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Deep Vein Thrombosis
Geno J. Merli
CHAPTER 60
DEEP VEIN THROMBOSIS: PROPHYLAXIS AND TREATMENT 1. What three primary factors promote venous thromboembolic disease? Development of venous thrombosis is promoted by the following (Virchow’s triad): • Venous blood stasis • Injury to the intimal layer of the venous vasculature • Abnormalities in coagulation or fibrinolysis
2. List the risk factors for thromboembolic disease. The numerous risk factors for thromboembolic disease include surgery, trauma, immobility, cancer, pregnancy, prolonged immobilization, estrogen-containing oral contraceptives or hormone replacement therapy, and acute medical illnesses. A more complete listing of these risk factors is given in Table 60.1. 3. What is the natural history of venous thrombosis? Resolution of fresh thrombi occurs by endogenous fibrinolysis and organization. Fibrinolysis results in actual clot dissolution. Organization reestablishes venous blood flow by reendothelializing and incorporating into the venous wall residual clot not dissolved by fibrinolysis. 4. Can patients with deep venous thrombosis be accurately diagnosed clinically? No. The clinical diagnosis of deep venous thrombosis is neither sensitive nor specific. Less than 50% of patients with confirmed deep venous thrombosis present with the classic symptoms and signs of deep vein thrombosis (DVT), which include pain, tenderness, redness, swelling, and Homan’s sign (calf pain with dorsiflexion of the foot). This sole use of clinical findings is artificial because clinicians Table 60.1. Risk Factors for Deep Venous Thromboembolism • Surgery • Trauma (major or lower extremity) • Immobility, lower extremity paresis • Cancer (active or occult) • Cancer therapy (hormonal, chemotherapy, angiogenesis inhibitors, or radiotherapy) • Venous compression (tumor, hematoma, arterial abnormality) • Previous history of thromboembolic disease • Obesity • Pregnancy and postpartum period • Prolonged immobilization • Lower extremity or pelvic trauma or surgery • Surgery with greater than 30 min of general anesthesia • Congestive heart failure • Nephrotic syndrome • Estrogen-containing oral contraceptives or hormone replacement therapy • Selective estrogen receptor modulators • Inflammatory bowel disease • Acute medical illness • Myeloproliferative disorders • Paroxysmal nocturnal hemoglobinuria • Central venous catheter • Inherited or acquired thrombophilia • Increasing age
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514 PART IX VENOUS THROMBOEMBOLIC DISEASE couple the medical and surgical history, concomitant medical problems, medications, and risk factors to decide on further testing to confirm DVT. 5. Where is the most common origin for thrombi that result in pulmonary emboli? Thrombosis in the deep veins of the lower extremities accounts for 90% to 95% of pulmonary emboli. Less common sites of origin include thrombosis in the right ventricle; in the upper extremity, prostatic, uterine, and renal veins; and, rarely, in superficial veins (Fig. 60.1). 6. How is the diagnosis of lower extremity deep vein thrombosis confirmed? Diagnostic evaluation of suspected DVT includes a clear correlation among clinical probability, test selection, and test interpretation. Contrast venography is no longer appropriate as the initial diagnostic test in patients exhibiting DVT symptoms, although it remains the gold standard for confirmatory diagnosis of DVT. It is nearly 100% sensitive and specific and provides the ability to investigate the distal and proximal venous system for thrombosis. Venography is still warranted when noninvasive testing is inconclusive or impossible to perform, but its use is no longer widespread because of the need to administer a contrast medium and the increased availability of noninvasive diagnostic strategies. Ultrasound is safe and noninvasive and has a higher specificity than impedance plethysmography for the evaluation of suspected DVT. With color-flow Doppler and compression ultrasound, DVT is diagnosed based on the inability to compress the common femoral and popliteal veins. In patients with lower extremity symptoms, the sensitivity is 95% and specificity 96%. The diagnostic accuracy of ultrasound in asymptomatic patients, those with recurrent DVT, or those with isolated calf DVT is less reliable. The sensitivity of ultrasound improves with serial testing in untreated patients. Repeat testing at 5 to 7 days will identify another 2% of patients with clots not apparent on the first ultrasound. Serial testing can be particularly valuable in ruling out proximal extension of a possible calf DVT. Because the accuracy of ultrasound in diagnosing calf DVT is acknowledged to be lower (81% for DVT below the knee vs. 99% for proximal DVT), follow-up ultrasounds at 5 to 7 days
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Fig. 60.1. Common sites of deep vein thrombosis (DVT) in the lower body. 1, Left iliac vein; 2, common femoral vein; 3, termination of deep femoral vein (profunda femoris); 4, femoral vein; 5, popliteal vein at adductor canal; 6, posterior tibial vein; 7, intramuscular veins of calf. (From Pfenninger, J. L., & Fowler, G. C. [2010]. Pfenninger and Fowler’s procedures of primary care [3rd ed.]. Philadelphia, PA: Saunders.)
