke) at risk for a VTE due to immobility Study Arms Betrixaban: 160 day 1, 80 mg daily 35-42 days vs. Enoxaparin:40 mg daily 6-14 days *Dose reduced for CrCl 15-30 OR on P-gb inhibitors N Engl J Med 2016; 375:534-544. Primary Efficacy Composite (DVT, non-fatal PE or VTE death) Major Bleeding Betrixaban Superior Non-Significant 4.4% vs. 6% (RR 0.75 [95% CI, 0.61-0.91]) 0.67% vs. 0.57% (p=0.554) Clinically relevant non-major bleeding: 2.45% vs. 1.02% (p<0.001) 131 Andexxa®: Dosing ◼ Based on specific FXa inhibitor, dose of FXa inhibitor and time since the patient’s last dose of the FXa inhibitor 132 Andexxa® Package Insert: 09/2020 UIHC Protocol Andexxa® ◼ ◼ Due to lack of clinical efficacy, limited availability, risk for adverse events, and cost, the P&T Subcommittee it is a Protocol Drug “High” dose ~$50,000 and “low” dose ~$25,000 ALL the following protocol criteria must be met to dispense: Apixaban- or rivaroxaban-related acute life-threatening, active intracranial hemorrhage (ICH) Must have received apixaban or rivaroxaban within the last 18 hours or, for instances when the last dose of apixaban/rivaroxaban is unknown, the anti-Xa (enoxaparin assay) must be >0.4 IU/mL Glasgow coma score >7 Estimated ICH volume <60 mL ICH score <3 (for those patients with primary ICH) Expected survival >1 month Does NOT have sever sepsis/septic shock Has NOT received PCCs (Kcentra), recombinant Factor VIIa (NovoSeven) or FVIII inhibitor bypassing activity (FEIBA) Has NOT had a major thrombotic event in past 2 weeks 133