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Anticoagulation Patient Case 7. B.G. is a 62-year-old male (height 175 cm, weight 110 kg) hospitalized for a heart failure exacerbation. He has symptoms when doing only limited exertion and has been out of bed only to use the bathroom for the past 3 days. His medical history also includes stable i...

Anticoagulation Patient Case 7. B.G. is a 62-year-old male (height 175 cm, weight 110 kg) hospitalized for a heart failure exacerbation. He has symptoms when doing only limited exertion and has been out of bed only to use the bathroom for the past 3 days. His medical history also includes stable ischemic heart disease, hypertension, type 2 diabetes, and a PE 2 years ago. He smokes 2 packs/day and drinks 1 glass of wine with dinner most evenings. His medications include bisoprolol 5 mg orally daily, lisinopril 10 mg orally daily, aspirin 81 mg orally daily, ranolazine 1000 mg orally twice daily, furosemide 40 mg orally daily, spironolactone 25 mg orally daily, and metformin 1000 mg orally twice daily. His blood pressure today is 110/70 mm Hg and heart rate is 58 beats/minute. His laboratory values are normal except for a BNP of 1498 ng/mL. Which is the most appropriate VTE prevention strategy for B.G.? A. Administer fondaparinux 5 mg subcutaneously daily. B. Administer apixaban 2.5 mg orally twice daily. C. Administer enoxaparin 40 mg subcutaneously daily. D. His risk does not warrant prophylactic therapy. G. Special Populations – Box 6 provides information on use of VTE prophylaxis in special populations. Box 6. Use of Venous Thromboembolism Prophylaxis in Special Populations Severe Renal Insufficiency • Patients with renal insufficiency are at higher risk of bleeding, regardless of the anticoagulant used • Patients with SCr > 2.5 mg/dL have been excluded from most clinical trials • Enoxaparin should be dosed at 30 mg subcutaneously once daily, regardless of the indication for CrCl < 30 mL/min • Dalteparin does not seem to significantly accumulate in patients with severe renal insufficiency until the CrCl is < 20 mL/min when prophylactic doses are used • Fondaparinux, rivaroxaban, and dabigatran are contraindicated in patients with a CrCl < 30 mL/min and apixaban in patients with a CrCl < 25 mL/min • Patients receiving hemodialysis (renal failure) should receive subcutaneous LDUH Obesity • American College of Chest Physicians guidelines recommend possible weight-adjusted dosing in patients with obesity but provide no insight regarding at what weight this should be considered or what the “adjusted” dosing should be. Patients with obesity are at considerable risk of PE, but data from clinical trials on drug dosing are limited • Studies suggest that the typical LMWH prophylactic dose results in less anticoagulant effect, but clinical outcomes data are lacking • Enoxaparin 40 mg subcutaneously twice daily has been more efficacious than 30 mg subcutaneously twice daily in patients undergoing bariatric surgery • It is reasonable to use enoxaparin 40 mg subcutaneously twice daily, enoxaparin 0.5 mg/kg subcutaneously twice daily, or LDUH 7500 units three times daily in patients with a BMI > 40 kg/m 2 or weight > 120 kg • Injections of enoxaparin into the thigh in patients with obesity have a lower bioavailability than injections into the abdomen ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-161 Anticoagulation Box 6. Use of Venous Thromboembolism Prophylaxis in Special Populations (Cont’d) Pregnancy • Warfarin has been associated with congenital abnormalities when used during the first trimester and is therefore contraindicated. Although warfarin could be used during the second trimester, it is typically avoided throughout pregnancy • A n LMWH or LDUH can be used throughout pregnancy • DOACs currently have no role in pregnancy CrCl = creatinine clearance; DOAC = direct oral anticoagulant; LDUH = low-dose unfractionated heparin; LMWH = low-molecular-weight heparin; PE = pulmonary embolism. IV. TREATMENT OF VENOUS THROMBOEMBOLISM A. Introduction 1. A round 2 million symptomatic and asymptomatic cases of VTE occur in the United States each year, with 25% having sudden death as the initial PE symptom. a. Around 600,000 cases of PE each year b. More than 60,000–100,000 deaths from DVT/PE each year in the United States 2. Consequences of VTE a. 33% will develop a recurrent VTE event within 10 years. b. 30%–50% of patients develop postthrombotic syndrome (swelling, pain, discoloration, and scaling). c. After a DVT event, 20% of patients die within the following year. d. After a PE event, 40% of patients die within the following year. B. Pathophysiology 1. Venous thrombosis forms from the components of the Virchow triad: venous stasis, vascular injury, and/or an inherited or acquired hypercoagulable state. 