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Anticoagulation 5. Bridging therapy a. After mechanical valve placement, patients should receive bridge therapy with an injectable anticoagulant for at least 5 days and should have an INR within the therapeutic range. b. For patients with mechanical heart valves undergoing a minor procedure (e.g...

Anticoagulation 5. Bridging therapy a. After mechanical valve placement, patients should receive bridge therapy with an injectable anticoagulant for at least 5 days and should have an INR within the therapeutic range. b. For patients with mechanical heart valves undergoing a minor procedure (e.g., dental extraction or cataract removal) in which bleeding is easily controlled, warfarin should be continued with a therapeutic INR (class 1 recommendation). c. For patients with a bileaflet mechanical aortic valve and no other risk factors for TE undergoing an invasive procedure and a temporary interruption of warfarin, no bridging is needed while the INR is subtherapeutic (class 1 recommendation). d. For patients undergoing an invasive procedure with a mechanical aortic valve with risk factors for TE, an older-generation mechanical aortic valve, or a mechanical mitral valve, bridging anticoagulant therapy while the INR is subtherapeutic is reasonable, with the risk of bleeding weighed against the risk of thrombosis (class 2a recommendation). Patient Case Questions 5 and 6 pertain to the following case. S.D. is a 62-year-old female (height 165 cm, weight 80 kg) with a history of significant primary mitral regurgitation. Her echocardiogram reveals significant leaflet flaring that is not amendable to mitral valve repair. She also has a history of hypertension, dyslipidemia, and gout. Her medications include lisinopril 10 mg orally daily, hydrochlorothiazide 25 mg orally daily, simvastatin 40 mg orally daily, and allopurinol 300 mg orally daily. Her heart rate is 68 beats/minute and blood pressure is 128/74 mm Hg. Her CrCl is 68 mL/minute. She is scheduled to undergo valve replacement surgery and will receive a mechanical mitral valve. You are discussing the oral anticoagulant postoperative plan with S.D.’s team. 5. Which is the optimal regimen for preventing thrombosis? A. Adjusted-dose warfarin to an INR goal of 2.5–3.5 plus aspirin 81 mg orally daily. B. Adjusted-dose warfarin to an INR goal of 2.0–3.0 plus aspirin 81 mg orally daily. C. Adjusted-dose warfarin to an INR goal of 2.0–3.0. D. Adjusted-dose warfarin to an INR goal of 2.5–3.5. 6. Which best describes thrombotic risk in patients with valve replacement surgery? A. Bioprosthetic valves carry a higher risk of thrombosis than mechanical valves. B. The highest risk of thrombosis with bioprosthetic valve placement is during the first year after surgery. C. All patients with mechanical heart valves require bridging therapy during invasive procedures. D. Valve replacement in the mitral position carries a higher risk of thrombosis than in the aortic position. III. PREVENTION OF VENOUS THROMBOEMBOLISM A. Risk of Developing VTE 1. VTE consists of a deep vein thrombosis (DVT), a PE, or both. 2. Box 5 lists risk factors for developing VTE. Risk factors are cumulative. a. Not all risk factors carry equal risk; patients with certain risk factors such as orthopedic surgery, trauma, cancer, certain hypercoagulable states, and a previous VTE have the highest risk of developing VTE. b. Table 10 lists risks of VTE according to different patient groups. These event rates have typically been determined by venography in clinical trials and do not reflect the rates of symptomatic DVT or PE. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-149 Anticoagulation 3. 