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The currently available anticoagulants include unfractionated heparin, LMWHs, fondaparinux, vitamin K antagonists (ie, warfarin), and direct-acting oral anticoagulants (DOACs) (ie, dabigatran, rivaroxaban, apixaban, edoxaban, betrixaban). (For a discussion of the injectable DTIs, see section Heparin-Induced Thrombocytopenia above.)
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CLASSES OF ANTICOAGULANTS
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A. Unfractionated Heparin and LMWHs
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Unfractionated heparin is a biologic product most commonly derived from porcine intestinal tissue rich in heparin-bearing mast cells. It is heterogeneous with respect to sulfation and polymer length; individual molecules may range from 3000 to 30,000. Only about one-third of the molecules in a given preparation of unfractionated heparin contain the crucial pentasaccharide sequence necessary for binding of antithrombin and exerting its anticoagulant effect upon thrombin. Heparin is highly negatively charged, and upon intravenous infusion, it binds to a large array of blood components, such as endothelial cells, platelets, mast cells, and plasma proteins. The degree of anticoagulation with unfractionated heparin is typically monitored by aPTT or anti-Xa level in patients who are receiving the drug in therapeutic doses, although the pharmacokinetics of unfractionated heparin are poorly predictable. Only a fraction of an infused dose of heparin is metabolized by the kidneys, making it safe to use in most patients with significant kidney disease.
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The LMWHs are produced from chemical depolymerization of unfractionated heparin, resulting in products of lower molecular weight (mean molecular weight, 4500–6500d, depending on the LMWH). Due to less protein and cellular binding, the pharmacokinetics of the LMWHs are much more predictable than those of unfractionated heparin, allowing for fixed weight-based dosing. All LMWHs are principally renally cleared and must be avoided or used with extreme caution in individuals with creatinine clearance less than 30 mL/min. A longer half-life permits once- or twice-daily subcutaneous dosing, allowing for greater convenience and outpatient therapy in selected cases. Most patients do not require monitoring, although monitoring using the anti-Xa activity level is appropriate for patients with moderate kidney disease, those with elevated body mass index or low weight, and selected pregnant patients. LMWHs are associated with a lower frequency of heparin-induced thrombocytopenia and thrombosis (approximately 0.6%) than unfractionated heparin (3%).
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Fondaparinux is a synthetic molecule consisting of the highly active pentasaccharide sequence found in LMWHs. As such, it exerts almost no thrombin inhibition and works to indirectly inhibit factor Xa through binding to antithrombin. Fondaparinux, like the LMWHs, is almost exclusively metabolized by the kidneys, and should be avoided in patients with creatinine clearance less than 30 mL/min. Predictable pharmacokinetics allow for weight-based dosing.
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C. Vitamin K Antagonist (Warfarin)
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The vitamin K antagonist warfarin inhibits the activity of the vitamin K–dependent carboxylase that is important for the posttranslational modification of coagulation factors II, VII, IX, and X. Although warfarin is taken orally, leading to a significant advantage over the heparins and heparin derivatives, interindividual differences in nutritional status, comorbid diseases, concomitant medications, and genetic polymorphisms lead to a poorly predictable anticoagulant response. Individuals taking warfarin must undergo periodic monitoring to verify the intensity of the anticoagulant effect, reported as the INR, which corrects for differences in potency of commercially available thromboplastin used to perform the PT.1
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D. Direct-Acting Oral Anticoagulants
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Unlike warfarin, the DOACs (1) have a predictable dose effect and therefore do not require laboratory monitoring, (2) have anticoagulant activity independent of vitamin K with no need for dietary stasis, and (3) are renally metabolized to varying degrees so there are restrictions or dose reductions related to reduced kidney function (Table 14–10). While the DOACs have fewer drug interactions than warfarin, if DOACs are given with potentially interacting medications, there is no reliable way to measure the impact on anticoagulant activity of the concomitant administration. There is also no reliable way to measure adherence. Data remain limited on use of DOACs in morbidly obese patients (more than 120 kg or BMI greater than or equal to 40) in VTE treatment. The clinician must carefully consider kidney function, concomitant medications, indication for use, candidacy for lead-in parenteral therapy (as required for acute VTE treatment with edoxaban and dabigatran only) and anticipated patient adherence. Providers must be careful to dose each DOAC properly for the indication, kidney function, and weight of patient, and to check for drug interactions. (See Table 14–10 for details.) There is a reversal agent available for dabigatran and for the anti-Xa inhibitors apixaban and rivaroxaban (Table 14–11).