2. Components of the Virchow triad are broken down into a list of risk factors (see Box 5). Risk factors are cumulative, and some carry a higher risk than others (e.g., previous VTE, cancer, orthopedic surgery). 3. Thrombus typically begins in the cusps of venous valves, where blood is more static. Vascular injury because of trauma or hypoxia initiates the clotting cascade with interaction between endothelial tissue factor and factor VII. 4. A n embolism from a DVT will lodge itself in the next available capillary bed, which is in the pulmonary vasculature, leading to PE. 5. Despite therapy, areas of vascular damage may never fully recover, which leads to a continued risk of recurrent DVT events. 6. Thrombosis often forms in and around venous valves, causing them to curl. Despite therapy, these valves may not recover their initial shape and function, which leads to continued venous stasis and continued risk of recurrent DVT and postthrombotic syndrome. 7. Most upper extremity DVTs are related to the use of central venous catheters. C. Clinical Presentation and Assessment 1. Deep Vein Thrombosis a. Although many cases are asymptomatic, these acute asymptomatic DVTs can still have long-term complications. b. Most thrombi begin in the lower extremities. c. Superficial vein thrombosis typically does not embolize unless it extends into a deep vein, is at least 5 cm long, or is within 10 cm of the saphenofemoral junction. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-162 Anticoagulation d. e. Proximal DVTs are more likely to embolize than isolated calf DVTs. Signs and symptoms are nonspecific (Box 7) and need to be confirmed with the appropriate diagnostic test. i. The Wells model can be used to determine the patient’s pretest probability having a DVT and guide further diagnostic testing (Table 20). ii. Patients with low (3%) or moderate (17%) pretest probability using the Wells model should continue to assessment with D-dimer. If D-dimer is elevated (greater than 500 ng/mL for most assays), the patient should continue to diagnostic imaging. iii. Patients with a high pretest probability (75%) should continue to duplex ultrasonography or other imaging studies to confirm diagnosis. iv. D-dimer is a breakdown product of fibrin and fibrinogen and is typically elevated in the setting of VTE. Although D-dimer is sensitive for clot formation, it is nonspecific and can also be elevated from conditions such as inflammation and infection. Therefore, a positive test does not tell the clinician whether it is VTE or something else. A negative test helps rule out thrombosis. v. Venography is the gold standard diagnostic tool, but it is invasive (injecting dye into a vein in the heel/ankle), may be painful, and is rarely used in clinical practice. vi. Duplex ultrasonography is most commonly used in clinical practice for diagnosing DVT. It is noninvasive and inexpensive and has higher specificity and sensitivity than older versions of Doppler ultrasonography. Box 7. Clinical Presentation of Deep Vein Thrombosis and Pulmonary Embolism Deep Vein Thrombosis (+) Homan sign (pain in back of knee with dorsiflexion of the foot) Leg pain Calf tenderness Swelling Skin discoloration (redness) Leg warmth Pulmonary Embolism Tachycardia Tachypnea Palpitation Dyspnea Cough/hemoptysis Chest pain ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-163 Anticoagulation Table 20. Wells Clinical Model for Evaluating the Pretest Probability of DVTa Clinical Characteristics Active cancer (cancer treatment within previous 6 mo or currently receiving palliative treatment) Paralysis, paresis, or recent plaster immobilization of the lower extremities Recently bed confinement for ≥ 3 days or major surgery within the previous 12 wk requiring general or regional anesthesia Localized tenderness along the distribution of the deep venous system Entire leg swollen Calf swelling at least 3 cm larger than that on the