5 Parenteral & Hospital Anticoagulation 2023v2 comp-compressed.pdf

Anticoagulation: Parenteral & Hospital 1 T. Michael Farley, PharmD, BCPS, BC-ADM, BCIDP Clinical Associate Professor University of Iowa and Mercy Hospital Iowa City Outline Introduction and History Enoxaparin & Heparin Prophylactic Vs. Therapeutic Anticoagulation VTE Prophylaxis VTE Hospital Tre...

Anticoagulation: Parenteral & Hospital 1 T. Michael Farley, PharmD, BCPS, BC-ADM, BCIDP Clinical Associate Professor University of Iowa and Mercy Hospital Iowa City Outline Introduction and History Enoxaparin & Heparin Prophylactic Vs. Therapeutic Anticoagulation VTE Prophylaxis VTE Hospital Treatment HIT Diagnosis and Treatment Bridging/Periprocedural Anticoagulants Objectives Understand PK and Strengths and Weakness of Enoxaparin & Heparin including monitoring & use in special populations Contrast Prophylactic Vs. Therapeutic Anticoagulation Review VTE Treatment with Focus on Hospital Understand HIT Diagnosis/Testing and Treatment Options Define and describe guideline requirements for bridging Formulate Periprocedural Anticoagulant Plans Anti-thrombotics: Anti-cogulants, Anti-platelets, Thrombolytics 4 Anticoagulants & Cascade The Western Journal of Emergency Medicine 17(3):264-270 5 Available Anticoagulants Betrixaban Edoxaban Apixaban Rivaroxaban Oral Agents Dabigitran Warfarin 1940 1950 1960 Ximelagatran 1970 1980 1990 2000 2010 2015 2018 LMWH UFH Fondaparinux Argatroban & Bivalirudin Parenteral Agents 6 Why Anticoagulate in the Hospital? RISK OF CLOTTING (Venous or Arterial) VTE Risk – In Hospital VTE Treatment – In & outside of hospital Clot has occurred: ê progression, new clots A. Fib - In & outside of hospital Acute Coronary Syndrome – In Hospital Special Situations: HIT, Valve Replacement 7 Anticoagulant Indications 2023 VTE Prevention VTE Treatment (↑ doses) HIT Heparin ✔ ✔ No ✔ ✔ Enoxaparin ✔ ✔ No ✔ ✔ Fondaparinux ✔ ✔ ✔ Warfarin ✔ ✔ ✔ϕ ✔* Dabigatran ✔ Surgical (Sx) ✔ ? ✔ Rivaroxaban ✔Sx & ✔ ✔ (off-label) ✔ ✔Sx ✔ ✔ (off-label) ✔ ✔ ? ✔ Apixaban Medical Edoxaban Betrixaban Bridging A. Fib Long Term ACS (Acute, in addition to antiplatelet tx) ✔ ✔ ✔Medical Bivalirudin Argatroban ✔ ✔ ✔ ✔ ✔ 8 * Warfarin is only PO agent for mechanical heart valve anticoagulation Sx = Surgical ϕ when platelets >150K Heparins (LMWH & UFH) available in the U.S. GENERIC NAME TRADE NAME MOLECULAR WEIGHT (daltons) HALF – LIFE In minutes Anti- Xa:IIa Dalteparin (LMWH) Fragmin 5,000 120-420 2.7:1 Enoxaparin (LMWH) Lovenox 4,500 270-420 (4.5-7 hrs) 3.6:1 - 14,000 60-90 1:1 Standard Heparin (UFH) 9 Mechanism of Heparins Unfractionated heparin inactivates both: Factor IIa (Thrombin) and Factor Xa LMWH has increased affinity for Factor Xa (Smaller IIa effect) -Fondiparinux is only a pentasaccharide sequence 10 Weitz. NEJM, 1997; 337:688 Low Molecular Weight Heparin LMWHs approved in US Enoxaparin (Lovenox®) Generic commonly used Dalteparin (Fragmin®) 11 Low Molecular Weight Heparin Pharmacokinetics ~100% bioavailable via SQ Peak effect in 2.5-4 hours Cleared renally Half-life prolonged in renal impairment Normal Half-Life 4.5-7 hrs Renal dose adjustments needed CrCl <30 ml/min 12 Enoxaparin Pharmacokinetics Plasma Concentration Time to peak effect Enox: 2-4 hours En 0 4 ox ap Half-life Enox: 4.5-7 hours ar in 8 13 12 Frydman AM et al. J Clin Pharmacol 1988; 28: 609-18 Prophylaxsis vs. Therapeutic Dosing Partial vs. “Full” Treatment VTE Prevention = Prophylactic A.Fib Anticoagulation = Therapeutic Even if “preventing” stroke VTE Treatment = Therapeutic Highest doses Low Molecular Weight Heparin Dosing Given via SQ injection in abdomen Therapeutic Enoxaparin: 1mg/kg q12 hours or 1.5mg/kg q24 hours = 1.5-2mg/kg/day Renal Adjustment if CrCl<30: 1mg/kg q24 hours Dalteparin: 200 anti-Xa IU/kg (max 18,000 IU) q24 hours 15 Enoxaparin Pharmacokinetics 1.5 mg/kg q 24hrs Plasma Concentration 1 mg/kg