Chapter 60 DEEP VEIN THROMBOSIS: PROPHYLAXIS AND TREATMENT 515 are reasonable, because most calf DVTs that extend proximally will do so within days of the initial presentation (Fig. 60.2). 7. When should prophylaxis of deep venous thrombosis be considered? Two factors must be weighed in deciding to initiate prophylaxis of deep venous thrombosis: the degree of risk for thrombosis and the risk of prophylaxis. The risk factors for deep venous thrombosis are cumulative. The primary risk of pharmacologic prophylaxis is hemorrhage, which is generally uncommon if no coagulation defects or lesions with bleeding potential exist.
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Fig. 60.2. Normal and abnormal compression of the femoral vein with ultrasound examination. Top images: Transverse image of the femoral artery (A) and vein (thin white arrow) before (Non Comp) and after (Comp) compression with the sonographic transducer, demonstrated normal vein collapse with compression. Bottom images: There is minimal compression of the common femoral vein (thick white arrow) in this patient with DVT. (Top images from Rumack, C. M., Wilson, S. R., Charboneau, J. W., & Levine, D. [2010]. Diagnostic ultrasound [4th ed.]. Philadelphia, PA: Mosby. Bottom images from Mason, R. J., Broaddus, V. C., Martin, T., King, T. E., Schraufnagel, D., Murray, J. F., et al. [2010]. Murray and Nadel’s textbook of respiratory medicine [5th ed.]. Philadelphia, PA: Saunders.)
516 PART IX VENOUS THROMBOEMBOLIC DISEASE 8. What prophylactic measures are available? Approaches to prophylaxis of DVT include antithrombotic drugs and pneumatic-compressive devices. Heparin, low-molecular-weight heparin (LMWH), fondaparinux, and warfarin are effective in preventing DVT. Subcutaneous heparin has been the mainstay of DVT prophylaxis with efficacy in multiple surgical and medical scenarios. The LMWHs have been shown to be as effective or superior to unfractionated heparin in different clinical circumstances. Warfarin dosing to maintain an international normalized ratio (INR) between 2 and 3 also poses a low risk of bleeding and is effective in patients with total hip arthroplasty, total knee arthroplasty, and hip fracture surgery. However, warfarin takes several days to develop a full antithrombotic effect. Antiplatelet drugs such as aspirin are not effective in DVT prophylaxis in the general medical population, but aspirin has been used with efficacy in the orthopedic surgery population. The two factor Xa inhibitors, rivaroxaban and apixaban, have been approved for venous thromboembolic (VTE) prophylaxis in total hip and knee arthroplasty, while the factor IIa inhibitor dabigatran has received approval only for VTE prophylaxis in total hip arthroplasty. Intermittent pneumatic-compressive devices effect prophylaxis by maintaining venous flow in the lower extremities and are especially efficacious in patients who cannot receive anticoagulant medications. Modalities available include compressive devices applied to the feet alone, covering the calves, or extending to the thighs. No version has been shown to provide superior prophylaxis. There has been concern that compression stockings used for prophylaxis may cause unintended skin trauma without substantial benefit. 9. What is the approach to deep vein thrombosis prophylaxis in the hospitalized, medically ill patient? The acutely ill medical patient admitted to the hospital with congestive heart failure or severe respiratory disease or who is confined to bed and has one or more additional risk factors (including active cancer, previous VTE, sepsis, acute neurologic disease, or inflammatory bowel disease) should receive DVT prophylaxis with the following agents: • Unfractionated heparin: 5000 U subcutaneously (SC) every 8 or 12 hours • LMWH: Dalteparin 5000 IU SC every 24 hours or enoxaparin 40 mg SC every 24 hours • Fondaparinux: 2.5 mg SC every 24 hours 10. Should patients undergoing surgery receive deep vein thrombosis prophylaxis based on specific recommendations for each respective procedure? Yes. Most surgical procedures have defined recommendations for preventing DVT in the postoperative period if age and other clinical comorbidities demonstrate an elevated risk based upon risk assessment models such as that of the Rogers or Caprini score. The various prophylaxis regimens for different surgical procedures are listed in Table 60.2. 