asymptomatic side (measured 10 cm below tibial tuberosity) Pitting edema confined to the symptomatic leg Collateral superficial veins (non-varicose) Previously documented DVT Alternative diagnosis at least as likely as DVT Score 1 1 1 1 1 1 1 1 1 -2 Clinical probability of DVT: low = 0; moderate = 1 or 2; high ≥ 3. In patients with symptoms in both legs, the more symptomatic leg is used. DVT = deep vein thrombosis. a 2. Pulmonary embolism a. PE is classified as massive (hemodynamic instability including systolic blood pressure less than 90 mm Hg and cardiogenic shock), submassive (normal systolic blood pressure, right ventricular dysfunction, and positive biomarkers [e.g., elevated troponin]), and nonmassive (hemodynamic stability). Similar to DVT cases, many PE cases are asymptomatic. More than 90% of thrombi begin in the lower extremities and embolize. b. Signs and symptoms are nonspecific (see Box 7) and require confirmation with the appropriate diagnostic test. i. The Wells model can be used to determine the pretest probability of a patient’s having a PE (Table 21). ii. Patients who have a low (3%–10%) or moderate (15%–35%) pretest probability using the Wells model should continue to assessment with D-dimer. If D-dimer is elevated, the patient should continue to diagnostic imaging. iii. Other patients should continue to CT or other imaging studies to confirm the diagnosis. iv. D-dimer is similar to use with DVT. Serum concentrations are typically elevated in patients with PE. v. CT pulmonary angiography (CTPA) with radiographic contrast is the most common (and preferred) test used to diagnose PE. Positive results have good specificity and generally confirm the diagnosis. Both the sensitivity and the specificity of the test are improved with central emboli over those that are more peripheral. vi. Ventilation/perfusion (V/Q) scan may be used if CTPA is unavailable or if the patient has renal insufficiency and/or hypersensitivity to contrast dye. V/Q scan measures the distribution of blood flow and airflow in the lungs. A “mismatch” between blood flow and airflow in one area confers a high probability of PE. Specificity can be impaired in patients with heart failure, chronic obstructive pulmonary disease, or asthma. A scan with a negative finding has good specificity and generally rules out the diagnosis of PE. Findings reported as low or intermediate probability require additional diagnostic testing. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-164 Anticoagulation Table 21. Wells Criteria Clinical Model for Evaluating the Pretest Probability of PEa Clinical Characteristic Cancer Hemoptysis Previous PE or DVT Heart rate > 100 beats/min Recent surgery or immobilization Clinical signs of DVT Alternative diagnosis less likely than PE Score 1 1 1.5 1.5 1.5 3 3 Clinical probability of PE: low 0–1; moderate 2–6; high ≥ 7. DVT = deep vein thrombosis; PE = pulmonary embolism. a D. Acute Treatment of VTE 1. Three approaches to VTE treatment (Table 22) 2. The 2021 American College of Chest Physicians guidelines prefer DOACs to warfarin for patients with VTE without cancer because of reduced bleeding risk and greater convenience for patients and health care providers. 3. The 2020 ASH guidelines also prefer DOACs to warfarin for the treatment of VTE. Table 22. Approaches to VTE Treatment Treatment Strategy Bridging therapy Switching therapy Monotherapy Anticoagulant Choices Injectable anticoagulant (UFH, LMWH, or fondaparinux) initiated with warfarin and overlapped for at least 5 days and until the INR is ≥ 2.0. Then discontinue injectable anticoagulant and continue warfarin dose-adjusted to INR target of 2.5 (±0.5) for indicated duration Injectable anticoagulant (UFH, LMWH, or fondaparinux) for first 5 days; then discontinue injectable anticoagulant therapy and initiate dabigatran or edoxaban for the indicated duration Initiate rivaroxaban or apixaban at higher initial dose and then convert patient to lower maintenance dose for the indicated duration LMWH = low-molecular-weight heparin; UFH = unfractionated heparin. 