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Routine monitoring is not recommended for patients taking DOACs. However, there are clinical scenarios where assessing anticoagulant activity may be helpful, including active bleeding, pending urgent surgery, suspected therapeutic failure, or concern for accumulation. Drug-specific anti-Xa levels are not widely available, and guidance is lacking regarding clinical approach to the results. DOACs have varying effects on the PT and aPTT. In the absence of drug-specific levels, a normal dilute thrombin time excludes the presence of clinically relevant dabigatran levels; an elevated aPTT suggests clinically relevant levels of dabigatran. An elevated PT suggests clinically relevant levels of rivaroxaban. However, a normal aPTT or normal PT does not rule out clinically significant amounts of dabigatran or rivaroxaban, respectively.
+
Douxfils
J
et al. Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians. J Thromb Haemost. 2018;16:209.
[PubMed: 29193737]
+
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PREVENTION OF VENOUS THROMBOEMBOLIC DISEASE
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The frequency of venous thromboembolic disease (VTE) among hospitalized patients ranges widely. Up to 60% of VTE cases occur during or after hospitalization, with especially high incidence among critical care patients and high-risk surgical patients.
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Avoidance of fatal PE, which occurs in up to 5% of high-risk inpatients as a consequence of hospitalization or surgery, is a major goal of pharmacologic prophylaxis. Tables 14–12 and 14–13 provide risk stratification for DVT/VTE among hospitalized surgical and medical inpatients. Standard pharmacologic prophylactic regimens are listed in Table 14–14; prophylactic anticoagulation regimens differ in their recommended duration of use. Prophylactic strategies should be guided by individual risk stratification, with all moderate- and high-risk patients receiving pharmacologic prophylaxis, unless contraindicated. Contraindications to VTE prophylaxis for hospital inpatients at high risk for VTE are listed in Table 14–15. In patients at high risk for VTE with absolute contraindications to pharmacologic prophylaxis, mechanical devices such as intermittent pneumatic compression devices should be used, ideally in portable form with at least an 18-hour daily wear time.
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It is recommended that VTE prophylaxis be used judiciously in hospitalized medical patients who are not critically ill since a comprehensive review of evidence suggested harm from bleeding in low-risk patients given low-dose heparin and skin necrosis in stroke patients given compression stockings. Risk assessment models like the Padua Risk Score (Table 14–13) and the IMPROVE risk score can help clinicians identify patients who may benefit from DVT prophylaxis. The IMPROVE investigators also developed a bleeding risk model that may aid in identifying acutely ill medical inpatients at increased risk for bleeding: https://www.outcomes-umassmed.org/IMPROVE/risk_score/index.html. While two of the anti-Xa oral anticoagulants (betrixaban and rivaroxaban) have been approved for extended duration prophylaxis after discharge for medically ill patients, how to identify those who will have clinical benefit from this practice is still unclear.
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The Caprini score may help guide decisions in surgical patients about VTE prophylaxis (https://www.mdcalc.com/caprini-score-venous-thromboembolism-2005). In addition, certain high-risk surgical patients should be considered for extended-duration prophylaxis of up to 1 month, including those undergoing total hip replacement, hip fracture repair, and abdominal and pelvic cancer surgery. If bleeding is present, if the risk of bleeding is high, or if the risk of VTE is high for the inpatient (Table 14–12) and therefore combined prophylactic strategies are needed, some measure of thromboprophylaxis may be provided through mechanical devices such as intermittent pneumatic compression devices and graduated compression stockings.
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A. Primary VTE Prevention in Patients with Active Cancer
++
Some ambulatory cancer patients undergoing chemotherapy who are at moderate to high risk of VTE (Khorana risk score ≥ 2) (https://www.mdcalc.com/khorana-risk-score-venous-thromboembolism-cancer-patients) may benefit from pharmacologic DVT prophylaxis, although bleeding risk is increased and caution should be taken, particularly in patients with gastrointestinal or intracranial malignancy, and other risk factors for anticoagulant-related bleeding (such as thrombocytopenia and kidney dysfunction). DOACs should be avoided when there are possible interactions with chemotherapeutic agents.