4. Risk stratification a. Low risk (DVT incidence less than 10% without thromboprophylaxis) i. Minor surgery in patients younger than 40 with no additional risk factors ii. Medically ill patients who are fully mobile b. Moderate risk (DVT incidence 10%–40% without thromboprophylaxis) i. In general, patients undergoing open gynecologic or urologic surgery ii. Medically ill patients, patients with need for bed rest c. High risk (DVT incidence 40%–80% without thromboprophylaxis) i. Major surgery in patients older than 40 plus a prior VTE ii. Cancer iii. Hypercoagulable state iv. Hip or knee arthroplasty, hip fracture surgery v. Major trauma vi. Spinal cord injury Regimens vary depending on patient risk and clinical trial results. a. Mechanical prophylaxis i. Includes graduated (elastic) compression stocking (limited efficacy) and intermittent pneumatic compression (IPC) ii. IPC must be on the patient for at least 18 hours/day to show efficacy. iii. Both types of mechanical prophylaxis are poorly tolerated by patients. iv. For patients at high risk of bleeding, such as immediately after surgery, with intent to substitute pharmacologic prophylaxis once hemostasis has occurred v. Also, may be used in patients at highest risk, such as those with spinal cord injury, in combination with pharmacologic prophylaxis b. Pharmacologic prophylaxis i. Low-molecular-weight heparin (LMWH) – Subcutaneous enoxaparin or dalteparin ii. Low-dose UFH (LDUH) – Subcutaneously twice daily or three times daily iii. Fondaparinux – Subcutaneously daily iv. Warfarin – adjusted-dose to target INR – in orthopedic surgery v. DOACs – Dabigatran, rivaroxaban, and apixaban – in orthopedic surgery; rivaroxaban – for extended prophylaxis in the medically ill vi. Aspirin – Questionable data, but listed as a possible agent in orthopedic surgery ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-150 Anticoagulation Box 5. Risk Factors for Developing VTE Age ≥ 40 Surgery (e.g., orthopedic, thoracic, abdominal, and genitourinary) Trauma (e.g., fracture of the spine, pelvis, femur, or tibia; spinal cord injuries) Hypercoagulable states (e.g., resistance to activated protein C [factor V Leiden], deficiencies in antithrombin, protein C or protein S, antiphospholipid antibodies Central venous catheterization Estrogen use or selective estrogen receptor modulators Erythropoiesis-stimulating agents Previous VTE Cancer and its treatment (e.g., pancreas, lung, ovary, testes, urinary tract, breast, stomach) Immobility or lower extremity paresis Certain medical disease states/conditions (e.g., stroke, or paralysis, acute infection, chronic obstructive pulmonary disease, inflammatory bowel disease, nephrotic syndrome, varicose veins, heart failure, acute MI, pregnancy) Smoking Obesity MI = myocardial infarction; VTE = venous thromboembolism. Table 10. Venous Thromboembolism Risk in Different Hospitalized Patient Groups Patient Group Medically ill patients Heart failure Chronic obstructive pulmonary disease Infection Critical care patients General surgery Major gynecologic surgery Major urologic surgery Neurosurgery Stroke Major orthopedic surgery Total hip replacement surgery Hip fracture surgery Total knee replacement surgery Major trauma Patients with spinal cord injury Deep Vein Thrombosis Prevalence Without Prophylaxis (%) 10–20 10–20 15–40 15–40 15–40 15–20 20–50 40–60 57 60 84 40–80 60–80 ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-151 Anticoagulation B. Orthopedic Surgery 1. Typically considered one of the highest-risk settings for developing VTE a. More than 50% of patients have a VTE event without prophylaxis. b. DVT rates are higher in knee surgery, and PE rates are higher in hip surgery. 2. Throughout the hospital stay, both mechanical prophylaxis with IPC and pharmacologic prophylaxis are recommended. 3. American College of Chest Physicians guidelines: Pharmacologic prophylaxis of VTE in orthopedic surgery (Table 11) a. Total knee arthroplasty: LMWH, fondaparinux, apixaban, rivaroxaban, dabigatran, adjusted-dose warfarin, LDUH, aspirin b. Total hip arthroplasty: LMWH, fondaparinux, apixaban, rivaroxaban, dabigatran, adjusted-dose warfarin, LDUH, aspirin c. Hip fracture surgery: LMWH, fondaparinux, adjusted-dose warfarin, aspirin 4. See Table 11 for prophylactic dosing regimens. 