11. Are there specific surgical groups that require extended deep vein thrombosis prophylaxis following hospital discharge? • For a patient undergoing total hip replacement, total knee replacement, and hip fracture surgery, extended DVT prophylaxis is recommended for up to 35 days after surgery with LMWH, unfractionated heparin, fondaparinux, warfarin, rivaroxaban, apixaban, dabigatran, or acetylsalicylic acid (ASA). • For selected high-risk general surgery patients undergoing major cancer surgery or who have previously had venous thromboembolism, it is recommended that DVT prophylaxis be continued with LMWH: enoxaparin 40 mg SC every 24 hours or dalteparin 5000 IU SC every 24 hours for 35 days. 12. What treatment regimens are available for the treatment of deep vein thrombosis? Several treatment regimens using unfractionated heparin (UFH), an LMWH, or a direct oral anticoagulant (DOAC) are available for the treatment of DVT. These are listed in Table 60.3. 13. Which low-molecular-weight heparins are renally excreted? All the LMWHs are renally excreted. Enoxaparin is the only LMWH that has a recommended dose for creatinine clearance less than 30 mL/min (1 mg/kg SC every 24 hours). All other LMWHs listed here should not be used with creatinine clearance less than 30 mL/min. 14. When should warfarin be started in the treatment regimens for deep vein thrombosis listed earlier? Older dosing protocols proposed a delay in warfarin administration, but this only prolongs the therapeutic onset of warfarin and may extend the hospitalization. Given the long period until therapeutic benefit, warfarin should be given on the first day of treatment with UFH or an LMWH
Chapter 60 DEEP VEIN THROMBOSIS: PROPHYLAXIS AND TREATMENT 517 Table 60.2. Deep Vein Thrombosis Prophylaxis Regimens for Various Surgeries General/Urologic/Gastrointestinal/Gynecologic/Bariatric/Vascular/Plastic/ Reconstructive Surgery The following regimens are for patients undergoing major surgical procedures for benign or malignant disease and associated DVT risk factors: • Unfractionated heparin: 5000 U SC q8h • LMWH: Enoxaparin 40 mg SC q24h, dalteparin 5000 IU SC q24h • External pneumatic compression sleeves plus one of the above regimens • Fondaparinux 2.5 mg SC q24h can be considered for patients with a history of heparin-associated thrombocytopenia. • Roux-en-Y gastric bypass: BMI <50 kg/m2 40 mg SC q12h,BMI >50 kg/m2 60 mg SC q12h Orthopedic Surgery The following regimens are for patients undergoing orthopedic surgery: Total Hip/Knee Surgery • LMWH: Enoxaparin SC 40 mg qday as dose option, enoxaparin 30 mg SC q12h, dalteparin 5000 IU SC q24h • Unfractionated heparin: 5000 U SC q8h • Fondaparinux 2.5 mg SC q24h • Rivaroxaban 10 mg q24h Dabigatran 220 mg every 24 h (initiation of first dose 24 h postoperatively)— approved in the United States only for total hip arthroplasty • Aspirin (optimal dosing not universally agreed upon) • Warfarin 5 mg on the evening of surgery, then adjust dose to achieve an INR of 2 to 3 • Intermittent pneumatic compression devices Hip Fracture • LMWH: Enoxaparin 40 mg SC qday as dose option, enoxaparin 30 mg SC q12h, dalteparin 5000 IU SC q24h • Unfractionated heparin: 5000 U SC q8h • Fondaparinux 2.5 mg SC q24h • Αspirin (optimal dosing not universally agreed upon) • Warfarin 5 mg on the evening of surgery, then adjust dose to achieve an INR of 2 to 3 • Intermittent pneumatic compression devices Neurosurgery The following regimens are for patients undergoing neurosurgery: • External pneumatic compression sleeves are the prophylaxis of choice. • Combination therapy with either unfractionated heparin (5000 U SC q8h or q12h) or LMWH (enoxaparin 40 mg SC q24h) can be used, Coronary Artery Bypass Surgery The following regimens are for patients undergoing coronary artery bypass surgery: • LMWH (preferred over unfractionated heparin): enoxaparin 40 mg SC q24h or dalteparin 5000 IU SC q24h • Unfractionated heparin: 5000 U SC q8h • Fondaparinux 2.5 mg SC q24h for patients with history of heparin-induced thrombocytopenia • External pneumatic compression sleeves for high-bleeding-risk patients DVT, Deep vein thrombosis; INR, international normalized ratio; LMWH, low-molecular-weight heparin.