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B. Primary VTE Prevention, Diagnosis, and Treatment in Patients with Severe COVID-19
++
Patients with severe COVID-19 appear to have an increased incidence of thrombotic complications, including venous (DVT, PE) and arterial (stroke, limb occlusion) events. Risk is especially high in the critical care setting. Although the reasons for this hypercoagulability are not yet well understood, the profound systemic inflammatory response associated with severe COVID-19 is thought to play a role. While the hypercoagulability in COVID-19 resembles DIC, laboratory and clinical findings are somewhat different. Laboratory findings in patients with severe COVID-19 may include markedly elevated D-dimer and modestly prolonged prothrombin time. However, patients with COVID-19 tend to have elevated fibrinogen levels; thrombocytopenia is rare and nonsevere; and bleeding complications are unusual. Thrombosis in patients with COVID-19 is associated with a poor prognosis and often occurs despite standard pharmacologic prophylaxis.
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1. Risk stratification and initial prognostication of patients with severe COVID-19
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Given the prevalence and prognostic value of abnormal laboratory findings at presentation, patients with COVID-19 should have RP/INR, PTT, D-dimers, and fibrinogen measured. When results are abnormal, especially significantly elevated D-dimers or decreased fibrinogen, admission for monitoring should be considered even in patients who are otherwise clinically stable. Worsening laboratory parameters during hospitalization should prompt consideration of transfer to a higher level of care and heightened clinical suspicion for thrombosis.
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2. VTE prophylaxis for patients with severe COVID-19
++
In the absence of strong contraindications, all patients hospitalized with COVID-19 should receive pharmacologic VTE prophylaxis. LMWH is preferred over unfractionated heparin to minimize staff exposure and the chance of heparin-induced thrombocytopenia.
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For patients with a prior history of VTE who take an oral anticoagulant for secondary prevention at the time of admission, transition to LMWH should be considered due to its shorter half-life and potential anti-inflammatory properties.
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For updated recommendations regarding pharmacologic dosing and post-discharge prophylaxis, refer to professional society guidance (links at end of this section) since guidance in this area is evolving rapidly.
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3. Diagnosis and management of thromboembolic disease in patients with severe COVID-19
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Logistical challenges complicate the diagnosis of thromboembolism in patients with COVID-19 due to patient instability and risks of staff exposures. D-dimers are generally elevated in hospitalized patients who have COVID-19. A substantial increase in D-dimers may suggest COVID-19–associated coagulopathy with or without thrombotic events. Clinicians should remain vigilant for signs and symptoms of thrombosis and consider obtaining surveillance laboratory testing at least every 3–4 days with low threshold for imaging. Ideally, thrombosis should be confirmed radiographically, but in situations where these studies cannot safely be obtained and clinical suspicion is very high, empiric treatment may be considered.
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Guidance from the Anticoagulation Forum (https://acforum.org/web/), the International Society for Thrombosis and Haemostasis (https://academy.isth.org/isth/#!*menu=8*browseby=2*sortby=1*label=19794), and the American Society for Hematology (https://www.hematology.org/covid-19) is evolving and should be frequently consulted.
+
Al Yami
MS
et al. Direct oral anticoagulants for extended thromboprophylaxis in medically ill patients: meta-analysis and risk/benefit assessment. J Blood Med. 2018;9:25.
[PubMed: 29503590]
+
Carrier
M
et al; AVERT Investigators.
Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2019;380:711.
[PubMed: 30511879]
+
Connors
JM
et al. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135:2033.
[PubMed: 32339221]
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Falck-Ytter
Y
et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e278S.
[PubMed: 22315265]
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Gould
MK
et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e227S.
[PubMed: 22315263]
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Kahn
SR
et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e195S.
[PubMed: 2231526]
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Khorana
AA
et al; CASSINI Investigators.
Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med. 2019;380:720.