5. Duration of prophylactic treatment: At least 10–14 days of pharmacologic prophylaxis; however, extended prophylaxis of 35 days is suggested, especially in hip replacement or fracture surgery 6. Practical issues a. LDUH (5000 units every 8–12 hours) has consistently shown insufficient protection against VTE in patients undergoing orthopedic surgery and should therefore not be considered an acceptable alternative. b. Although aspirin has a recommendation from the American Society of Hematology (ASH), the American College of Chest Physicians, and the American Academy of Orthopaedic Surgeons guidelines, it is based on limited data with several limitations. c. Patients placed on mechanical prophylaxis after surgery because of a high risk of bleeding should have their risk of bleeding consistently reassessed, with pharmacologic prophylaxis initiated as soon as the bleeding risk is decreased. d. Patients undergoing knee arthroscopy typically do not need VTE prophylaxis beyond early mobilization unless they have additional VTE risk factors or have a complicated procedure. In those cases, patients should receive VTE prophylaxis with a DOAC or LMWH. e. Dalteparin (an LMWH) has shown rates of VTE similar to enoxaparin 40 mg once daily in hip replacement surgery. i. Heterogeneity in studies comparing dalteparin with enoxaparin in those undergoing knee replacement surgery exists. One trial showed that dalteparin was inferior to enoxaparin 30 mg twice daily for the primary composite outcome of VTE and death. ii. Dalteparin was inferior to enoxaparin 30 mg twice daily in patients undergoing knee replacement surgery. f. Rivaroxaban has shown a superior reduction in VTE events compared with enoxaparin 40 mg once daily in hip replacement surgery and enoxaparin 40 mg once daily and enoxaparin 30 mg twice daily in knee replacement surgery. Although major bleeding was not significantly increased in these studies, the definition of major bleeding did not include surgical site bleeding (considered nonmajor bleeding). g. Apixaban has shown a superior reduction in VTE events compared with enoxaparin 40 mg once daily in hip replacement surgery, with no significant increase in major bleeding. Apixaban did not meet the statistical criteria for noninferiority when compared with enoxaparin 30 mg twice daily in knee replacement surgery, though the event rates were similar (9.0% apixaban vs. 8.8% enoxaparin). Although there was no difference in major bleeding, the combination of major and clinically relevant nonmajor (CRNM) bleeding was significantly reduced with apixaban. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-152 Anticoagulation h. i. Timing of initiation of VTE prophylaxis after surgery is an important and complicated issue. The risk of thromboembolic events begins immediately after surgery; therefore, VTE prophylaxis is usually more effective when initiated earlier instead of later. The challenge is that early VTE prophylaxis is also associated with increased bleeding compared with VTE prophylaxis initiated later. VTE prophylaxis after elective spinal surgery can typically be initiated 12–24 hours after the operation. Prophylaxis may need to be delayed if the surgical site remains open. Table 11. VTE Prophylaxis in Orthopedic Surgery Orthopedic Indication Enoxaparin Dalteparin Fondaparinux Knee replacement surgery 30 mg SC q12hr initiated 12–24 hr after surgery 2500 units SC administered 6–8 hr after surgery; then 5000 units SC q24hra Hip replacement surgery 30 mg SC q12hr initiated 12–24 hr after surgery OR 40 mg SC q24hr initiated 12 (±3) hr before surgery 2500 units SC administered 4–8 hr after surgery; then 5000 units SC q24hr OR 5000 units SC q24hr initiated the evening before surgery Warfarin Dabigatran Rivaroxaban Apixaban 2.5 mg SC q24hr Initiated initiated 6–8 hr preoperatively after surgery or the evening of the surgical day with adjusted dosing to achieve a target INR of 2.5–0.5 110 mg PO initiated 1–4 hr after surgery; then 220 mg PO once dailya (off-label) 10 mg PO once daily initiated 6–10 hr after surgeryc 2.5 mg PO BID, initiated 12–24 hr after surgery 2.5 mg SC q24hr Initiated initiated 6–8 hr preoperatively after surgery or the evening of the surgical day with adjusted dosing to achieve a target INR of 2.5–0.5 110 mg PO initiated 1–4 hr after surgery; then 220 mg PO once dailyb 10 mg PO once daily initiated 6–10 hr after surgeryc 2.5 mg PO BID, initiated 12–24 hr after surgery Insufficient evidence Insufficient evidence Hip fracture surgery 30 mg SC Insufficient q12hr initiated evidence 12–24 hr after surgerya; 40 mg SC q24hr initiated 12 (±3) hr before surgery Spinal surgery Mechanical prophylaxis using IPC is preferred to pharmacologic