Venous Thromboembolism Drugs & Diseases (Student Notes 2024)

**Venous Thromboembolism** **Drugs & Diseases: Cardio-Renal I** Gregory J. Hughes PharmD, BCPS, BCGP Clinical Professor \| St. John's University Email: Book: [A Medication Guide to Internal Medicine Tests & Procedures, 1^st^ ed](https://www-sciencedirect-com.jerome.stjohns.edu/book/97803237900...

**Venous Thromboembolism** **Drugs & Diseases: Cardio-Renal I** Gregory J. Hughes PharmD, BCPS, BCGP Clinical Professor \| St. John's University Email: Book: [A Medication Guide to Internal Medicine Tests & Procedures, 1^st^ ed](https://www-sciencedirect-com.jerome.stjohns.edu/book/9780323790079/a-medication-guide-to-internal-medicine-tests-and-procedures) (free through SJU) **Objectives:** - Describe basic pathophysiologic events which occur in VTE - Select a drug dosage regimen for a particular patient with VTE considering concurrent disease states and other drug therapies - Develop a monitoring plan for drug efficacy and adverse drug events - Design alternative treatment regimens for patients who experience treatment failures or adverse drug events **Content questions:** - Describe findings characteristic of VTE - Recommend therapy to prevent VTE based on patient risk factors - Describe the nuances in using warfarin & DOACs for management of VTE - Design a treatment plan for the management of VTE - Select appropriate therapy for VTE considering a patient's comorbid conditions - Create a plan to monitor for safety and efficacy for the various therapies used in treating VTE - Recommend therapy to address the hemorrhagic complications associated with agents used in the management of VTE - Identify patient characteristics that preclude the use of various agents in the management of VTE - Compare and contrast: heparin versus LMWH, and warfarin versus DOACs, in the management of VTE **Additional Readings:** - Shapiro NL, Hellenbart EL. Chapter 11: Thrombosis. In: Zeind CS, Carvalho MG, et al. *Applied Therapeutics: The Clinical Use of Drugs, 12e*. Baltimore, MD: Lippincott Williams & Wilkins; 2023. - Kearon C, Ornelas J, Blaivas A, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. *Chest* 2016;149(2):315-52. Available at: - Ortel TL, Neumann I, Ageno W, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. *Blood Adv* 2020;4(19):4693-4738. Available at: - HughesMedicine.com -- related topics - Prescribing information -- dabigatran, rivaroxaban, apixaban, edoxaban. Available online. **Abbreviations:** ABG = arterial blood gas, aPTT = activated partial thromboplastin time, bid = twice daily, ASH = American Society of Hematology, BP = blood pressure, CBC = complete blood count, ClCr = creatinine clearance, CT = computed tomography, CXR = chest X-ray, DOAC = direct oral anticoagulant, DTI = direct thrombin inhibitors, DVT = deep vein thrombosis, EKG = electrocardiogram, GI = gastrointestinal, H/H = hemoglobin / hematocrit; HIT = heparin-induced thrombocytopenia, IM = intramuscular, INR = international normalized ratio, IV = intravenous, LDUH = low dose unfractionated heparin, LMWH = low molecular weight heparin, PE = pulmonary embolism, po = orally, prn = as needed, PT = prothrombin time, QOL = quality of life, SC = subcutaneous, SCr = serum creatinine, t1/2 = half-life, VKA = vitamin K antagonist, VTE = venous thromboembolism, V/Q = ventilation/perfusion, WBC = white blood count, x = times/for, yo = years old, 2/2 = secondary to **Definitions:** - Thrombosis -- formation of a fibrin clot (= clotting factors + platelets) -- not inherently "bad" - DVT -- clot forming in any venous bed -- usually the deep veins of the lower extremities at the valves -- can extend proximally, retrograde, and in girth - Embolism -- part of a clot that breaks off, travels, and is trapped somewhere else, preventing distal oxygen delivery - PE -- primary complication of DVT -- embolization of clot to [.] - "heparin" typically refers to "unfractionated heparin" (so LDUH is low dose unfractionated heparin, a particular dosing strategy using heparin) **Background:** - PE -- \~100k people die annually in the US, many within one hour; preceded by DVT in 80% of patients - For 25%, death is first symptom - Complications include: ↓QOL, post-thrombotic syndrome, chronic venous