4. Bridging therapy approach to VTE treatment a. Because of the delay in achieving systemic anticoagulation with warfarin therapy and the significant thrombus burden in patients with VTE, an injectable anticoagulant is initiated on the suggestion of a VTE and bridged to warfarin if the diagnosis is confirmed. b. Table 23 shows dosing of injectable anticoagulants for VTE treatment. Achieving therapeutic anticoagulation within the first 24 hours has been associated with reduced rates of recurrent VTE events. c. If using the bridging therapy approach, the American College of Chest Physicians guidelines recommend initial injectable anticoagulant therapy with an LMWH or fondaparinux over intravenous or subcutaneous UFH. Weight-adjusted dosing should be based on actual body weight. d. Warfarin dosing in the stable outpatient setting is similar to that discussed in the AF section, including a target INR of 2.5 (goal 2.0–3.0). In acute situations, dosing may depend on cofactors that drive initial dosing approaches. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-165 Anticoagulation e. Bridging to warfarin would likely be the preferred approach in the following: i. W hen patients have renal dysfunction because patients in the DOAC trials were excluded if their CrCl was less than 30 mL/minute (less than 25 mL/minute for apixaban) ii. W hen patients cannot afford DOAC therapy iii. When the transition to outpatient therapy makes acquiring a DOAC difficult. Pharmacists play a crucial role in helping to confirm insurance coverage and other transition issues in these patients. Table 23. Dosing of Injectable Anticoagulants for VTE Treatment Agent and Route Dosing Unfractionated Heparin IV UFHa Weight adjusted with an initial bolus of 80 units/kg (max initial bolus of 10,000 units), followed by an initial infusion of 18 units/kg/hr (max initial infusion of 2000 units/hr). Subsequent doses should be adjusted to maintain the institution’s goal aPTT SC UFH 333 units/kg, followed by 250 units/kg administered q12hr without aPTT monitoringb Low-Molecular-Weight Heparin (SC) Enoxaparin 1 mg/kg q12hr or 1.5 mg/kg q24hrc; if CrCl < 30 mL/min, administer 1 mg/kg q24hr d Dalteparin 100 units/kg q12hr or 200 units/kg q24hr; CrCl < 30 mL/min – Contraindicatede Pentasaccharide (SC) Fondaparinux Weight < 50 kg – Administer 5 mg q24hr Weight 50–100 kg – Administer 7.5 mg q24hr Weight > 100 kg – Administer 10 mg q24hr CrCl 30–50 mL/min – 50% dose reduction CrCl < 30 mL/min – Contraindicated IV administration is preferred because of improved dosing precision. Outpatient treatment option for patients who cannot afford low-molecular-weight heparin or have a contraindication to other anticoagulants. c 1.5 mg/kg q24hr should be avoided in patients with current or history of malignancy, weight > 120 kg, deep vein thrombosis with iliac vein involvement, or antiphospholipid syndrome. d Not FDA approved for VTE treatment in patients without cancer, which may create insurance coverage issues. e Dosing for VTE in patients with active cancer includes 200 units/kg SC q24hr for 30 days, then 150 units/kg SC q24hr thereafter. IV = intravenous(ly); q = every; SC = subcutaneous(ly); UFH = unfractionated heparin; VTE = venous thromboembolism. a b 5. Switching therapy approach in VTE treatment a. Dabigatran was evaluated in the RE-COVER I (n=2539) and II (n=2568) trials. The trials had the same design, and both enrolled patients with a DVT (67%–69%), a PE (21%–23%), or both (9%–10%). i. All patients received a median of 9 days of injectable anticoagulation. Patients randomized to dabigatran 150 mg orally twice daily started the drug after discontinuing the injectable (Table 24). Patients randomized to dose-adjusted warfarin started the drug at the same time as the injectable anticoagulant and were bridged to an INR of 2.0–3.0 for at least 5 days. Patients were treated for 6 months. TTR in warfarin group was 59.9% in RE-COVER I and 56.9% in RE-COVER II. ii. In the combined trials (n=5107), the primary end points of symptomatic VTE events were similar between dabigatran and warfarin (2.4% vs. 2.2%; p=NS). Noninferiority was achieved (p<0.001). iii. Major bleeding was not significantly reduced with dabigatran (1.4% vs. 2.0%; HR 0.73; 95% CI, 0.48–1.11). iv. Major and CRNM bleeding combined were significantly reduced with dabigatran compared with warfarin 5% vs. 8.5% (HR 0.62; 95% CI, 0.50–0.76). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-166 Anticoagulation b. 6.  