prophylaxis unless the patient is considered at high risk of VTE. If the patient has additional risk factors, including advanced age, malignancy, neurologic deficit, prolonged immobility, previous VTE, or an anterior-posterior surgical approach, LMWH or LDUH is suggested 2.5 mg SC q24hr Initiated Insufficient initiated 6–8 hr preoperatively evidence after surgery or the evening of the surgical day with adjusted dosing to achieve a target INR of 2.5–0.5 Not FDA approved. CrCl > 30 mL/min. c CrCl ≥ 15 mL/min. BID = twice daily; IPC = intermittent pneumatic compression; LDUH = low-dose unfractionated heparin; LMWH = low-molecular-weight heparin; PO = oral(ly); q = every; SC = subcutaneous(ly); VTE = venous thromboembolism. a b C. Non-orthopedic Surgery 1. Consists of a heterogeneous group of patients and surgical procedures with varying risk. Risk assessment models such as Caprini may be used to assess VTE risk and, subsequently, indication for pharmacologic prophylaxis in patients undergoing general non-orthopedic or abdominal-pelvic surgery. Table 12 shows a detailed Caprini risk assessment model. Table 13 describes association of VTE risk with recommendations for pharmacologic and/or mechanical prophylaxis according to the 2012 American College of Chest Physicians guidelines. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-153 Anticoagulation 2. 3. 4.  harmacologic prophylaxis, when indicated, may include LMWH or LDUH. Table 14 lists prophylactic P dosing regimens. Risk factors for major bleeding for patients undergoing general non-orthopedic surgery include active bleed; history of major bleed; known and untreated bleeding disorder; severe renal or hepatic failure; thrombocytopenia; acute stroke; uncontrolled hypertension; concomitant use of anticoagulants, antiplatelets, or thrombolytic drugs; and lumbar puncture, epidural, or spinal anesthesia within the previous 4 hours or next 12 hours. The 2012 American College of Chest Physicians guidelines further elaborate on indications for pharmacologic prophylaxis for patients undergoing cardiac, thoracic, craniotomy, spinal, and surgical procedures related to major traumas. If indicated, LMWH or LDUH will be favored for pharmacologic prophylaxis. See Table 14 for details on prophylactic dosing regimens. Table 12. Caprini Risk Assessment for VTE in General Non-orthopedic or Abdominal Pelvic Surgery Caprini Points 1 2 3 5 Associated Risk Factors Age 41–60 BMI > 25 kg/m2 Minor surgery or history of major surgery (< 1 month) Certain medications (OCPs, HRT) Pregnancy or postpartum Swollen or varicose veins in the legs History of unexplained or recurrent spontaneous abortion Sepsis (< 1 mo ago) History of IBD Acute MI Congestive heart failure (< 1 mo ago) Serious lung disease or abnormal pulmonary function (e.g., pneumonia < 1 mo ago) Medical patient on bed rest Age 61–74 Arthroscopic surgery Major open surgery (> 45 min in duration) Laparoscopic surgery (> 45 min in duration) Malignancy Immobility (bed confinement > 72 hr) Immobilizing plaster cast Central venous access Age ≥ 75 Personal or family history of VTE Inherited/acquired hypercoagulable conditions (e.g., factor V Leiden, lupus anticoagulant, prothrombin G20210A, presence of anticardiolipin antibodies) Elevated serum homocysteine HIT Other congenital or acquired thrombophilia Stroke (< 1 mo ago) Elective arthroplasty Hip, pelvis, or leg fracture Acute spinal cord injury or recent multiple traumas (< 1 month ago) HIT = heparin-induced thrombocytopenia; HRT = hormone replacement therapy; IBD = inflammatory bowel disease; MI = myocardial infarction; OCP = oral contraceptive pill. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-154 Anticoagulation Table 13. VTE Prophylaxis for Patients Undergoing General Non-orthopedic or Abdominal-Pelvic Surgery VTE Risk Very low Low Moderate VTE Risk (%) < 0.5 1.5 3 Caprini Score 0 1 or 2 3 or 4 High 6 ≥5 High (cancer surgery) — N/A Average Bleeding Risk High Bleeding Risk (~1%) (~2%) Early ambulation Mechanical prophylaxis (IPC preferred) LMWH, LDUH, or IPC Mechanical prophylaxis (IPC preferred) LMWH, LDUH IPC AND Add LMWH or IPC LDUH once bleeding risk diminishes LMWH or LDUH IPC AND Add LMWH or IPC LDUH once (extended-duration prophylaxis bleeding risk diminishes with LMWH upon discharge) High risk (LMWH or LDUH contraindicated) — N/A Low-dose aspirin (160 mg) or fondaparinux AND IPC IPC Add low-dose aspirin (160 mg) or fondaparinux once bleeding risk diminishes IPC = intermittent pneumatic compression; LDUH = low-dose unfractionated heparin; LMWH = low-molecular-weight heparin; N/A = not applicable; VTE = venous thromboembolism. 