to minimize the period of bridging anticoagulation. Warfarin dosing need not wait until the day of discharge, as this may mean costly bridging therapy for the patient as an outpatient. The usual dose is 5 to 10 mg daily. 15. Can the international normalized ratio in patients treated with warfarin be influenced by food and drug intake? Yes. Warfarin is influenced by numerous medications and dietary components. INR monitoring must be vigilant when medication and dietary changes occur. Foods rich in vitamin K, such as leafy green
518 PART IX VENOUS THROMBOEMBOLIC DISEASE Table 60.3. Regimens for the Treatment of Deep Vein Thrombosis Unfractionated Heparin • Administer intravenous bolus of UFH (80 U/kg or 5000 U) followed by continuous infusion of 18 U/kg per hour or 1300 U/h. The activated partial thromboplastin time (APTT) is checked q6h to adjust the infusion to achieve the therapeutic aPTT of the hospital laboratory. • Subcutaneous UFH at 333 U/kg is the initial dose, followed in 12 h by 250 U/kg SC q12h. Monitoring of the APTT is not necessary. Low-Molecular-Weight Heparin • Enoxaparin 1 mg/kg SC q12 h or 1.5 mg/kg SC q24h • Dalteparin 200 IU/kg SC q24h • Tinzaparin 175 IU/kg SC q24h Fondaparinux • Fondaparinux dosed by weight range: Less than 50 kg, 5 mg SC; 50 to 100 kg, 7.5 mg SC q24h; more than 100 kg, 10 mg SC q24h Oral Anti-Xa Inhibitors • Rivaroxaban 15 mg q12h for 21 days; then 20 mg/d to complete 3 or 6 months of treatment • Apixaban 10 mg q12h for 7 days; then 5 mg q12h to complete 3 to 6 months of treatment • Edoxaban: This agent is initiated only after 5 to 10 days of therapeutic LMWH or IV UFH at the following schedule: 60 mg q24h for 3 to 6 months. Do not use this agent if the creatinine clearance is greater than 95 mL/min. Oral Anti-IIa Inhibitor • Dabigatran 150 mg q12h for 3 to 6 months. This agent is initiated only after 5 to 10 days of therapeutic LMWH or IV UFH at the following schedule: 150 mg q12h for 3 to 6 months. aPTT, Activated partial thromboplastin time.
vegetables, will lower the INR level and diminish the anticoagulant effect of warfarin. Medications such as erythromycin and phenytoin may increase the serum concentration of warfarin, which can increase bleeding risk. Substances such as ginkgo biloba and cranberry juice may also increase the risk of bleeding in combination with warfarin. A full medication inventory including that of supplements is essential to reducing complications associated with the use of vitamin K antagonists (VKAs). Antiplatelet agents have an anticoagulant effect that enhances the bleeding risk associated with warfarin use. 16. When should these therapeutic regimens for treating deep vein thrombosis be discontinued and warfarin remain as the sole therapy? These therapies must be used for at least 5 days and until the INR is between 2 and 3 for 2 consecutive days. 17. What is the target international normalized ratio for treating patients with deep vein thrombosis? The target INR for the treatment of DVT to prevent recurrent disease is 2 to 3. 18. How long should patients with acute deep vein thrombosis be treated with warfarin? For patients with DVT secondary to a transient risk factor, 3 months of warfarin is appropriate. Unprovoked (previously called “idiopathic”) proximal DVT in patients without risk factors for bleeding should receive long-term warfarin therapy with a target INR of 2 to 3. Patients with DVT and cancer should receive LMWH for 3 to 6 months as the initial approach to management and long-term treatment with either warfarin or LMWH until the cancer is resolved or in remission. 19. Does thrombosis of the great saphenous vein usually require full-dose anticoagulation? The great saphenous vein is a superficial vein, not a deep vein. Full-dose anticoagulation is usually not required if the area of superficial phlebitis is not near the common femoral junction. The American College of Chest Physicians (ACCP) has recommended that greater saphenous vein thrombosis that is
Chapter 60 DEEP VEIN THROMBOSIS: PROPHYLAXIS AND TREATMENT 519 greater than 5 cm in length should receive treatment with fondaparinux 2.5 mg daily, enoxaparin 40 mg daily, or dalteparin 5000 U daily for 6 weeks. 20. What is the currently preferred name for the superficial femoral vein? The femoral vein. The superficial femoral vein has been reclassified as the femoral vein because of how often with its former name it was mistakenly thought to be a superficial vein. 21. When can patients with acute deep vein thrombosis ambulate? Patients can ambulate with acute DVT and should not be placed on bed rest unless the lower extremity is painful and cannot bear weight. 22. Can patients with acute deep vein thrombosis be treated as outpatients? Yes. The LMWH and DOAC regimens listed here can be used to treat patients in the outpatient setting. The same principles of management should be followed using these agents as with inpatient treatment. 