q 12 hours 0 4 8 12 Frydman AM et al. J Clin Pharmacol 1988; 28: 609-18 16 24 Enoxaparin: Sizes 150mg/1ml syringe (concentrated) 120mg/0.8 ml syringe (concentrated) 100mg/1.0 ml syringe 80mg/0.8 ml syringe 60mg/0.6 ml syringe 40mg/0.4 ml syringe 30mg/0.3 ml syringe Hospital Only: 300 mg/3 mL (3 mL) vial 17 Low Molecular Weight Heparin Adverse Effects Hemorrhage (4-13%) Thrombocytopenia: <1% UFH is 3x+ more likely Boxed warning: Increased risk of spinal/epidural hematoma in patients undergoing spinal or epidural anesthesia or spinal puncture 18 Enoxaparin in Special Populations Obesity Generally recommend to dose based on total body weight 1mg/kg q 12 hours preferred over 1.5mg/kg q 24 hours Renal impairment Clearance of anti-Xa effect strongly correlated with CrCl Increased risk for bleeding Enoxaparin 1 mg/kg every 24 hours for renal impairment (<30 ml/min) Generally recommend UFH for severe renal impairment (CrCl<15mL/min) Pregnancy LMWHs do not cross the placenta Pregnancy category B 19 Enoxaparin in CrCl 30-50 ml/min Increased bleeding risk noted… (Arch Intern Med. 2012;172(22):1713-1718) Those with moderate renal function (CrCl 30-50) had an increased rate of major bleeding 22% vs 5.7% in in 164 patients. Greater accumulation with no dose adjustment Options to consider: 1.5mg/kg/QD vs 1mg/kg/BID (Thromb Res. 2005;116(1):41-50.) 100 kg patient 150 mg vs 200mg per day, less enoxaparin Rounding down to next lowest via size 90 kg patient using 1mg/kg BID, use 80mg SQ BID instead of 100mg Using a lower dose per kg after first dose (0.8 mg/kg) 20 Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism. J Thromb Thrombolysis. 2016; 41: 165–186. Low Molecular Weight Heparin Monitoring Routine monitoring for efficacy not necessary Baseline CBC with platelets, repeat every 3-7 days Anti-factor Xa monitoring not routinely recommended Consider in significant renal impairment, low body weight (<50kg), morbid obesity, prolonged therapy, or when used in pregnancy Specific dosing algorithms based on anti-Xa levels not well established 21 Low Molecular Weight Heparin Contraindications Hypersensitivity to LMWH, UFH, pork products, sulfites History of HIT Active bleeding Considerations Cost (cash price) Lovenox 100 mg BID x 5 days: ~$250-600 Enoxaparin 100 mg BID x 5 days: ~$20-100 Patient administration issues Self administered 22 Low Molecular Weight Heparins (LMWH = Enoxaparin) Advantages (vs UFH) Disadvantages Longer half life Partial protamine response (25-40%) Improved efficacy Variable effect with renal failure, obesity Predictable kinetics Concern for bleeding Less heparin-induced thrombocytopenia Cost-effective Lower monitoring burden 23 Bruising with SQ LMWH Case: Dose LMWH 53 year old with DVT in Leg 80 kg (176 lbs), 72” (6’, 183 cm), BMI 23.9 Scr is 0.8 mg/dl, Est CrCl = 110 ml/min What dose of Enoxaparin would you give him? 25 26 Unfractionated Heparin (UFH) Site of Action: IIa / Xa (ratio 1:1) Elimination: non-renal Half life: dose dependent ~ 1.5 hours Route: intravenous or subcutaneous Monitoring: aPTT or Anti-Xa Therapeutic goal ~ 1.5-2.5 times normal control value (control ~30 sec) 27 Heparin (UFH): useful in special situations High bleed risk Consider half life & reversibility Heparin: shortest t ½ and is fully reversed with protamine Poor Renal Function Heparin is primarily cleared extra-renally Reticuloendothelial system and endothelial cells Some renal/hepatic at large doses Why not the standard? Highest risk of HIT (more to come) Narrow therapeutic window (For therapeutic only) monitor PTT q6 hours Therapeutic Heparin (UFH) Initial dosing for treatment of VTE Intravenous UFH 80 units/kg bolus 18 units/kg/hr infusion Max doses used in some hospitals. Dosing for Cardiac (ACS) – 60 units/kg bolus , 15 units/kg/hr infusion Monitoring Activated partial thromboplastin time (aPTT) or Anti-Xa level Therapeutic range is hospital