[PubMed: 30786186]
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McBane
RD 2nd
et al. Anticoagulation in COVID-19: a systematic review, meta-analysis, and rapid guidance from Mayo Clinic. Mayo Clin Proc. 2020;95:2467.
[PubMed: 33153635]
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Rosenberg
DJ
et al. External validation of the IMPROVE Bleeding Risk Assessment Model in medical patients. Thromb Haemost. 2016 Aug 30;116(3):530–6.
[PubMed: 27307054]
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Schünemann
HJ
et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients. Blood Adv. 2018;2:3198.
[PubMed: 30482763]
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TREATMENT OF VENOUS THROMBOEMBOLIC DISEASE
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A. Anticoagulant Therapy
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Treatment for VTE should be offered to patients with objectively confirmed DVT or PE, or to those in whom the clinical suspicion is high for the disorder but who have not yet undergone diagnostic testing (see Chapter 9). The management of VTE primarily involves administration of anticoagulants; the goal is to prevent recurrence, extension and embolization of thrombosis and to reduce the risk of post-thrombotic syndrome. Suggested anticoagulation regimens are found in Table 14–16.
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B. Selecting Appropriate Initial Anticoagulant Therapy
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Most patients with DVT alone may be treated as outpatients, provided that their risk of bleeding is low and they have good follow-up. Table 14–17 outlines proposed selection criteria for outpatient treatment of DVT.
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Among patients with PE, risk stratification at time of diagnosis should direct treatment and triage. Patients with persistent hemodynamic instability are classified as high-risk patients (previously referred to as having “massive PE”) and have an early PE-related mortality of more than 15%. These patients should be admitted to an intensive care unit and generally receive thrombolysis and anticoagulation with intravenous heparin. Intermediate-risk patients (previously, “submassive PE”) have a mortality rate of up to 15% and should be admitted to a higher level of inpatient care, with consideration of thrombolysis on a case-by-case basis. Catheter-directed techniques, if available, may be an option for patients who are poor candidates for systemic thrombolysis and/or in centers with expertise. Low-risk patients have a mortality rate less than 3% and are candidates for expedited discharge or outpatient therapy.
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For hemodynamically stable patients, additional assessment focusing on right ventricular dysfunction is warranted to differentiate between low-risk, low-intermediate risk, and high-intermediate risk PE. The Bova score (https://www.mdcalc.com/bova-score-pulmonary-embolism-complications) and the simplified PE severity index accurately identify patients at low risk for 30-day PE-related mortality (Table 14–18) (eTable 14–3) who are potential candidates for expedited discharge or outpatient treatment. Because the Bova score includes serum troponin and evidence of right ventricular dysfunction (by CT or echocardiography), it also identifies patients with high-intermediate risk PE who warrant close monitoring and may require escalation of therapy. An RV/LV ratio less than 1.0 on chest CT angiogram has been shown to have good negative predictive value for adverse outcome but suffers from inter observer variability. Echocardiography may provide better assessment of right ventricular dysfunction when there is concern. Serum biomarkers such as B-type natriuretic peptide and troponin are most useful for their negative predictive value, and mainly in combination with other predictors.
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Selection of an initial anticoagulant should be determined by patient characteristics (kidney function, immediate bleeding risk, weight) and the clinical scenario (eg, whether thrombolysis is being considered, active cancer, thrombosis location) as described in Table 14–16.
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1. Parenteral anticoagulants
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In patients in whom parenteral anticoagulation is being considered, LMWHs are more effective than unfractionated heparin in the immediate treatment of DVT and PE; they are preferred as initial treatment because of predictable pharmacokinetics, which allow for subcutaneous, once- or twice-daily dosing with no requirement for monitoring in most patients. Accumulation of LMWH and increased rates of bleeding have been observed among patients with severe kidney disease (creatinine clearance less than 30 mL/min), leading to a recommendation to use intravenous unfractionated heparin preferentially in these patients. If concomitant thrombolysis is being considered, unfractionated heparin is indicated. Patients with VTE and a perceived higher risk of bleeding (ie, post-surgery) may be better candidates for treatment with unfractionated heparin than LMWH given its shorter half-life and reversibility. Unfractionated heparin can be effectively neutralized with the positively charged protamine sulfate while protamine may only have partial reversal effect on LMWH. Use of unfractionated heparin leads to heparin-induced thrombocytopenia and thrombosis in approximately 3% of patients, so daily complete blood counts are recommended during the initial 10–14 days of exposure.