doxaban was evaluated in the Hokusai-VTE trial (n=8240), which included patients with a DVT E (60%), a PE (30%), or both (10%). i. All patients received a median of 7 days of injectable anticoagulant. Patients randomized to edoxaban 60 mg orally daily (or 30 mg orally daily based on body weight [60 kg or less] or moderate renal insufficiency [CrCl 30–50 mL/minute] or in patients who received potent P-gp inhibitors concomitantly) started the drug after discontinuing the injectable. Patients randomized to dose-adjusted warfarin started the drug at the same time as the injectable anticoagulant and were bridged to an INR of 2.0–3.0 for at least 5 days. Patients were followed for 12 months. The reduced edoxaban dose was used in 18% of patients with maintained efficacy and safety. TTR in the warfarin group was 63.5%. ii. The primary end point of symptomatic VTE events was similar between edoxaban and warfarin (3.2% vs. 3.5%; p=NS). Noninferiority was achieved (p<0.001). iii. The patient subgroup enrolled with a severe PE, defined as producing right ventricular dysfunction (n=938), had a significant 48% reduction in the primary end point compared with warfarin (3.3% vs. 6.2%, HR 0.52; 95% CI, 0.28–0.98). iv. Major bleeding was not significantly reduced with edoxaban (1.4% vs. 1.6%) overall. v. Major and CRNM bleeding combined was significantly reduced with edoxaban compared with warfarin (8.5% vs. 10.3%). Monotherapy approach in VTE treatment a. Rivaroxaban was evaluated in the EINSTEIN DVT (n=3449) and EINSTEIN PE (n=4832) trials. Although the trial designs were the same, they included different patient populations. i. Rivaroxaban 15 mg orally twice daily for 21 days, followed by 20 mg orally daily thereafter was initiated and compared with enoxaparin 1 mg/kg subcutaneously every 12 hours bridged to dose-adjusted warfarin therapy (INR 2.0–3.0). TTR in the warfarin group was 57.7% in EINSTEIN DVT and 62.7% in EINSTEIN PE. Median duration of injectable anticoagulant was 8 days. Investigators determined whether patients would be treated for 3, 6, or 12 months. Only 12% and 5% of patients were treated for 3 months in the EINSTEIN DVT and PE trials, respectively. ii. Many patients in the rivaroxaban arms of EINSTEIN DVT (73%) and EINSTEIN PE (93%) still received injectable anticoagulation before enrolling in the study. These patients were transitioned to rivaroxaban upon entering the trial. Efficacy and safety outcomes did not differ regardless of whether patients received initial doses of injectable anticoagulation before receiving rivaroxaban. iii. In the combined trials (n=8282), the primary end point of symptomatic VTE events was similar between rivaroxaban and standard care (2.1% vs. 2.3%; p=0.41). Noninferiority was achieved (p<0.001). iv. Major bleeding was reduced by a relative 46% with rivaroxaban compared with standard care (1% vs. 1.7%; p=0.002), whereas CRNM bleeding did not differ (8.6% vs. 8.4%). v. Patients with fragility (age older than 75, CrCl less than 50 mL/minute, or weight less than 50 kg) had a greater than 70% significant relative reduction in major bleeding, with each component of fragility reaching statistical significance independently. b. Apixaban was evaluated in the AMPLIFY (n=5395) trial, which included patients with a DVT (65%), a PE (25%), or both (9%). i. Apixaban 10 mg orally twice daily for 7 days, then 5 mg orally twice daily thereafter was initiated and compared with enoxaparin 1 mg/kg subcutaneously every 12 hours bridged to dose-adjusted warfarin therapy (INR 2.0–3.0). Median duration of injectable anticoagulant was 6.5 days, and TTR in those randomized to warfarin was 61%. Patients were treated for 6 months. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-167 Anticoagulation ii. 8 6% of patients in the apixaban arm initially received at least one dose of injectable anticoagulant before entering the study. These patients were transitioned to apixaban upon entering the trial. Efficacy and safety outcomes did not differ regardless of whether patients received initial doses of injectable anticoagulation before receiving apixaban. iii. The primary end point of symptomatic VTE events was similar between apixaban and standard care (2.3% vs. 2.7%; p=NS). Noninferiority was achieved (p<0.001). iv. Major bleeding was reduced by a relative 70% with apixaban compared with standard care (0.6% vs. 1.8%; p<0.001). v. CRNM bleeding was also reduced with apixaban (3.8% vs. 8.0%; p<0.001). Table 24. DOAC Dosing in VTE Agent Standard Dosing Dose Adjustmenta Avoid Usea Dabigatran 