specific Check at baseline and at 6 hours after initiation or dose adjustment ~90 min t1/2 x 4 = 6 hours 29 Example Heparin Nomogram using aPTT 30 Heparin Anti-Xa Nomogram 31 Prophylaxsis vs. Therapeutic Dosing Enoxaparin (LMWH) 30-40mg SQ daily-BID vs 1 mg/kg BID or 1.5 mg/kg daily Heparin (UFH) 5000 units SQ BID-TID vs 60-80 units/kg bolus then 15-18 units/kg/hour continuous infusion Prevention of Venous Thromboembolism (VTE) 33 Venous Thromboembolism (VTE) VTE is responsible for 15% of all hospital deaths 34 Venous Thrombosis DVT 2 Million PE Post-Phlebitic Syndrome 800,000 600,000 Silent PE 1 Million 10% Death 60,000 VTE: $2-5 billion / year Lancet 353:1386-89 35 Pulmonary Hypertension 30,000 Pathogenesis of VTE VTE usually occurs as a result of at least 1 of 3 underlying factors 36 Cases per 10,000 person-years 1000 100 Recently hospitalized 10 1 Hospitalized patients 37 Community residents Heit – Mayo Clin Proc 2001;76:1102 Assessing risk of VTE Risk Factor / Characteristic Odds Ratio Recent surgery w/ institutionalization 21.72 Trauma 12.69 Institutionalization without recent surgery 7.98 Malignancy with chemotherapy 6.53 Prior CVAD or pacemaker 5.55 Prior superficial vein thrombosis 4.32 Malignancy without chemotherapy 4.05 Neurologic disease with extremity paresis 3.04 Serious liver disease 0.10 Heit38JA, et al. Thromb Haemost. 2001; 86: 452 VTE Risk Scores - Medical The IMPROVE risk score: (prior VTE, active cancer, age >60 years, and thrombophilia) 0.4 to 0.5 % if 0 8 to 11 % in those with 3+ Padua prediction score: Low risk patients (score <4): 0.3 percent High risk patients (score ≥4): 2.2% (on tx) and 11% not The GENEVA risk score: Low-risk patients (score <3): 0.6 % (on tx) High risk patients (score ≥3): 3.2 % (on tx) 39 VTE Risk Scores – Caprini (Surgery) 40 41 Good News! Effective, safe, and cost-effective VTE prophylaxis is available! Pharmacologic Prophylaxis reduces DVT and PE by 50-65% Bleeding risk due to prophylaxis is rare HIT 2.37% with UFH (occasionally very serious) 0.06% with LMWH • Cost effectiveness of VTE prophylaxis has been repeatedly demonstrated. Geerts et al. Chest. 2004 Sep;126(3 Suppl):338S-400S. 42 Shojania KG et al. Making health care safer… .www.ahrq.gov/clinic/ptsafety/. Martel – Blood 2005;106:2710 Pharmacologic prophylaxis 43 Francis CW. NEJM 2007; 356 (14): 1438 Anticoagulant Indications 2023 VTE Prevention VTE Treatment (↑ doses) HIT Heparin ✔ ✔ No ✔ ✔ Enoxaparin ✔ ✔ No ✔ ✔ Fondaparinux ✔ ✔ ✔ Warfarin ✔ ✔ ✔ϕ ✔* Dabigatran ✔ Surgical (Sx) ✔ ? ✔ Rivaroxaban ✔Sx & ✔ ✔ (off-label) ✔ ✔Sx ✔ ✔ (off-label) ✔ ✔ ? ✔ Apixaban Medical Edoxaban Betrixaban Bridging A. Fib Long Term ACS (Acute, in addition to antiplatelet tx) ✔ ✔ ✔Medical Bivalirudin Argatroban ✔ ✔ ✔ ✔ ✔ 44 * Warfarin is only PO agent for mechanical heart valve anticoagulation Sx = Surgical ϕ when platelets >150K Pharmacologic prophylaxis Anticoagulant Prophylactic Dose Unfractionated Heparin (UFH) 5000-7500 International Units every 8-12 hours subcutaneously Low Molecular Weight Heparins (LMWH’s) Enoxaparin 40 mg daily subcutaneously; reduce dose to 30 mg daily in renal impairment Dalteparin 5000 IU daily subcutaneously Fondaparinux 2.5 mg daily subcutaneously Warfarin 5 – 10 mg initially, adjust dose based on INR (goal INR 2.5 ; goal INR range 2-3) DOACs Rivaroxaban 10mg PO daily (ortho or medical) Apixaban 2.5mg PO daily (ortho) Dabigatran 110-220mg PO daily (ortho) Edoxaban 30mg PO daily (ortho) Betrixaban 160-80mg PO daily (medical) Aspirin (Ortho Sx) Aspirin 325mg PO BID 45 Betrixaban (Bevyxxa) be-TRIX-a-ban Non-inferior to LMWH in general medical population for VTE prophylaxis Xa Inhibitor 80mg Capsule 2 capsules (160mg) for first dose, then 80mg daily Up to 42 days Renal adjustment to 40mg for CrCl <30 ml/min 46 VTE Prevention Special Populations Obesity Enoxaparin 30-40mg sq BID in patients with BMI ³ 40 Renal Insufficiency