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Weight-based, fixed-dose daily subcutaneous fondaparinux (a synthetic factor Xa inhibitor) may also be used for the initial treatment of DVT and PE, with no increase in bleeding over that observed with LMWH. Its lack of reversibility, long half-life, and renal clearance limit its use in patients with an increased risk of bleeding or kidney disease.
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2. Oral anticoagulants
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A. DIRECT-ACTING ORAL ANTICOAGULANTS
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DOACs have a predictable dose effect, few drug-drug interactions, rapid onset of action, and freedom from laboratory monitoring (Table 14–10). Dabigatran, rivaroxaban, apixaban, and edoxaban are approved for treatment of acute DVT and PE. While rivaroxaban and apixaban can be used as monotherapy eliminating the need for parenteral therapy, patients treated with dabigatran or edoxaban must first receive 5–10 days of parenteral anticoagulation and then be transitioned to the oral agent per prescribing information. Unlike warfarin, DOACs do not require an overlap since these agents are immediately active; the DOAC is started when the parenteral agent is stopped. Compared to warfarin and LMWH, the DOACs are all noninferior with respect to prevention of recurrent VTE; both rivaroxaban and apixaban have a lower bleeding risk than warfarin with LMWH bridge. While DOACs are recommended as first-line therapy for acute VTE according to the CHEST 2016 VTE guidelines, agent selection should be individualized with consideration of kidney function, concomitant medication use, indication, ability to use LMWH bridge therapy, cost, and adherence.
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If warfarin is chosen as the oral anticoagulant it will be initiated along with the parenteral anticoagulant, which is continued until INR is in therapeutic range. Most patients require 5 mg of warfarin daily for initial treatment, but lower doses (2.5 mg daily) should be considered for patients of Asian descent, older adults, and those with hyperthyroidism, heart failure, liver disease, recent major surgery, malnutrition, certain polymorphisms for the CYP2C9 or the VKORC1 genes or who are receiving concurrent medications that increase sensitivity to warfarin (eTable 14–4). Conversely, individuals of African descent, those with larger body mass index or hypothyroidism, and those who are receiving medications that increase warfarin metabolism (eg, rifampin) may require higher initial doses (7.5 mg daily). Daily INR results should guide dosing adjustments in the hospitalized patient while at least biweekly INR results guide dosing in the outpatient during the initial period of therapy (Table 14–19). Web-based warfarin dosing calculators incorporating clinical and genetic factors are available to help clinicians choose appropriate starting doses (eg, see www.warfarindosing.org). Because an average of 5 days is required to achieve a steady-state reduction in the activity of vitamin K–dependent coagulation factors, the parenteral anticoagulant should be continued for at least 5 days and until the INR is more than 2.0. Meticulous follow-up should be arranged for all patients taking warfarin because of the bleeding risk associated with initiation of therapy. Once stabilized, the INR should be checked at an interval no longer than every 6 weeks and warfarin dosing should be adjusted by guidelines (Table 14–20) since this strategy has been shown to improve the time patients spend in the therapeutic range and their clinical outcomes. Supratherapeutic INRs should be managed according to evidence-based guidelines (Table 14–21).
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C. Duration of Anticoagulation Therapy
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Recurrence rates of VTE after discontinuation of therapy—The clinical scenario in which the thrombosis occurred is the strongest predictor of recurrence and, in most cases, guides duration of anticoagulation (Table 14–22). In the first year after discontinuation of anticoagulation therapy, the frequency of recurrent VTE among individuals whose thrombosis occurred in the setting of a transient, major, reversible risk factor (such as surgery) is approximately 3% after completing 3 months of anticoagulation, compared with at least 8% for individuals whose thrombosis was unprovoked, and greater than 20% in patients with cancer. Men have a greater than twofold higher risk of recurrent VTE compared to women; recurrent PE is more likely to develop in patients with clinically apparent PE than in those with DVT alone and has a case fatality rate of nearly 10%; and proximal DVT has a higher recurrence risk than distal DVT.