5. Practical issues a. General surgery i. Meta-analysis comparisons between LDUH and LMWHs show similar efficacy in preventing DVT but a greater reduction in the incidence of PE when an LMWH is used. ii. Mechanical prophylaxis is sometimes inappropriately selected over pharmacologic prophylaxis because of concerns for bleeding in surgical patients. A meta-analysis of almost 34,000 surgical patients showed that the most common bleeding complications were injection-site bruising (6.9%) and wound hematomas (5.7%). Major bleeding complications occurred in less than 1% of patients. b. Neurosurgery i. Pharmacologic prophylaxis is typically administered with mechanical prophylaxis, and the combination is as safe as, and more effective than, mechanical prophylaxis alone. ii. Pharmacologic prophylaxis is typically initiated 18–24 hours after neurosurgery. c. Vascular surgery i. Routine prophylaxis is recommended for patients with additional risk factors such as advanced age, limb ischemia, long duration of surgery, and intraoperative local trauma. ii. Because of the few trials of patients undergoing vascular surgery, dosing recommendations are based on evidence for pharmacologic agents in general surgery. d. Gynecologic surgery i. Low-risk gynecologic surgical procedures (laparoscopic procedures or procedures lasting less than 30 minutes) do not require prophylaxis beyond early ambulation. ii. Those undergoing major surgery without malignancy should receive LDUH or LMWH. e. Gynecologic cancer surgery ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-155 Anticoagulation i. f. g. h. i.  DUH administered three times daily is more effective than twice daily. LDUH dosed three L times daily and LMWH have similar efficacy and safety. ii. In a subgroup analysis of a general surgery trial, fondaparinux was more effective than dalteparin in patients undergoing surgery for cancer. Urologic surgery i. Patients undergoing a transurethral or laparoscopic urologic procedure do not require prophylaxis beyond early ambulation. ii. Because of the few trials of patients undergoing urologic surgery, dosing recommendations are based on the evidence for pharmacologic agents in general surgery. Bariatric surgery: Higher doses of LMWH and LDUH are recommended. LDUH 7500 units three times daily for individuals with a BMI greater than 50 kg/m 2 and enoxaparin 40 mg twice daily for individuals with a BMI of 40 kg/m 2 or greater have been evaluated. Dalteparin 7500 units daily has been evaluated in a retrospective study using anti-Xa concentrations in a patient population with a mean BMI greater than 50 kg/m2. Thoracic surgery: Because of the few trials of patients undergoing thoracic surgery, dosing recommendations are based on the evidence for pharmacologic agents in general surgery. Coronary bypass surgery i. Because of the few trials of patients undergoing coronary artery bypass surgery, dosing recommendations are based on the evidence for pharmacologic agents in general surgery. ii. Because of concerns for the higher incidence of heparin-induced thrombocytopenia in patients undergoing cardiac surgery, LMWH may be preferred to LDUH for prophylaxis. Table 14. VTE Prophylaxis in Non-orthopedic Surgery Surgical Indication Unfractionated Heparin Enoxaparin Dalteparin Fondaparinux General surgery 5000 units SC q8hr or 5000 units SC q12hr 40 mg SC q24hr 5000 units SC q24hr 2.5 mg SC q24hr Neurosurgery 5000 units SC q8hr 40 mg SC q24hr Insufficient evidence Insufficient evidence Vascular surgery 5000 units SC q8hr or 5000 units SC q12hr 40 mg SC q24hr 5000 units SC q24hr 2.5 mg SC q24hr Gynecologic 5000 units SC q8hr or 5000 units SC q12hr 40 mg SC q24hr 5000 units SC q24hr 2.5 mg SC q24hr Urologic 5000 units SC q8hr or 5000 units SC q12hr 40 mg SC q24hr 5000 units SC q24hr 2.5 mg SC q24hr Laparoscopic Patients undergoing laparoscopic procedures with no additional VTE risk factors do not require prophylaxis beyond early ambulation Bariatric 5000 units SC q8hr 40 mg SC q12hr 7500 units SC q24hr 5 mg SC q24hr Thoracic 5000 units SC q8hr or 5000 units SC q12hr 40 mg SC q24hr 5000 units SC q24hr 2.5 mg SC q24hr Coronary bypass 5000 units SC q8hr or 5000 units SC q12hr 40 mg SC q24hr 5000 units SC q24hr Not discussed in current guidelines q = every; SC = subcutaneous(ly); VTE = venous thromboembolism. D. Hospitalized (Nonsurgical) Medical Patients ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-156 Anticoagulation 1. 