23. When should catheter-directed thrombolysis be used to treat acute deep vein thrombosis? In selected patients with extensive acute proximal iliofemoral DVT where symptoms have been present for less than 14 days—patients who are functionally active and who have a low bleeding risk—the use of pharmacomechanical thrombolysis is recommended if the appropriate expertise and resources are available. 24. Are inferior vena caval filters indicated for the initial treatment of acute deep vein thrombosis? No. Vena caval filters are indicated when the patient cannot receive anticoagulation for the treatment of acute DVT. In certain cases (temporary contraindication to anticoagulant therapy), retrievable vena caval filters have been placed, with the intention of removing them within a defined time (based on the specific filter), after which anticoagulation therapy could be reinstituted. 25. When are gradient elastic stockings recommended as part of the treatment of acute deep vein thrombosis? For patients with symptomatic DVT the use of gradient elastic stockings with an ankle pressure of 30 to 40 mm Hg is recommended. The pressure may not be tolerated because of the degree of lower extremity edema. Elastic bandages may be used because they can be adjusted to control swelling and the pain associated with increased external pressure. The elastic bandages can be used initially, but as the swelling recedes, gradient elastic stockings at 20 to 30 or 30 to 40 mm Hg may be applied. 26. When is a low-intensity international normalized ratio indicated for the treatment of deep vein thrombosis? For patients with idiopathic (unprovoked) DVT who have a strong preference for less frequent INR testing to monitor their therapy, it is recommended that after the first 3 months of therapy lowintensity therapy at an INR of 1.5 to 1.9 with less frequent INR monitoring be employed instead of stopping warfarin anticoagulation. 27. Can direct oral anticoagulants be used for extended treatment of deep vein thrombosis? Yes. The following DOACs have been approved for extended treatment of DVT after the initial 3 to 6 months of therapy: • Rivaroxaban 20 mg every day • Apixaban 2.5 mg every 12 hours • Dabigatran 150 mg every 12 hours Recommendations on short- and long-term DVT treatment from the ACCP are summarized in Table 60.4. 28. Should compression ultrasound be used at the time of discharge as routine screening in the patient who has undergone total joint replacement surgery? Asymptomatic patients who have undergone joint replacement surgery should not have compression ultrasound on discharge as a screening test for DVT because the ultrasound is not as sensitive and specific in asymptomatic patients. Appropriate DVT prophylaxis should be the approach to management.
520 PART IX VENOUS THROMBOEMBOLIC DISEASE Table 60.4. Summary of the 2016 American College of Clinical Pharmacy Recommendations on Antithrombotic Therapy for Venous Thromboembolism Choice of Long-Term (First 3 Months) and Extended (No Scheduled Stop Date) Anticoagulant Treatment • In patients with proximal DVT or PE, we recommend long-term (3-month) anticoagulant therapy over no such therapy. • In patients with DVT of the leg and no cancer, we suggest dabigatran, rivaroxaban, apixaban, or edoxaban as long-term (first 3 months) anticoagulant therapy over VKA therapy. • For patients with DVT of the leg or PE and no cancer who are not treated with dabigatran, rivaroxaban, apixaban, or edoxaban, we suggest VKA therapy over LMWH. • In patients with DVT of the leg or PE and cancer (“cancer-associated thrombosis”), we suggest LMWH as long-term (first 3 months) anticoagulant therapy over VKA therapy, dabigatran, rivaroxaban, apixaban, or edoxaban. • In patients with DVT of the leg or PE who receive extended therapy, we suggest that there is no need to change the choice of anticoagulant after the first 3 months. Duration of Anticoagulant Therapy • In patients with a proximal DVT of the leg or PE provoked by surgery, we recommend treatment with anticoagulation for 3 months over (i) treatment for a shorter period (grade 1B), (ii) treatment for a longer time-limited period (e.g., 6, 12, or 24 months), or (iii) extended therapy (no scheduled stop date). • In patients with a proximal DVT of the leg or PE provoked by a nonsurgical transient risk factor, we recommend treatment with anticoagulation for 3 months over (i) treatment for a shorter period (grade 1B) or (ii) treatment for a longer time-limited period (e.g., 6, 12, or 24 months) (grade 1B). We suggest treatment with anticoagulation for 3 months over extended therapy if there is a low or moderate bleeding risk (grade 2B) and recommend treatment for 3 months over extended therapy if there is a high risk of bleeding. • In patients with an isolated distal DVT of the leg provoked by surgery or by a nonsurgical transient risk factor, we suggest treatment with anticoagulation for 3 months over treatment for a shorter period (grade 2C). We recommend treatment with anticoagulation for 3 months over treatment for a longer time-limited period (e.g., 6, 12, or 24 months) (grade 1B), and we recommend treatment with anticoagulation for 3 months over extended therapy (no scheduled stop date). • In patients with an unprovoked DVT of the leg (isolated distal or proximal) or PE, we recommend treatment with anticoagulation for at least 3 months over treatment for a shorter period (grade 1B), and we recommend treatment with anticoagulation for 3 months over treatment of a longer timelimited period (e.g., 6, 12, or 24 months). • In patients with a first VTE that is an unprovoked proximal DVT of the leg or PE and who have a (i) low or moderate bleeding risk (see the text), we suggest extended anticoagulant therapy (no scheduled stop date) for 3 months (grade 2B). For patients with a (ii) high bleeding risk (see the text), we recommend 3 months of anticoagulant therapy over extended therapy (no scheduled stop date). • For patients with a second unprovoked VTE who have a (i) low bleeding risk (see the text), we recommend extended anticoagulant therapy (no scheduled stop date) for 3 months (grade 1B); for those with a (ii) moderate bleeding risk (see the text), we suggest extended anticoagulant therapy for 3 months (grade 2B); and for patients with a (iii) high bleeding risk (see the text), we suggest 3 months of anticoagulant therapy over extended therapy (no scheduled stop date). • For patients with DVT of the leg or PE and active cancer (“cancer-associated thrombosis”) who (i) do not have a high bleeding risk, we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months (grade 1B) or those who (ii) have a high bleeding risk, we suggest extended anticoagulant therapy (no scheduled stop date) for 3 months. DVT, Deep vein thrombosis; LMWH, low-molecular-weight heparin; PE, pulmonary embolism; VKA, vitamin K antagonist; VTE, venous thromboembolic. Adapted from Kearon, C., Akl, E. A., Ornelas, J., Blaivas, A., Jimenez, D., Bounameaux, H., et al. (2016). Antithrombotic therapy for VTE disease CHEST guideline and expert panel report. Chest, 149(2),315–352.
Chapter 60 DEEP VEIN THROMBOSIS: PROPHYLAXIS AND TREATMENT 521 Bibliography, Suggested Readings, and Websites British Thoracic Society Standards of Care Committee Pulmonary Embolism Guideline Development Group. (2003). British Thoracic Society guidelines for the management of suspected acute pulmonary embolism. Thorax, 58 (6), 470–483. Decousus, H., Leizorovicz, A., Parent, F., Page, Y., Tardy, B., Girard, P., et al. (1998). A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. New England Journal of Medicine, 338, 409–415. Falck-Ytter, Y., Francis, C. W., Johanson, N. A., Curley, C., Dahl, O. E., Schulman, S., et al. (2012). 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, 141(Suppl. 2), e278S–e325S. Gould, M. K., Garcia, D. A., Wren, S. M., Karanicolas, P. J., Arcelus, J. I., Heit, J. A., et al. (2012). 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, 141 (Suppl. 2), e227S–e277S. Kahn, S. R., Lim, W., Dunn, A. S., Cushman, M., Dentali, F., Akl, E. A., et al. (2012). 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, 141(Suppl. 2), e195S–e226S. Kearon, C., Akl, E. A., Ornelas, J., Blaivas, A., Jimenez, D., Bounameaux, H., et al. (2016). Antithrombotic therapy for VTE disease CHEST guideline and expert panel report. Chest, 149(2), 315–352. Kearon, C., Ginsberg, J. S., Julian, J. A., Douketis, J., Solymoss, S., Ockelford, P., et al. (2006). Comparison of fixed-dose weight adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. Journal of the American Medical Association, 296, 935–942. Koopman, M. M., Prandoni, P., Piovella, F., Ockelford, P. A., Brandjes, D. P., van der Meer, J., et al. (1996). Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. New England Journal of Medicine, 334, 682–687. Levine, M., Gent, M., Hirsh, J., Leclerc, J., Anderson, D., Weitz, J., et al. (1996). A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep vein thrombosis. New England Journal of Medicine, 334, 677–681. Mechanick, J. I., Youdim, A., Jones, D., et al. (2013). Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric patient—2013 update. Obesity, 21(Suppl.), S1–S27. Merli, G. J. (2008). Pathophysiology of venous thrombosis and the diagnosis of deep vein thrombosis-pulmonary embolism in the elderly. Cardiology Clinics, 26, 203–219. Merli, G., Spiro, T., Olsson, C. G., Abildgaard, U., Davidson, B. L., Eldor, A., et al. (2001). Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. Annals of Internal Medicine, 134, 191–202. Nicolaides, A. N., Fareed, J., Kakkar, A. K., & Breddin, H. K. (2006). Prevention and treatment of venous thromboembolism. International consensus statement (guidelines according to scientific evidence). International Angiology, 25 (2), 101–161. Snow, V., Qaseem, A., Barry, P., Hornbake, E. R., Rodnick, J. E., Tobolic, T., et al. (2007). Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Annals of Internal Medicine, 146 (3), 204–210. The Matisse Investigators. (2003). Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. New England Journal of Medicine, 349, 1695–1702. Wells, P. S., Anderson, D. R., Rodger, M. A., Forgie, M. A., Florack, P., Touchie, D., et al. (2005). A randomized trial comparing two low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism. Archives of Internal Medicine, 165, 733–738.