150 mg PO BID after 5–10 days of injectable anticoagulation None • CrCl ≤ 30 mL/min • Avoid use with CrCl 30–50 mL/min and concomitant use of P-gp inhibitors • P-gp inducers (e.g., rifampin) • Chemotherapy agents – Vinblastine, doxorubicin, imatinib, crizotinib, vandetanib, sunitinib, abiraterone, and enzalutamide Rivaroxaban 15 mg PO BID with food None for 21 days, followed by 20 mg PO daily with food. After 6 mo, dose can be reduced to 10 mg daily for extendedphase treatment. The 10-mg dose need not be administered with food • CrCl ≤ 30 mL/min • Strong CYP3A4 and P-gp inducersb • Moderate-severe hepatic impairment (Child-Pugh class B or C) • Strong CYP3A4 and P-gp inhibitorsc • Chemotherapy agents – Vinblastine, doxorubicin, imatinib, crizotinib, vandetanib, sunitinib, abiraterone, and enzalutamide Apixaban 10 mg PO BID for 7 days, followed by 5 mg PO BID. After 6 mo, dose can be reduced to 2.5 mg PO BID for extended-phase treatment 50% dose reduction if receiving 5 or 10 mg PO BID with strong CYP3A4 and P-gp inhibitors (e.g., protease inhibitors, itraconazole, ketoconazole, conivaptan) • Severe hepatic impairment (Child-Pugh class C) • Strong CYP3A4 and P-gp inducersb • If receiving 2.5 mg BID – Strong CYP3A4 and P-gp inhibitorsc • Chemotherapy agents – Vinblastine, doxorubicin, imatinib, crizotinib, vandetanib, sunitinib, abiraterone, and enzalutamide Edoxaband 60 mg PO once daily after 5–10 days of injectable anticoagulation 30 mg once daily • CrCl 15–50 mL/min • Potent P-gp inhibitor (verapamil, dronedarone, or quinidine) • Weight ≤ 60 kg • CrCl < 15 mL/min • P-gp inducers (e.g., rifampin) • Chemotherapy agents – Vinblastine, doxorubicin, imatinib, crizotinib, vandetanib, sunitinib, abiraterone, and enzalutamide CrCl in the DOAC trials was calculated using the Cockcroft-Gault equation with total body weight. Strong CYP3A4 and P-gp inducers include rifampin, phenytoin, carbamazepine, and St. John’s wort. c Strong CYP3A4 and P-gp inhibitors include protease inhibitors, itraconazole, ketoconazole, and conivaptan. d Efficacy data are lacking with edoxaban for VTE treatment in patients with a CrCl > 95 mL/min. BID = twice daily; DOAC = direct oral anticoagulant; PO = oral(ly); VTE = venous thromboembolism. a b ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-168 Anticoagulation 7. Outpatient therapy a. A round 80% of patients with a DVT can be treated on an outpatient basis. b. Most patients with a low-risk PE can also be treated at home. Use of outpatient treatment for PE may vary depending on geographic practices. Increased education is needed to promote this practice. The ability to use a DOAC without injectable anticoagulation offers an attractive option and easier transition of care. Rivaroxaban was shown to be safe and effective using this approach in a small trial (HoT-PE) and significantly reduced resource use (MERCURY PE). Data with other DOACs are still developing. c. The 2021 American College of Chest Physicians guidelines recommend outpatient treatment of low-risk PE. E. Secondary Prevention of VTE 1. All patients with VTE should be treated for at least 3 months (Table 25). 2. Patients without a transient or reversible cause should be considered for long-term, potentially indefinite, oral anticoagulant therapy. Data analyses consistently show significant reductions in VTE with continued therapy for 12–24 additional months. Once therapy is discontinued, VTE rates approach those of patients who did not receive extended therapy. 3. American College of Chest Physicians guidelines state that the oral anticoagulant need not be changed if therapy is continued beyond 3 months. 4. Options a. Adjusted-dose warfarin to an INR of 2.0–3.0 b. Dabigatran 150 mg twice daily has been noninferior to warfarin for efficacy, with similar major bleeding but less major and CRNM bleeding (RE-MEDY trial). Dabigatran was superior to placebo for efficacy, with similar major bleeding but more major and CRNM bleeding (RE-SONATE trial). c. Rivaroxaban 20 mg daily was superior to placebo for efficacy, with similar major bleeding and more major and CRNM bleeding (EINSTEIN-Extension trial). Both rivaroxaban 20 mg and rivaroxaban 10 mg once daily were superior to aspirin, with similar safety (EINSTEIN CHOICE) in patients who had already completed 6 months of therapy (see Table 25). d. Apixaban 5 mg and 2.5 mg twice daily were