Enoxaparin 30mg sq qday or UFH 5000 units sq BID-TID Elderly Higher bleeding risks Altered pharmacokinetics Underweight ~0.5 mg/kg enoxaparin per day target 47 Non-pharmacological prophylaxis Compression elastic stockings Thrombo-Embolus Deterrent (TED) Stockings Knee or Thigh-length antiembolism stockings Intermittent pneumatic compression Sequential compression devices (SCDs) “Kendalls” 48 VTE Treatment DVT and PE Anatomy https://www.youtube.com/watch?v=V9wt1yFt0FQ 50 DVT and PE anatomy 51 Treatment of VTE Goals of therapy Prevent thrombus extension Prevent acute PE Reduce mortality Prevent development of complications Post thrombotic syndrome Chronic thromboembolic pulmonary hypertension 52 Anticoagulant Indications 2023 VTE Prevention VTE Treatment (↑ doses) HIT Heparin ✔ ✔ No ✔ ✔ Enoxaparin ✔ ✔ No ✔ ✔ Fondaparinux ✔ ✔ ✔ Warfarin ✔ ✔ ✔ϕ ✔* Dabigatran ✔ Surgical (Sx) ✔ ? ✔ Rivaroxaban ✔Sx & ✔ ✔ (off-label) ✔ ✔Sx ✔ ✔ (off-label) ✔ ✔ ? ✔ Apixaban Medical Edoxaban Betrixaban Bridging A. Fib Long Term ACS (Acute, in addition to antiplatelet tx) ✔ ✔ ✔Medical Bivalirudin Argatroban ✔ ✔ ✔ ✔ ✔ 53 * Warfarin is only PO agent for mechanical heart valve anticoagulation Sx = Surgical ϕ when platelets >150K Diagnosis Acute VTE D-dimer Fibrin degradation product Predicative but not specific CT with contrast VQ scan Therapeutic Options Anticoagulation Prevents clot enlargement/new clots while body dissolves clot over days to weeks Thrombolytic therapy for a small % of (unstable) patients 54 Thrombolytics 55 Anti-thrombic Therapy for PE 56 Anti-thrombic Therapy for PE For Hemodynamically unstable PE patients SBP < 90 mmhg, +/- Right heart strain Small minority of PE cases Recombinant tissue plasminogen activator (TPA) binds to fibrin, increases plasminogen affinity and activation 100mg dose for PE treatment No TPA “window” for PE indication 2-hour infusion Monitor: BP, HR and Sign/Sx of Bleeding 50mg dose in smaller/high bleed risk patients? Followed by Heparin or other anticogulation Held during TPA infusion Started when aPTT is < twice the upper limit of normal, post TPA Circulation. 2011;123:1788-1830 Chest 2016;149(2):315-352 TPA Use Algorithm Pulmonary Embolism Hypotensive? Hypotensive (SBP<90) Normotensive + Biomarkers or abnormal echo? Yes TPA Indicated TPA? (Sub-massive) No No TPA 58 Contraindications to Antithrombotics Absolute Any active bleeding Recent brain, eye, or spinal cord surgery Malignant hypertension Spinal anesthesia or lumbar puncture Relative Recent major surgery Pre-existing coagulation or platelet defect, thrombocytopenia, or other coagulation abnormality Platelets <75 K Inaccessible ulcerative lesion (e.g., GI tract) Elevated INR/DOAC therapy 59 Treatment of VTE Anticoagulant Therapy Inpatient (high risk VTE) or outpatient (DVTs and low risk PEs) Heparin/LMWH/others PLUS warfarin DOAC options: Rivaroxaban or apixaban without bridging Dabigatran or edoxaban AFTER 5-10 days of parenteral agent Inferior vena cava filters Not recommended Only if contraindication to anticoagulation 60 Initial Heparin Anticoagulation Onset Heparin Infusion (IV) Plasma Concentration Eno x SQ aparin (Lov eno x) Heparin better for: High Risk PE Renal Failure High Bleed Risk Time to peak effect Enoxaparin (LMWH): 2-4 hours Heparin (UFH): instant if bolus given Half-life Enoxaparin: (LMWH) 4.5-7 hours Heparin (UFH): 1.5 hours 0 2 4 6 hours Frydman AM et al. J Clin Pharmacol 1988; 28: 609-18 61 Chest 2016 “In patients with DVT of the leg or PE and no cancer, as long-term (first 3 months) anticoagulant therapy, we suggest dabigatran, rivaroxaban, apixaban, or edoxaban over vitamin K antagonist (VKA) therapy (Grade 2B).” Antithrombotic therapy for vte disease: chest guideline and expert panel report. Kearon C, Akl EA, Ornelas J, et al. Chest 2016;149(2):315-352. Categories of Oral Anticoagulants Direct Thrombin Inhibitors: Dabigatran Direct Factor Xa inhibitors: Rivaroxaban, Apixaban, Edoxaban, Betrixaban 63 VTE/PE Treatment Efficacy Hazard ratios (HR) for recurrent VTE and VTE-related death 64 and their 95% confidence intervals (CI) in phase 3 trials comparing NOACs with conventional therapy for acute VTE treatment. Blood. 