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1. Provoked versus unprovoked VTE
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Patients with provoked VTE are generally treated with a minimum of 3 months of anticoagulation, whereas unprovoked VTE should prompt consideration of indefinite anticoagulation provided the patient is not at high risk for bleeding. Merely extending duration of anticoagulation beyond 3 months for unprovoked PE will not reduce risk of recurrence once anticoagulation is stopped; if anticoagulants are stopped after 3, 6, 12, or 18 months in such a patient, the risk of recurrence after cessation of therapy is similar. Individual risk stratification may help identify patients most likely to suffer recurrent disease and thus most likely to benefit from ongoing anticoagulation therapy. Normal D-dimer levels 1 month after cessation of anticoagulation are associated with lower recurrence risk, although some would argue not low enough to consider stopping anticoagulant therapy, particularly in men.
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2. Risk scoring systems to guide therapy duration
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The HERDOO2 risk scoring system uses body mass index, age, D-dimer, and post-phlebitic symptoms to identify women at lower risk for recurrence after unprovoked VTE (https://www.mdcalc.com/herdoo2-rule-discontinuing-anticoagulation-unprovoked-vte). The Vienna Prediction Model, a simple scoring system based on age, sex, D-dimer, and location of thrombosis, can help estimate an individual’s recurrence risk to guide duration of therapy decisions.
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3. Cancer-related VTE
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LMWH has been the mainstay of treatment for cancer-related VTE based on lower VTE recurrence in cancer patients treated with dalteparin compared with warfarin. Studies have also shown that DOACs (edoxaban, rivaroxaban, and apixaban) are at least as effective as LMWH for VTE treatment. The use of edoxaban and rivaroxaban is at the expense of increased bleeding, particularly for patients with gastrointestinal cancer. The International Society for Thrombosis and Haemostasis suggests use of specific DOACs for cancer patients with a diagnosis of acute VTE, no drug-drug interactions, and a low risk of bleeding but suggests use of LMWH for those with a high risk of bleeding, including patients with luminal gastrointestinal cancers with an intact primary tumor, and those at risk for bleeding from the genitourinary or gastrointestinal tract. For patients with intracranial malignancy and VTE, bleeding risk depends on tumor type (primary versus metastatic) and other characteristics; whenever possible, interdisciplinary consultation is recommended to help determine risk of initiating anticoagulation. DOACs do not appear to confer higher bleeding risk compared to LMWH in patients with brain tumors. Clinicians must be aware that chemotherapeutic agents may interact with DOACs and their use should be avoided in cases of potential interactions because there is no easily accessible and reliable way to measure the anticoagulant effect of DOACs.
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4. Thrombophilia workup in determining duration
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Laboratory workup for thrombophilia is not recommended routinely for determining duration of therapy because clinical presentation is a much stronger predictor of recurrence risk. The workup may be pursued in patients younger than 50 years, with a strong family history, with a clot in unusual locations, or with recurrent thromboses (Table 14–23). In addition, a workup for thrombophilia may be considered in women of childbearing age in whom results may influence fertility and pregnancy outcomes and management or in those patients in whom results will influence duration of therapy. An important hypercoagulable state to identify is antiphospholipid syndrome because these patients have a marked increase in recurrence rates, are at risk for both arterial and venous disease, in general receive bridge therapy during any interruption of anticoagulation, and should not receive DOACs as first-line antithrombotic therapy due to increased arterial events compared to warfarin. Due to effects of anticoagulants and acute thrombosis on many of the tests, the thrombophilia workup should be delayed in most cases until at least 3 months after the acute event, if indicated at all (Table 14–24). The benefit of anticoagulation must be weighed against the bleeding risks posed, and the benefit-risk ratio should be assessed at the initiation of therapy, at 3 months, and then at least annually in any patient receiving prolonged anticoagulant therapy. Bleeding risk scores, such as the Riete score (https://www.mdcalc.com/riete-score-risk-hemorrhage-pulmonary-embolism-treatment) have been developed to estimate risk of these complications. Their performance, however, may not offer any advantage over a clinician’s subjective assessment, particularly in older individuals. Consideration of bleeding risk is of particular importance when identifying candidates for extended duration therapy for treatment of unprovoked VTE; it is recommended that patients with a high risk of bleeding receive a defined course of anticoagulation, rather than indefinite therapy, even if the VTE was unprovoked.