superior to placebo for efficacy, with similar safety (AMPLIFY-Extension) in patients who had already completed 6 months of therapy (see Table 25). e. No long-term trials of edoxaban have been completed beyond the Hokusai-VTE trial. f. Aspirin (100 mg daily) had a 32% relative reduction in recurrent VTE events compared with placebo in two trials after patients completed at least 6 months of oral anticoagulant therapy. Relative reductions in patients receiving a DOAC compared with placebo are typically 70%–80%. The only trial comparing a DOAC with aspirin was the EINSTEIN CHOICE, in which both rivaroxaban doses were superior to aspirin for efficacy, with similar low rates of bleeding. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-169 Anticoagulation Table 25. Duration of Anticoagulation Therapy in Patients with VTE Indication Provoked VTEa Therapy Duration 3 mo First unprovoked VTE or provoked by persistent risk factor At least 3 mo; then reassess for extended-phase anticoagulation First episode of VTE with inherited or acquired thrombophiliab At least 3 mo; then reassess for extended-phase anticoagulation First episode of cancerassociated VTE At least 3–6 mo and consider extended duration until cancer resolves and cancer treatment is completed Indefinite Second VTE (provoked or unprovoked) Comments Recommendation applies to both proximal DVT and PE Continue oral anticoagulant therapy if patient is not at high risk of bleeding and is adherent to therapy Risk-benefit of indefinite therapy should be reassessed at least annually Preference for extended-phase anticoagulation with low-dose apixaban (2.5 mg twice daily) or rivaroxaban (10 mg once daily) over aspirin If discontinuing anticoagulant therapy, aspirin therapy is suggested to prevent recurrent VTE Continue oral anticoagulant therapy if patient is not at high risk of bleeding and is adherent to therapy Dose-adjusted warfarin to INR target of 2.5 (goal 2.0–3.0) is preferred to other anticoagulants in patients with antiphospholipid syndrome Risk-benefit of indefinite therapy should be reassessed at least annually Apixaban, edoxaban, rivaroxaban, or LMWH is recommended over other anticoagulants LMWH is preferred to factor Xa inhibitors in patients with luminal GI malignancies Applies to patient not at high risk of bleeding Provoked VTE = transient or reversible risk factors including surgery, hospitalization, plaster cast immobilization within 3 mo, estrogen, pregnancy, prolonged travel (> 8 hr), lesser leg injuries, or immobilization within 6 wk. b Factor V Leiden; prothrombin G20210A; antiphospholipid syndrome; excess factor VIII; deficiency in protein C or protein S; antithrombin deficiency. DVT = deep vein thrombosis; LMWH = low-molecular-weight heparin; PE = pulmonary embolism; VTE = venous thromboembolism. a F. Treatment of Cancer-Associated VTE 1. Cancer is a significant risk factor for developing thrombosis. a. 15% of patients with cancer develop venous or arterial thrombosis. b. Cancer increases the risk of initial VTE by 4- to 9-fold. c. Chemotherapy can increase the risk by up to 6.5-fold. d. VTE is the second leading cause of death in most cancers. e. Risk of VTE varies depending on cancer type and patient- and treatment-related factors. 2. Historically, LMWH has been the preferred anticoagulant in the treatment of cancer-associated VTE because it has shown better efficacy than warfarin without a risk of bleeding. 3. With growing evidence related to the efficacy and safety of DOACs in this patient population, the ISTH, American College of Chest Physicians, American Society of Clinical Oncology (ASCO), and National Comprehensive Cancer Network (NCCN) have provided recommendations for use. Table 26 presents guideline recommendations for parenteral or oral anticoagulants. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-170 Anticoagulation Table 26. Clinical Guideline Recommendations for Treatment of Cancer-Associated VTE Clinical Guidelines ISTH (2018) Recommendations ASCO (2020) American College of Chest Physicians (2021) NCCN (2022) • Low risk of bleeding: Rivaroxaban or edoxaban preferred (LMWH acceptable alternative) • High risk of bleedinga: LMWH preferred (rivaroxaban or edoxaban acceptable alternatives) • Initial treatment (5–10 days): LMWH, UFH, fondaparinux, or rivaroxaban • Long-term treatment (6 mo): LMWH, edoxaban, rivaroxaban preferred to VKA • General strategy: Factor Xa inhibitor preferred to LMWH • Presence of luminal GI malignancy: LMWH or apixaban preferred to edoxaban or rivaroxaban • Patients without gastric or gastroesophageal lesions: DOACs (apixaban, edoxaban, rivaroxaban) preferred • Patients with gastric or gastroesophageal lesions: LMWH preferred (dalteparin > enoxaparin) High risk of bleeding considered luminal GI cancers, genitourinary or bladder cancers, active abnormalities of GI mucosal (e.g., duodenal ulcers, gastritis, esophagitis, or colitis). DOAC = direct oral anticoagulant; GI = gastrointestinal; LMWH = low-molecular-weight heparin; UFH = unfractionated heparin; VKA = vitamin K antagonist. a 4. Landmark trials for DOACs used in cancer-associated VTE: a. Factor Xa inhibitors i. Edoxaban (Hokusai-VTE trial) and rivaroxaban (SELECT-D) have been compared with dalteparin in studies of patients with cancer-induced thrombosis. Collectively, these DOACs showed reduced recurrent VTE, but with an increased incidence of major bleeding. Most of the excess bleeding occurred in patients with upper gastrointestinal cancers. ii. Apixaban (ADAM-VTE and Caravaggio) provided efficacy similar to dalteparin with similar major bleeding. The similar major bleeding in the overall trial results may have been due to lower enrollment of patients with upper GI cancers. b. Direct thrombin inhibitor i. Data are limited with the use of dabigatran in cancer-associated thrombosis, especially compared with LMWH. A trial that compared dabigatran with VKA showed similar efficacy and incidence of bleeding. ii. Guidelines do not currently recommend routine use of dabigatran in cancer-associated thrombosis. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-171 Anticoagulation Patient Case 8. A 48-year-old male (height 178 cm, weight 90 kg) presents to the ED with pain and swelling in his left leg. On examination, his leg is warm to the touch and tender and has 3+ pitting edema below the knee. His D-dimer is positive, and his duplex ultrasonography identifies a femoral-popliteal DVT. He understands that he will need to receive anticoagulant therapy but wants to avoid any injections, if possible. He has good insurance coverage. His other medical conditions are hypertension, HIV, and dyslipidemia. His medications include benazepril 20 mg orally daily, ritonavir 100 mg orally daily, darunavir 800 mg orally daily, emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg orally daily, and atorvastatin 10 mg orally daily. His vital signs are stable, and his CrCl is 78 mL/minute. Which is the most appropriate anticoagulant regimen to initiate for this patient? A. Rivaroxaban 15 mg orally twice daily for 21 days, followed by 20 mg orally daily. B. Edoxaban 60 mg orally daily. C. Warfarin 2.5 mg orally daily. D. Apixaban 5 mg orally twice daily for 7 days, followed by 2.5 mg orally twice daily. V. REVERSAL OF ANTICOAGULATION A. Blood Products 1. In the reversal of anticoagulant therapy, blood products are often part of the management of major bleeding. 2. W hole blood is spun into red cells and platelet-rich plasma. The platelet-rich plasma is spun again to create platelets and plasma, and the plasma is frozen (FFP). 3. Packed RBCs (PRBCs) a. Not used for reversal but for management of bleeding to provide oxygen delivery to tissues. b. 1 unit (around 250 mL) has an Hct of 70%–80% (twice whole blood) and can increase a patient’s Hgb by 1–2 g/dL. c. Risks include transfusion reactions (e.g., chills, fever, urticaria, tachycardia), infection, and transfusion-related lung injury. 4. Platelets a. May be used for reversal of antiplatelet therapy, but data are inconsistent b. Each unit (200–300 mL) contains 300,000–600,000 platelets/mm3. c. Same risk as with PRBCs d. Commonly part of a massive transfusion protocol 5. FFP a. Cells have been spun out of blood, and the plasma contains the proteins in blood, mainly clotting factors. b. Must be frozen within 8 hours of blood collection and good for 12 months c. Commonly underdosed for reversing warfarin therapy – Takes several units (around 4 units) i. Typical dose is 15–20 mL/kg (around 1.2–1.6 L). ii. Critically ill patients: 30 mL/kg (around 2.4 L) d. Requires type-and-crossing e. Takes 30–45 minutes to thaw f. Risks similar to risks with PRBCs and platelets ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-172