2014 Aug 14;124(7):1020-8. Major and All-Cause Bleeding Hazard ratios (HR) for major bleeding or major plus clinically relevant non-major bleeding (CRNB) and their 95% confidence 65 intervals (CI) in phase 3 trials comparing NOACs with conventional therapy for acute VTE treatment. DOACs I.E. Eliquis (Apixaban) or Xarelto (Rivaroxaban) VS Coumadin (Warfarin) for PE/DVT Treatment 2023 Eliquis or Xarelto Warfarin o ~10 Years Experience ü ~50 Years Experience o Similar Effectiveness o Similar Effectiveness ü Lower Bleeding Risk o Standard Bleeding Risk o Antidotes approved (PCC, Andexxa) o Antidote with years of use o Not all hospitals carry ü No Dietary Limitations ü No required Lab Tests ü Fast Onset (no injections) ü Fewer Drug Interactions o Limited data in high BMI/Obesity o Cost $$$ (Copay variable) ü CHEST Guideline 1st Option o 66 Vitamin K + PCC Antidote o Dietary Limitations (Green Leaf Veg.) o INR Lab test every 1-2 wks o Slow Onset (5-10 days injections) o Many Drug Interactions ü High BMI – Record of Safety ü Cost $ o CHEST Guideline 2nd Option Outpatient Treatment for low-risk PE? • Low Risk Patients • No O2 requirement, Low PESI score (mortality risk), normal vitals • RCTs with LMWH have shown non-inferiority • All DOACs approved for PE and DVT • Inpatient vs. outpatient not specified by FDA • 1.7% of PE cases treated as outpatient Am J Med. 2016 Sep;129(9):974-7. Eur Respir J. 2013 Jul;42(1):134-44. 67 DOAC Onset Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Brand Name Coumadin Pradaxa Xarelto Eliquis Savaysa Target Vit K Dependent Factors Thrombin Factor Xa Factor Xa Factor Xa Bioavailability 100% 7% 80% 60% 62% Dosing OD BID OD (BID) BID OD Time of peak effect 5-7 days 1-3 hours 2-4 hours 1-2 hours 1-2 hours Half-life 40 hrs 14-17 hrs 7-11 hrs 8-14 hrs 5-11 hrs Renal clearance 0% 80% 33% 27% 50% Drug Interactions P-GP 3A4/P-GP 3A4/P-GP P-GP Many Yeh CH, Gross PL, Weitz JI. Evolving use of new oral anticoagulants for treatment of venous thromboembolism. Blood. 2014 Aug 14;124(7):1020-8. 68 Enoxaparin vs DOAC st (1 Dose) Plasma Concentration Time to peak effect Enoxaparin: 2-4 hours Rivaroxavan: 2-4 hrs Ri 0 4 En ox ap ar in Half-life Enox: 4.5-7 hours Rivaroxavan: 7-12 hrs va ro xa ba n 8 12 Frydman AM et al. J Clin Pharmacol 1988; 28: 609-18 Rohde G. J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Sep 1;872(1-2):43-50 69 DOAC: VTE Treatment Courses Start of Treatment à à à 3 months 21 Days Rivaroxaban 15mg BID ê 20mg Daily 7 Days Apixaban 10mg BID ê 5mg BID Parenteral Anticoagulant (Enoxaparin, Heparin) Dabigatran 150mg BID --------------5-10 days ------------Parenteral Anticoagulant (Enoxaparin, Heparin) Edoxaban 60mg Daily 70 Treatment of DVT & PE Rivaroxaban, Apixaban No bridging required (onset similar to Lovenox) Higher dose for first 21 days with Rivaroxaban 15mg PO BID x 21 days Then 20 mg daily Higher dose for first 7 days with Apixaban 10mg PO BID x 7 days Then 5mg BID Dabigatran, Edoxaban After 5-10 days of parenteral anticoagulant Not bridging, sequential treatment A.Fib dosing Non-inferior vs. Warfarin in DVT and PE trials A. Fib vs VTE DOAC & Renal Adj. TRADE NAME OK FOR CRCL >95 Rivaroxaban AFIB Xarelto YES Rivaroxaban -VTE- Xarelto Yes Apixaban AFIB Eliquis YES Apixaban -VTE- Eliquis Normal Renal Fxn CRCL 50-30 (94-50 ml/min) 20 mg QD CRCL 3015 CRCL <15 Ø 15mg QD 15mg BID x 21 days then 20mg daily 5-2.5mg BID* Ø Ø (SCr >2.5 or CrCl <25 ml/min not studied) YES 10mg BID x 7 days then 5mg BID Ø (SCr >2.5 or CrCl <25 ml/min not studied) * 5 mg twice daily unless patient has any 2 of the following: Age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL, then reduce dose to 2.5 mg twice daily 72 A. Fib vs VTE DOAC & Renal Adj. TRADE NAME OK FOR CRCL >95 NORMAL DOSE CRCL 50-30 CRCL 3015 Dabigatran AFIB Pradaxa YES 150 mg BID Dabigatran -VTE- Pradaxa YES 150 mg BID CRCL <15 Ø 75mg BID Ø (CrCl < 30 ml/min not studied) (after 5-10 days of parenteral) Edoxaban AFIB Savaysa NO 60mg QD 30mg QD Ø Edoxaban -VTE- Savaysa Not stated (not rec) 60mg QD 30mg QD Ø (after 5-10 days of parenteral) 73 Note: Presence of p-glycoprotein inhibitors changes dosing or limits use Treatment of VTE Special situations Superficial vein thrombosis Mild – supportive care and warm or cool compresses, NSAIDs High Risk – Low dose LMWH, DOAC, or fondaparinux for 45 days Fondaparinux preferred per CHEST guidelines Subsegmental PE (very small PE) and no DVT clinical surveillance over anticoagulation (2021, 2016 Chest) Upper extremity DVT Anticoagulation treatment (for 3 months) Removal of central line if present and possible. 74 Chest 2021; 160:e545 Cancer and VTE Edoxaban – An open-label noninferiority randomized trial (Hokusai VTE - 1050 patients) with cancer-associated VTE Similar efficacy and bleeding Higher bleeding in upper GI cancers Rivaroxaban – A pilot study (SELECT-D) of 406 cancer patients. Increased GI bleeding Apixaban vs LMWH (Caravaggio trial - 1155 patients) Similar efficacy and bleeding 75 Cancer and VTE: Update Meta- Analysis DOAC (Chest. 2021; 160(6):e545.) DOAC had a lower VTE recurrence rate (RR 0.62, 95% CI 0.43-0.91) no difference in the rate of major bleeding (DOAC vs standard) CHEST 2021 – DOACs favored over LMWH NCCN (National Comprehensive Cancer Network) 2020 – favors DOACs for cancer associated VTE in those without GI cancers. American Society of Hematology 2021 Guideline – DOACs or LMWH may be considered. 76 Chest 2021; 160:e545 Heparin Induced Thrombocytopenia 77 Heparin Induced Thrombocytopenia HIT is a prothrombotic drug reaction caused by plateletactivating IgG antibodies that recognize platelet factor 4 (PF4)/heparin complexes and destroy platelets then initiate coagulation via thrombin. IgG antibody Formation of immune complexes (PF4-heparin-IgG) Formation of PF4-heparin complexes Microparticle release Platelet PF4 Heparin EC injury PF4 release Platelet activation* Fc receptor Heparin-like molecules Blood vessel Diagnosis of HIT: 4T Score 4Ts category 2 points 1 point 0 points Platelet count fall > 50% and platelet nadir ≥ 20 Platelet count fall of 30%Platelet count fall < 30% 50% or platelet nadir 10or platelet nadir < 10 19 Timing of platelet count fall Clear onset days 5-10 or platelet fall ≤ 1 day (prior heparin exposure within 30 days) Consistent with days 5-10 fall, but not clear (eg, missing platelet counts); Platelet count ≤ 4 days onset after day 10; or fall without recent exposure ≤ 1 day (prior heparin exposure 30-100 days ago) Thrombosis or other sequelae New thrombosis (confirmed); skin necrosis; acute systemic reaction postintravenous unfractionated heparin bolus Progressive or recurrent thrombosis; nonnecrotizing (erythematous) skin lesions; suspected thrombosis (not proven) None Other causes of thrombocytopenia None apparent Possible Definite Thrombocytopenia The 4Ts score of 1-3 = low , 4-5 = intermediate and 6-8 = high probability of HIT oTher Causes of Thrombocytopenia Primary immune thrombocytopenia (ITP) Drug-induced thrombocytopenia (DITP) Sulfonamides, Acetaminophen, Ibuprofen, Naproxen, Piperacillin, Vancomycin Glycoprotein IIb/IIIa inhibitors Infections: HIV, Hep C, Epstein-Barr virus, H. pylori Sepsis Hypersplenism/chronic liver disease Alcoholism Rheumatologic/autoimmune disorders Pregnancy Myelosuppresion Cancer Inherited thrombocytopenias ELISA or HIT Ab Test Enzyme Linked Immuno Assay Qunatifies ammount of HIT Antibodies Faster results than SRA in most cases High False Postive Rates Good Negative Predictive