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D. Secondary Prevention
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Antithrombotic therapy offered after the initial 3–6 months of treatment should be considered in patients with VTE that is not majorly provoked; it is most compelling for those with unprovoked VTE. For most patients who continue to take a DOAC to prevent recurrence, the dose can be reduced to prophylactic intensity after the initial 6–12 months of therapy. In patients deemed poor candidates for ongoing DOAC or warfarin use but who warrant some secondary prevention, low-dose (81–100 mg) aspirin may be used; however, this will provide far less reduction in risk of recurrent VTE with similar bleeding risk.
+
Bova
C
et al; Bova Score Validation Study Investigators. A prospective validation of the Bova score in normotensive patients with acute pulmonary embolism. Thromb Res. 2018;165:107.
[PubMed: 29631073]
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Connors
JM. Thrombophilia testing and venous thrombosis. N Engl J Med. 2017;377:2298.
[PubMed: 29211668]
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Cuker
A
et al. Reversal of direct oral anticoagulants: guidance from the Anticoagulation Forum. Am J Hematol. 2019;94:697.
[PubMed: 30916798]
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Garcia
D
et al. Diagnosis and management of the antiphospholipid syndrome. N Engl J Med. 2018;378:2010.
[PubMed: 29791828]
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Kearon
C
et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149:315.
[PubMed: 26867832]
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Khorana
AA
et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2018;16:1891.
[PubMed: 30027649]
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Konstantinides
SV
et al. The 2019 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2019;40:3453.
[PubMed: 31697840]
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Li
A
et al. Direct oral anticoagulant for the prevention of thrombosis in ambulatory patients with cancer: a systematic review and meta-analysis. J Thromb Haemost. 2019;17:2141.
[PubMed: 31420937]
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Li
A
et al. Direct oral anticoagulant (DOAC) versus low-molecular-weight
heparin (LMWH) for treatment of cancer associated thrombosis (CAT): a systematic review and meta-analysis. Thromb Res. 2019;173:158.
[PubMed: 29506866]
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Streiff
MB
et al. NCCN Guidelines Insights: Cancer-Associated Venous Thromboembolic Disease, Version 2.2018. J Natl Compr Canc Netw. 2018;16:1289.
[PubMed: 30442731]
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Witt
DM
et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv. 2018;2:3257.
[PubMed: 30482765]
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E. Thrombolytic Therapy
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Anticoagulation alone is appropriate treatment for most patients with PE; however, those with high-risk, massive PE, defined as PE with persistent hemodynamic instability, have an in-hospital mortality rate that approaches 30% and, absent contraindications (Table 14–25), require immediate thrombolysis in combination with anticoagulation (Table 14–26). Systemic thrombolytic therapy has been used in carefully selected patients with intermediate-risk, submassive PE, defined as PE without hemodynamic instability but with evidence of right ventricular compromise and myocardial injury. Thrombolysis in this cohort decreases risk of hemodynamic compromise but increases the risk of major hemorrhage and stroke. A lower dose of tPA commonly used for PE treatment has been evaluated in small trials but additional data are needed to recommend its use. Catheter-directed therapy for acute PE may be considered for high-risk or intermediate-risk PE when systemic thrombolysis has failed or as an alternative to systemic thrombolytic therapy.
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In patients with large proximal iliofemoral DVT, data from randomized controlled trials are conflicting on the benefit of catheter-directed thrombolysis in addition to treatment with anticoagulation; the CaVenT trial showed some reduction in risk of postthrombotic syndrome, but the larger ATTRACT trial failed to show reduction in postthrombotic syndrome but did find an increased risk of major bleeding.
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Chiasakul
T
et al. Thrombolytic therapy in acute venous thromboembolism. Hematology Am Soc Hematol Educ Program. 2020;2020:612.
[PubMed: 33275702]
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Hennemeyer
C
et al. Outcomes of catheter-directed therapy plus anticoagulation versus anticoagulation alone for submassive and massive pulmonary embolism. Am J Med. 2019;132:240.