insufficiency - US Surgeon General -- PE is most common preventable cause of death in hospitalized patients - Medicare -- DVT and PE are " [ ] " after hip or knee replacements -- reimbursement penalty **Etiology:** - Platelets role -- exposure to subendothelial substances results in platelet adhesion -- adhered platelet releases substances that activate aggregation of other platelets -- forms a "platelet plug" - Clotting cascade -- exposure to subendothelial substances results in activation of both the intrinsic and extrinsic pathways (see figure in any therapeutics textbook) - Both pathways converge with activation of factor X→Xa, then II→IIa, then I→Ia (fibrin clot) - Factor II and IIa are known as prothrombin and thrombin - Factor I and Ia are known as fibrinogen and fibrin - Counterbalanced by clotting inhibitors: antithrombin, protein C, protein S, plasminogen, plasmin - Arterial thrombi -- primarily [.] - Venous thrombi -- primarily [.] **Risk factors:** include abnormalities in: (see Virchow's triad figure in any therapeutics textbook for a more complete list) - Classically can use Virchow's triad: - Blood flow ( [ ] ) -- e.g., immobilization, atrial fibrillation - Clotting components (hypercoagulable state) -- e.g., antiphospholipid syndrome, protein C/S deficiency, cancer - Surfaces that contact blood (endothelial injury) -- e.g., catheters, tumors - Assessed by various Risk Assessment Models (e.g., Padua \[≥4 = high risk\], IMPROVE-VTE \[≥2 = high risk\]) **Presentation:** - DVT - Symptoms -- unilateral leg swelling, warmth, tenderness, pain, Homans' sign, asymptomatic - Tests -- increased D-dimer (sensitive but nonspecific), Duplex/Doppler/Ultrasound ( [ ] ) - Can be treated as an outpatient - PE - Symptoms -- tachypnea, tachycardia, dyspnea, pleuritic chest pain, anxiety, cough, hemoptysis - Tests -- increased D-dimer, CXR, EKG, ABG (all nonspecific), V/Q scan (tells probability), CT angiography ( [ ] but requires injection of contrast) - Generally, [not] treated as an outpatient **[Prevention:]** - Every hospitalized patient should be [ ] for risk of VTE - Nonpharmacologic: graduated compression stockings, intermittent pneumatic compression devices, leg exercises, early post-operative ambulation - Mechanical prophylaxis [ ] effective in preventing VTE in general and surgical patients - Associated with less bleeding versus pharmacologic prophylaxis - Risk of skin breakdown, require maintenance, frequently not used correctly - Use in those whose bleeding risk is too high to receive pharmacologic prophylaxis - Pharmacologic - Generally proven efficacy - Increased bleeding risk - Agent selection depends on specific indication, renal function, comorbid conditions - **Guideline recommendations:** - Acutely ill medical patient: - pharmacologic suggested over no parenteral - pharmacologic suggested over mechanical prophylaxis - LMWH recommended over DOAC **Class review:** **LDUH:** - Dose is 5,000 units SC q8-12hr depending on the indication -- no definitive differences in bleeding or efficacy - Low dose costs \~\$1 per 5,000 unit/mL vial for the hospital - Available as many different [ ] -- be careful! **LMWH:** - More costly per dose - Enoxaparin has been studied the most **Fondaparinux:** - Dose is 2.5 mg SC q24hr via prefilled syringe - Avoid use if ClCr \ LMWH \> VKA or UFH - Drug choices depend largely on situation (inpatient required vs. outpatient, cost, ability to self-administer SC injections, renal function, comorbidities) and patient exclusion for different agents - Extended therapy -- can continue same agent or switch if factors warrant it - Duration -- depends on risk of recurrence (important factors include reversible risk factor identified, cancer) - Provoked by surgery or transient risk factor: 3 months only - Unprovoked: extended therapy -- based on bleeding risk (i.e., if high risk, 3 months only) - Recurrence: usually extended therapy - Active cancer: extended therapy - Consider aspirin in anyone that stops anticoagulation **Class review:** **Fondaparinux:** - Role - For initial and/or long-term therapy - Dose - Daily SC dose: 5 mg if \100 kg - Monitoring - General monitoring as for any anticoagulant -- periodic CBC, platelet, SCr, fecal occult blood (prn) - No use for checking coagulation