Value Optical density (OD) values Marker of antibody levels ↑ OD = greater risk of HIT Weakly + HIT Ab test is unlikely to be true HIT SRA needed to confirm HIT ELISA OD Result Likelihood of SRA Positive Result <0.4 0.0 to 0.1% 0.4 to <1.0 1 to 5% 1.0 to <1.4 18 to 30% 1.4 to <2.0 19 to 45% >2.0 89 to 100% Serotonin Release Assay (SRA) Gold Standard for HIT diagnosis “Functional” Assay Reliable Results $$$ Treatment of HIT Stop any heparin treatment, including heparin line flushes or use of heparin coated catheters Platelet transfusions contraindicated LMWH contraindicated due to cross-reactivity Warfarin contraindicated initially Platelets >150K prior to starting Start alternative anti-coagulation, even without any signs of thrombosis DOAC (Apixaban or Rivaroxaban) Argatroban Bivalrudin Fondaparinux 84 Anticoagulant Indications 2023 VTE Prevention VTE Treatment (↑ doses) HIT Heparin ✔ ✔ No ✔ ✔ Enoxaparin ✔ ✔ No ✔ ✔ Fondaparinux ✔ ✔ ✔ Warfarin ✔ ✔ ✔ϕ ✔* Dabigatran ✔ Surgical (Sx) ✔ ? ✔ Rivaroxaban ✔Sx & ✔ ✔ (off-label) ✔ ✔Sx ✔ ✔ (off-label) ✔ ✔ ? ✔ Apixaban Medical Edoxaban Betrixaban Bridging A. Fib Long Term ACS (Acute, in addition to antiplatelet tx) ✔ ✔ ✔Medical Bivalirudin Argatroban 85 ✔ ✔ ✔ ✔ * Warfarin is only PO agent for mechanical heart valve anticoagulation Sx = Surgical ✔ ϕ when platelets >150K Treatment: Direct Thrombin Inhibitors Argatroban Given intravenously 2.0 mcg/kg/min Lower starting dose of 0.5 to 1.2 mcg/kg/minute for ICU Heart failure, postcardiac surgery, liver dysfunction FDA Approved for HIT Monitor by APTT (~1.5-2.5x baseline) q 2 hours T ½ = 40 min Metabolized in liver Preferred in renally impaired patients 86 Argatroban & INR Elevation Argatroban causes a false elevation of the PT/INR INR of >4 is therapeutic when patients are on both warfarin and argatroban 5 days of overlap suggested Once therapeutic INR is reached, turn off Argatroban and recheck INR in 4-6 hours Allows Argatrogan to clear system t/12 = 40 minutes INR should then be near normal range of 2-3 in most patients. 87 Treatment: Direct Thrombin Inhibitors Bivalirudin Given intravenously 0.15 to 0.2 mg/kg/hr infusion Monitor by APTT (1.5-2.5x baseline) q 2 hours FDA approved for HIT in Cardiac Surgery Population Off label in general medical population T ½ = 25 min Eliminated enzymatic (80%) / renal (20%) Preferred in hepatically impaired patients 88 DOACs for HIT1 Safest in clinically stable patients Apixaban HIT with Thrombosis: 10 mg twice daily × 1 week, then 5 mg twice daily Isolated HIT (no thrombus): 5 mg twice daily until platelet count recovery Rivaroxaban HIT with Thrombosis: 15 mg twice daily × 3 weeks, then 20 mg daily Isolated HIT (no thrombus): 15 mg twice daily until platelet count recovery 1- American Society of Hematology 2018 guidelines for management of venous 89 thromboembolism:heparin-induced thrombocytopenia. Blood Adv. 2018;2(22). Treatment: Indirect Factor Xa Inhibitor Fondaparinux (Arixtra) 7.5mg SQ daily 5-10mg weight based adjustment Off Label use for HIT Contraindicated in renal impairment t ½ = 21 hours Sometimes used for prophylaxis ( lower doses) for those with a history of HIT. 90 Bridging Definition Bridging: The process of transition from a rapid acting (parenteral) anticoagulant to a slower onset oral anticoagulant (warfarin) Procedural Bridging: The process whereby an OAC is discontinued and replaced by a subcutaneous or intravenous anticoagulant before and/or following an invasive procedure. 91 Bridging Concept Warfarin Enoxaparin [Minimum of 5 days] INR ≥ 2 [ 24 hours] -Overlap-92 Chest Guidelines Bridging Recommendation “In patients with acute DVT/PE we recommend early initiation of VKA (eg, same day as parenteral therapy is started) over delayed initiation, and continuation of parenteral anticoagulation for a minimum of 5 days and until the international normalized ratio (INR) is 2.0 or above for at least 24 h (Grade 1B) .” 