2. 3. 4.  heterogeneous group of hospitalized nonsurgical patients A Risk of VTE is typically lower than in surgical patients, but medically ill patients make up around 60% of all VTE cases because of the higher number of medically ill patients. Risk assessment models such as the Padua Prediction Score may be used to assess the VTE risk and, subsequently, the indication for pharmacologic prophylaxis in hospitalized nonsurgical medical patients. Table 15 shows a detailed Padua Prediction Score risk assessment model. Table 16 describes pharmacologic and/or mechanical prophylactic recommendations according to the 2012 American College of Chest Physicians guidelines. The ASH guidelines recommend LMWH or fondaparinux over LDUH or DOAC (e.g., low-dose rivaroxaban). Table 17 describes VTE prophylactic dosing for hospitalized (nonsurgical) patients. Guidelines recommend against pharmacologic prophylaxis beyond the period of patient immobilization or acute hospital stay. Table 15. VTE Risk Assessment with Padua Prediction Score in Hospitalized Medical Patients Risk Factors Active cancera Previous VTEb Reduced mobilityc Known thrombophilic conditiond Recent (< 1 mo) trauma and/or surgery Older age (≥ 70) Cardiac and/or respiratory failure Acute MI or ischemic stroke Acute infection and/or rheumatologic disorder Obesity (BMI ≥ 30 kg/m2) Active hormonal treatment Score 3 3 3 3 2 1 1 1 1 1 1 Local or distant metastases and/or recipient of chemotherapy or radiotherapy within the past 6 mo. Excludes individuals with a history of superficial vein thrombosis. c Anticipated bed rest for at least 3 days. d Defects of antithrombin, protein C or protein S, factor V Leiden, G20210A prothrombin mutation, antiphospholipid syndrome. MI = myocardial infarction; VTE = venous thromboembolism. a b Table 16. VTE Prophylaxis for Hospitalized (Nonsurgical) Medical Patients Padua Prediction Score <4 ≥4 VTE Risk Bleeding Risk Recommendation Low High — Low No prophylaxis LDUH, LMWH, or fondaparinux Alternative: Low-dose rivaroxaban Mechanical prophylaxis (GCS or IPC) Higha Risk outweighs benefit in medically ill patients with an active bleed or at high risk of bleeding. The strongest risk factors are those with an odds ratio > 3 for bleeding and include active gastroduodenal ulcer, history of bleeding within 90 days, and Plt < 50,000/mm3. GCS = gradual compression stocking; IPC = intermittent pneumatic compression; LDUH = low-dose unfractionated heparin; LMWH = low-molecular-weight heparin; VTE = venous thromboembolism. a ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-157 Anticoagulation 5. Practical issues a. In head-to-head trials of LDUH 5000 units subcutaneously every 8 hours and enoxaparin 40 mg subcutaneously daily, the regimens had similar efficacy, except for in medically ill patients (heart failure and ischemic stroke) at higher risk, in which enoxaparin may confer greater protection against VTE. In the same trials, enoxaparin had significantly less hematoma (greater than 5 cm) than LDUH. Although some data suggest a lower bleeding rate with LMWH in medically ill patients, these findings are not consistent across trials. b. Many clinical trials have not shown efficacy with LDUH 5000 units every 12 hours; therefore, LDUH 5000 units every 8 hours may be the preferred LDUH regimen. c. Enoxaparin 30 mg subcutaneously every 24 hours is recommended for patients with renal insufficiency (CrCl less than 30 mL/minute). d. Enoxaparin 20 mg once daily is equal in efficacy to unfractionated heparin (UFH) 5000 units every 12 hours but was found to be no more effective than placebo. Table 17. Venous Thromboembolism