panel -- (but shown to elevate anti-Xa if you do) - Contraindications - ClCr \< [ ] mL/min - Adverse effects - Hemorrhage - Not associated with HIT - [ ] -- when used during and after lumbar puncture, epidural or spinal anesthesia - Thrombocytopenia -- discontinue & do not use if platelets \100,000, asymptomatic - Management: platelet count should normalize [.] - Heparin-induced thrombocytopenia (HIT type II) - [ ] -mediated, 5-14 day onset (quicker if previously exposed) -- platelets decrease \> [ ] % - Platelets appear low because they are aggregated - Diagnosed with clinical suspicion plus laboratory confirmation of antibodies - Clinically manifests as thrombosis, high mortality - Higher rates with IV UFH versus SC UFH - Higher rates with UFH versus LMHW - Management: stop heparin and treat with argatroban, lepirudin, or bivalirudin - Add [ ] to profile -- avoid future exposure of all heparin products - Use the 4 T's to determine the probability of HIT (see ) **Intravenous DTI** (e.g., argatroban, lepirudin, bivalirudin) - Alternative anticoagulants used in HIT; bivalirudin also used for percutaneous coronary intervention - Continuous infusion dose titrated to target aPTT -- all increase INR so bridging to warfarin is difficult - Argatroban -- reduce dose if hepatic dysfunction - Lepirudin and bivalirudin -- reduce dose if renal dysfunction **Warfarin (Coumadin**®**, Jantoven**®)**:** - Role - Second drug when "bridging" from any parenteral agents above -- also for prevention as seen in chart - Why is "bridging" necessary when starting warfarin for VTE - [ ] to steady state for warfarin plus long time to steady state for clotting factors (varying t1/2) - Initial rise in INR 2/2 decrease in factor VII (shortest t1/2) but full anticoagulation requires reduction of other factors II and X also (longer t1/2) - Very short t1/2 of protein C and S (natural anticoagulants) means they decrease first, placing patient in [ ] state -- thrombus can extend - Can switch between warfarin and DOACs -- specific instruction in prescribing information of each - Dosing - Start on [ ] day of parenteral treatment, after diagnosis confirmed (if no intervention planned) - Parenteral anticoagulant should still be continued for ≥5 days [ ] until the INR is ≥2 - Loading dose an option but may lead to overanticoagulation and increased bleeding risk - Wide range of dosing - Increased sensitivity to warfarin in patients with age \>75 yo, heart failure, decreased po intake, diarrhea, drug interaction, renal disease, hepatic disease, hypoalbuminermia, malignancy, malnutrition - Dosing nomograms available to aid in achieving therapeutic INR in a timely manner while avoiding overanticoagulation (eg. ) - Must titrate to goal INR [ ] (therapeutic range 2-3) - Monitoring - Inpatient: daily - Outpatient: every few days after initiation and after adjustments and drug interactions, then as infrequent as every [ ] weeks when stable(rarely longer) - Adjust dose by calculating total weekly dose and increasing or decreasing by [ ] % - Unconventional dosing patterns - Adverse effects - Hemorrhage -- INR [ ] related to bleeding risk - Older patients are more sensitive to warfarin but not necessarily at higher risk of bleeding if managed appropriately - Skin necrosis -- rare -- occurs within days of initiation -- due to extensive thrombosis in microvasculature likely 2/2 rapid protein C & S depletion -- avoid by bridging with parenteral anticoagulants -- correct by discontinuing warfarin - Purple toe syndrome -- rare -- occurs 3-8 weeks after initiation -- due to cholesterol microembolization -- correct by discontinuing warfarin - Management of overanticoagulation - Holding warfarin alone will result in a decrease in INR but may take [ ] to return to normal - Can administer vitamin K -- large doses will cause prolonged resistance to warfarin - po: corrects INR in 1-2 days - IM: contraindicated - SC: unreliable absorption - IV: corrects INR within 24 hours -- potential for [ ] -- must dilute and administer slowly - For more: - Can administer fresh frozen plasma or factor concentrates but these have short t1/2 **INR** **Recommendation** --------------------------------------------- ------------------------------------------------------------- \