[PubMed: 30367851]
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Kiser
TH
et al. Half-dose versus full-dose
alteplase for treatment of pulmonary embolism. Crit Care Med. 2018;46:1617.
[PubMed: 29979222]
+
Konstantinides
SV
et al. 2019 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2019;40:3453.
[PubMed: 31697840]
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Vedantham
S
et al; ATTRACT Trial Investigators. Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis. N Engl J Med. 2017;377:2240.
[PubMed: 29211671]
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F. Nonpharmacologic Therapy
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1. Graduated compression stockings
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Graduated compressions stockings may provide symptomatic relief to selected patients with ongoing swelling but do not reduce risk of postthrombotic syndrome at 6 months. They are contraindicated in patients with peripheral vascular disease.
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2. Inferior vena caval (IVC) filters
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There is a paucity of data to support the use of IVC filters for the prevention of PE in any clinical scenario. There are two randomized, controlled trials of IVC filters for prevention of PE. In the first study, patients with documented DVT received full- intensity, time-limited anticoagulation with or without placement of a permanent IVC filter. Patients with IVC filters had a lower rate of nonfatal asymptomatic PE at 12 days but an increased rate of DVT at 2 years. In the second study, patients with symptomatic PE and residual proximal DVT plus at least one additional risk factor for severity received full intensity anticoagulation with or without a retrievable IVC filter. IVC filter use did not reduce the risk of symptomatic recurrent PE at 3 months. Most experts agree with placement of an IVC filter in patients with acute proximal DVT and an absolute contraindication to anticoagulation despite lack of evidence to support this practice. While IVC filters were once commonly used to prevent VTE recurrence in the setting of anticoagulation failure, many experts now recommend switching to an alternative agent or increasing the intensity of the current anticoagulant regimen instead. The remainder of the indications (submassive/intermediate-risk PE, free-floating iliofemoral DVT, perioperative risk reduction) are controversial. If the contraindication to anticoagulation is temporary (active bleeding with subsequent resolution), placement of a retrievable IVC filter may be considered so that the device can be removed once anticoagulation has been started and has been shown to be tolerated. Rates of IVC filter retrieval are very low, often due to failure to arrange for its removal. Thus, if a device is placed, removal should be arranged at the time of device placement.
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Complications of IVC filters include local thrombosis, tilting, migration, fracture, and inability to retrieve the device. When considering placement of an IVC filter, it is best to consider both short- and long-term complications, since devices intended for removal may become permanent. To improve patient safety, institutions should develop systems that guide appropriate patient selection for IVC filter placement, tracking, and removal.
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Presence of large iliofemoral VTE, unprovoked upper extremity DVT, IVC thrombosis, portal vein thrombosis, or Budd-Chiari syndrome for consideration of catheter-directed thrombolysis.
High-risk PE for urgent embolectomy or catheter-directed therapies.
Intermediate-risk PE if considering thrombolysis.
History of HIT or prolonged PTT plus renal failure for alternative anticoagulation regimens.
Consideration of IVC filter placement.
Clots in unusual locations (eg, renal, hepatic, or cerebral vein), or simultaneous arterial and venous thrombosis, to assess possibility of a hypercoagulable state.
Recurrent VTE while receiving therapeutic anticoagulation.
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Documented or suspected intermediate- or high-risk PE, low-risk PE at high risk for bleeding, poor candidate for outpatient treatment.
DVT with poorly controlled pain, high bleeding risk, or concerns about follow-up.
Large iliofemoral DVT for consideration of thrombolysis.
Acute DVT and absolute contraindication to anticoagulation for IVC filter placement.
Venous thrombosis despite therapeutic anticoagulation.
Suspected Paget-Schroetter syndrome (spontaneous upper extremity thrombosis related to thoracic outlet syndrome).
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Bikdeli
B
et al. Systematic review of efficacy and safety of retrievable inferior vena caval filters. Thromb Res. 2018;165:79.
[PubMed: 29579576]
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Kahn
SR
et al; SOX trial investigators. Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet. 2014;383:880.
[PubMed: 24315521]
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Mismetti
P
et al; PREPIC2 Study Group. Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial. JAMA. 2015;313:1627.
[PubMed: 25919526]