Prophylaxis in Hospitalized (Nonsurgical) Patients Low-Dose Unfractionated Heparin 5000 units SC q8hr or 5000 units SC q12hr Enoxaparin Dalteparin Fondaparinuxa Rivaroxaban 40 mg SC daily 5000 units SC daily 2.5 mg SC daily 10 mg orally daily Not FDA approved. q = every; SC = subcutaneous(ly). a 6. Extended prophylaxis a. Risk of VTE extends beyond discharge, with almost two-thirds of all events occurring within 30 days after hospitalization. b. Extended prophylaxis (35–42 days) with enoxaparin has shown a significant reduction in developing VTE, but with significantly more major bleeding than enoxaparin for 10 days. c. Rivaroxaban is the only available DOAC with FDA approval for use in VTE prophylaxis. Rivaroxaban is approved for extended VTE prophylaxis (35 ± 4 days) in medically ill patients with moderate to severe restricted morbidity and at least one of the following additional risk factors: 75 or older, prolonged immobilization, history of cancer, history of VTE, history of heart failure, thrombophilia, acute infectious disease contributing to hospitalization, or BMI greater than 35 kg/m 2. i. The MAGELLAN trial (n=8101) showed a significant reduction in VTE events with rivaroxaban 10 mg orally daily compared with enoxaparin 40 mg subcutaneously daily, but patients had significantly more major bleeding at day 35 (RR 0.65; 95% CI, 0.49–0.87; p=0.004). ii. A subpopulation analysis of MAGELLAN was conducted to reevaluate the risk-benefit profile. Five risk factors for major and fatal bleeding were identified and removed: treatment of active cancer during admission, use of dual antiplatelet therapy, history of bronchiectasis/pulmonary cavitation/pulmonary hemorrhage, active gastroduodenal ulcer in the previous 3 months, and active GI bleeding or any bleeding in the previous 3 months. These patients made up about 20% of the initial study population in the original MAGELLAN trial. iii. In the subpopulation (n=6447), VTE events were significantly reduced with rivaroxaban compared with enoxaparin/placebo (RR 0.68; 95% CI, 0.53–0.88), and major bleeding was not significantly increased (RR 1.48; 95% CI, 0.77–2.84). iv. Elimination of these five groups was prospectively studied in the MARINER trial, in which major bleeding was similar to placebo for extended VTE prophylaxis (HR 1.88; 95% CI, 0.84–4.23). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-158 Anticoagulation d. For those with moderate to severe immobility and other risk factors for VTE and not at high risk of bleeding, use of rivaroxaban for VTE prophylaxis will warrant extended duration of use for 35 days (±4), which includes during hospital stay and after discharge. E. Critically Ill Patients 1. Patients at very high risk of developing VTE 2. Typically includes patients in general critical care environments, including patients with trauma, acute spinal cord injury, and burns 3. Critically ill patients should be offered VTE prophylaxis with LMWH or LDUH unless there is evidence of bleeding or patients are at high risk of bleeding (Table 18). 4. Recommend mechanical prophylaxis for patients with active bleeding or at high risk. Substitute LMWH or LDUH when bleeding risk decreases. 5. The ASH guidelines recommend use of LMWH over LDUH. 6. Practical issues a. Trauma i. A meta-analysis showed LDUH to be no more effective than control. ii. Enoxaparin 30 mg twice daily has better efficacy than UFH 5000 units twice daily. iii. Observational analysis of 18,010 trauma patients showed a significant reduction in VTE events and death in patients receiving enoxaparin 30 mg twice daily compared with LDUH 5000 units three times daily. iv. Evidence for dalteparin is based on observational data. v. Pharmacologic prophylaxis can safely be initiated within 24–36 hours. Pharmacologic prophylaxis for patients with acute spinal cord injury may need to be delayed for 48–72 hours. vi. Patients with severe trauma (injury severity score greater than 23) may present with antithrombin deficiency; therefore, subcutaneous prophylaxis may be insufficient. Although not prospectively evaluated, an option may be to use an UFH infusion while the patient is in the ICU early in therapy. Only a slight increase in the activated PTT (aPTT) (35–45 