CHAPTER 60
DEEP VEIN THROMBOSIS: PROPHYLAXIS AND TREATMENT 1. What three primary factors promote venous thromboembolic disease? Development of venous thrombosis is promoted by the following (Virchow’s triad): • Venous blood stasis • Injury to the intimal layer of the venous vasculature • Abnormalities in coagulation or fibrinolysis
2. List the risk factors for thromboembolic disease. The numerous risk factors for thromboembolic disease include surgery, trauma, immobility, cancer, pregnancy, prolonged immobilization, estrogen-containing oral contraceptives or hormone replacement therapy, and acute medical illnesses. A more complete listing of these risk factors is given in Table 60.1. 3. What is the natural history of venous thrombosis? Resolution of fresh thrombi occurs by endogenous fibrinolysis and organization. Fibrinolysis results in actual clot dissolution. Organization reestablishes venous blood flow by reendothelializing and incorporating into the venous wall residual clot not dissolved by fibrinolysis. 4. Can patients with deep venous thrombosis be accurately diagnosed clinically? No. The clinical diagnosis of deep venous thrombosis is neither sensitive nor specific. Less than 50% of patients with confirmed deep venous thrombosis present with the classic symptoms and signs of deep vein thrombosis (DVT), which include pain, tenderness, redness, swelling, and Homan’s sign (calf pain with dorsiflexion of the foot). This sole use of clinical findings is artificial because clinicians Table 60.1. Risk Factors for Deep Venous Thromboembolism • Surgery • Trauma (major or lower extremity) • Immobility, lower extremity paresis • Cancer (active or occult) • Cancer therapy (hormonal, chemotherapy, angiogenesis inhibitors, or radiotherapy) • Venous compression (tumor, hematoma, arterial abnormality) • Previous history of thromboembolic disease • Obesity • Pregnancy and postpartum period • Prolonged immobilization • Lower extremity or pelvic trauma or surgery • Surgery with greater than 30 min of general anesthesia • Congestive heart failure • Nephrotic syndrome • Estrogen-containing oral contraceptives or hormone replacement therapy • Selective estrogen receptor modulators • Inflammatory bowel disease • Acute medical illness • Myeloproliferative disorders • Paroxysmal nocturnal hemoglobinuria • Central venous catheter • Inherited or acquired thrombophilia • Increasing age
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514 PART IX VENOUS THROMBOEMBOLIC DISEASE couple the medical and surgical history, concomitant medical problems, medications, and risk factors to decide on further testing to confirm DVT. 5. Where is the most common origin for thrombi that result in pulmonary emboli? Thrombosis in the deep veins of the lower extremities accounts for 90% to 95% of pulmonary emboli. Less common sites of origin include thrombosis in the right ventricle; in the upper extremity, prostatic, uterine, and renal veins; and, rarely, in superficial veins (Fig. 60.1). 6. How is the diagnosis of lower extremity deep vein thrombosis confirmed? Diagnostic evaluation of suspected DVT includes a clear correlation among clinical probability, test selection, and test interpretation. Contrast venography is no longer appropriate as the initial diagnostic test in patients exhibiting DVT symptoms, although it remains the gold standard for confirmatory diagnosis of DVT. It is nearly 100% sensitive and specific and provides the ability to investigate the distal and proximal venous system for thrombosis. Venography is still warranted when noninvasive testing is inconclusive or impossible to perform, but its use is no longer widespread because of the need to administer a contrast medium and the increased availability of noninvasive diagnostic strategies. Ultrasound is safe and noninvasive and has a higher specificity than impedance plethysmography for the evaluation of suspected DVT. With color-flow Doppler and compression ultrasound, DVT is diagnosed based on the inability to compress the common femoral and popliteal veins. In patients with lower extremity symptoms, the sensitivity is 95% and specificity 96%. The diagnostic accuracy of ultrasound in asymptomatic patients, those with recurrent DVT, or those with isolated calf DVT is less reliable. The sensitivity of ultrasound improves with serial testing in untreated patients. Repeat testing at 5 to 7 days will identify another 2% of patients with clots not apparent on the first ultrasound. Serial testing can be particularly valuable in ruling out proximal extension of a possible calf DVT. Because the accuracy of ultrasound in diagnosing calf DVT is acknowledged to be lower (81% for DVT below the knee vs. 99% for proximal DVT), follow-up ultrasounds at 5 to 7 days
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Fig. 60.1. Common sites of deep vein thrombosis (DVT) in the lower body. 1, Left iliac vein; 2, common femoral vein; 3, termination of deep femoral vein (profunda femoris); 4, femoral vein; 5, popliteal vein at adductor canal; 6, posterior tibial vein; 7, intramuscular veins of calf. (From Pfenninger, J. L., & Fowler, G. C. [2010]. Pfenninger and Fowler’s procedures of primary care [3rd ed.]. Philadelphia, PA: Saunders.)