93 Chest. 2012; 141: e24S-e43S Anticoagulation Interruption • Every year, nearly 250,000 North Americans require interruption of an oral anticoagulant for invasive procedures. Chest 2012;141:Suppl:e326S-50S. 94 BRIDGE Trial (2015) • Patients with low- and intermediate-risk atrial fibrillation receiving anticoagulation and undergoing surgery periprocedural bridging with LMWH did not alter arterial thromboembolism (vs. no bridging), but did é bleeding. • Mean CHADS2 score: 2 • Arterial Thromboembolism 0.4% vs. 0.3% (Placebo vs. LMWH) • Major bleeding 1.3% vs. 3.2% (Placebo vs. LMWH) Douketis JD, et al. Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation. NEJM. 2015. 373(9):823-33. www.wikijournalclub.org 95 Anticoagulation Bridging Anticoagulation perioperatively must be on a case-bycase basis1 Assess patient thrombotic risk2: • Low CHA2DS2-VASc = 1-4 (<5% annual risk) • Moderate CHA2DS2-VASc = 5-6 (5-10% annual risk) • High CHA2DS2-VASc = 7+ (>10% annual risk) Assess patient bleed risk2: • Major bleed or intracranial hemorrhage <3 months • Clotting abnormality (ASA, elevated INR, Low Plts) • Prior bleeding from bridging 1- Cardiac Risk of Noncardiac Surgery. J Am Coll Cardiol 2015;66:2140-2148. 2 - 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management in A.Fib. J Am Coll Cardiol. 2017 Feb 21;69(7):871-898. 96 SPARC Tool http://www.sparctool.com/97 Anticoagulation Periprocedurally Doherty JU et al. 2017 ACC Expert Consensus Decision Pathway for Periprocedural 98 Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation. J Am Coll Cardiol. 2017 Jan 5. PMID: 28081965 DOACs: Peri-Procedural Management Perioperative Management of Antithrombotic Therapy: An American College of Chest Physicians Clinical Practice Guideline. Chest. 2022 99 Nov;162(5):e207-e243. doi: 10.1016/j.chest.2022.07.025. Epub 2022 Aug 11. PMID: 35964704. DOACs: Peri-Procedural Management Dabigitran – very renal dependent: 24-120 hours Xa DOACs – 24-48 hour hold with good renal function (CrCl > 30 ml/min) Doherty JU et al. 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation. J Am Coll Cardiol. 2017 Jan 5. PMID: 28081965 100 High Bleed Risk: 48-72 hours post surgery Low Bleed Risk: 24 hours after surgery 101 Doherty JU et al. 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation. J Am Coll Cardiol. 2017 Jan 5. PMID: 28081965 Restart Parenteral or DOAC? New Development – DOACs in CKD Apixaban in End Stage Renal Disease in A.Fib Retrospective studies suggest similar efficacy and no increased bleeding risk with use of apixaban when compared to warfarin in patients with advanced CKD (CrCl <25 mL/minute) (Herndon 2019; Schafer 2018; Stanton 2017) and dialysis patients (Chokesuwattanaskul 2018; Reed 2018; Siontis 2018). Some experts avoid use of apixaban for all indications in patients with a severe reduction in kidney function (CrCl <25 mL/minute, including dialysis) since safety and efficacy remain untested and cannot be assured. Dose Unclear: Apixaban 5 mg twice daily resulted in fewer thromboembolic events and fewer major bleeding events while apixaban 2.5 mg twice daily only resulted in fewer major bleeding events compared to warfarin (Siontis 2018). 102 Lexi-Comp Online 2023 Anticoagulation in Covid LMWH and Heparin are preferred in hospitalized Trending d-dimer may be helpful https://www.covid19treatmentguidelines.nih.gov/therapies/statement-onanticoagulation-in-hospitalized-patients/ 103 Questions? 104 Transition to Rivaroxaban from Enxaparin SQ (Q12hrs) Enoxaparin SQ -12 Rivaroxaban PO 15mg PO BID -2 0 4 8 12 Frydman AM et al. J Clin Pharmacol 1988; 28: 609-18 Rohde G. J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Sep 1;872(1-2):43-50 105 Simultaneous Start-Stop 2 Hours prior 4 Hours prior 6 Hours prior Heparin IV to Enoxaparin SQ or DOAC Transition Heparin Infusion Enoxaparin SQ DOAC BID 0 4 106 8 12 16