seconds) would be targeted because VTE prevention is the goal. b. Acute spinal cord injury i. Use of LDUH three times daily had DVT and bleeding rates similar to enoxaparin twice daily, but PE was significantly reduced with enoxaparin. ii. Although enoxaparin 30 mg twice daily should be used during the acute injury period (about 2–3 weeks), either regimen can be used during the rehabilitation period. iii. In a retrospective case-control study, dalteparin 5000 units daily failed to show noninferiority to enoxaparin 30 mg twice daily in preventing VTE (9.7% vs. 1.6%). Further investigations of dalteparin are warranted. c. Burns – Current evidence in patients with burns is from only observational studies with LDUH, enoxaparin, and dalteparin. The most commonly used regimen is LDUH 5000 units subcutaneously every 12 hours. d. Critical care i. In medically ill or postoperative general surgery patients, LDUH or LMWH can be used. In orthopedic surgery or trauma, LMWH is preferred. ii. If mechanical prophylaxis is selected because of a patient’s high risk of bleeding, the patient should be reevaluated often and changed to pharmacologic prophylaxis when the bleeding risk decreases. iii. Some pharmacodynamic studies suggest that critical care patients with significant edema or critical care patients receiving vasopressors will not achieve detectable anti-Xa concentrations with LMWH. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-159 Anticoagulation iv. I n the largest trial of VTE prevention in critical care patients, dalteparin 5000 units subcutaneously once daily provided similar protection against proximal DVT and better protection against PE, similar bleeding, and less heparin-induced thrombocytopenia than UFH 5000 units twice daily. v. Dalteparin does not have significant accumulation in critical care patients with renal insufficiency. vi. A retrievable inferior vena cava filter may be considered for PE prophylaxis, but this practice has limited evidence and is controversial. Table 18. Venous Thromboembolism Prophylaxis in Critically Ill Patients Critical Care Setting Trauma Acute spinal cord injury Burns Critical care Low-Dose Low-Molecular-Weight Heparin Unfractionated Heparin Insufficient evidence Dalteparin 5000 units SC q24hr or enoxaparin 30 mg SC q12hr 5000 units SC q8hr Enoxaparin 30 mg SC q12hr or Enoxaparin 40 mg SC q24hr 5000 units SC q8hr or Dalteparin 5000 units SC q24hr or 5000 units SC q12hr Enoxaparin 40 mg SC q24hr 5000 units SC q8hr or Dalteparin 5000 units SC q24hr or enoxaparin 30 mg SC q12hr or 5000 units SC q12hr enoxaparin 40 mg SC q24hr Fondaparinux Insufficient evidence Insufficient evidence Insufficient evidence Insufficient evidence 2.5 mg SC daily may be an option in suspected HIT HIT = heparin-induced thrombocytopenia; q = every; SC = subcutaneous(ly). F. Duration of VTE Prophylaxis: Varies depending on patient risk and group (Table 19) Table 19. Duration of VTE Prophylaxis Indication General medically ill patients Major general surgery Major general surgery in patients with previous VTE Surgery for GI, GU, or gynecologic cancer Major orthopedic surgery (e.g., THA, TKA, HFS) Critical care patients Major trauma Patients with spinal cord injury Duration • Length of hospital stay or as long as immobile during acute illness • Rivaroxaban 31–39 days (inpatient and outpatient) • Length of hospital stay • Beyond hospital discharge for up to 28 days • Beyond hospital discharge for up to 28 days • At least 10–14 days; extending to outpatient period for a total of up to 35 days suggested • For the duration of the ICU stay with reevaluation when the patient is transferred to the general medical ward • Until hospital discharge and continued prophylaxis in patients with impaired mobility who undergo inpatient rehabilitation (up to 8 wk) • Until hospital discharge in patients with incomplete injuries • For 8 wk in patients with uncomplicated complete motor injury • For 12 wk or until discharge from rehabilitation in patients with complete motor injury and other risk factors GU = genitourinary; HFS = hip fracture surgery; THA = total hip arthroplasty; TKA = total knee arthroplasty; VTE = venous thromboembolism. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-160