Chapter 60 DEEP VEIN THROMBOSIS: PROPHYLAXIS AND TREATMENT 515 are reasonable, because most calf DVTs that extend proximally will do so within days of the initial presentation (Fig. 60.2). 7. When should prophylaxis of deep venous thrombosis be considered? Two factors must be weighed in deciding to initiate prophylaxis of deep venous thrombosis: the degree of risk for thrombosis and the risk of prophylaxis. The risk factors for deep venous thrombosis are cumulative. The primary risk of pharmacologic prophylaxis is hemorrhage, which is generally uncommon if no coagulation defects or lesions with bleeding potential exist.
A A
Non comp
Comp
Fig. 60.2. Normal and abnormal compression of the femoral vein with ultrasound examination. Top images: Transverse image of the femoral artery (A) and vein (thin white arrow) before (Non Comp) and after (Comp) compression with the sonographic transducer, demonstrated normal vein collapse with compression. Bottom images: There is minimal compression of the common femoral vein (thick white arrow) in this patient with DVT. (Top images from Rumack, C. M., Wilson, S. R., Charboneau, J. W., & Levine, D. [2010]. Diagnostic ultrasound [4th ed.]. Philadelphia, PA: Mosby. Bottom images from Mason, R. J., Broaddus, V. C., Martin, T., King, T. E., Schraufnagel, D., Murray, J. F., et al. [2010]. Murray and Nadel’s textbook of respiratory medicine [5th ed.]. Philadelphia, PA: Saunders.)
516 PART IX VENOUS THROMBOEMBOLIC DISEASE 8. What prophylactic measures are available? Approaches to prophylaxis of DVT include antithrombotic drugs and pneumatic-compressive devices. Heparin, low-molecular-weight heparin (LMWH), fondaparinux, and warfarin are effective in preventing DVT. Subcutaneous heparin has been the mainstay of DVT prophylaxis with efficacy in multiple surgical and medical scenarios. The LMWHs have been shown to be as effective or superior to unfractionated heparin in different clinical circumstances. Warfarin dosing to maintain an international normalized ratio (INR) between 2 and 3 also poses a low risk of bleeding and is effective in patients with total hip arthroplasty, total knee arthroplasty, and hip fracture surgery. However, warfarin takes several days to develop a full antithrombotic effect. Antiplatelet drugs such as aspirin are not effective in DVT prophylaxis in the general medical population, but aspirin has been used with efficacy in the orthopedic surgery population. The two factor Xa inhibitors, rivaroxaban and apixaban, have been approved for venous thromboembolic (VTE) prophylaxis in total hip and knee arthroplasty, while the factor IIa inhibitor dabigatran has received approval only for VTE prophylaxis in total hip arthroplasty. Intermittent pneumatic-compressive devices effect prophylaxis by maintaining venous flow in the lower extremities and are especially efficacious in patients who cannot receive anticoagulant medications. Modalities available include compressive devices applied to the feet alone, covering the calves, or extending to the thighs. No version has been shown to provide superior prophylaxis. There has been concern that compression stockings used for prophylaxis may cause unintended skin trauma without substantial benefit. 9. What is the approach to deep vein thrombosis prophylaxis in the hospitalized, medically ill patient? The acutely ill medical patient admitted to the hospital with congestive heart failure or severe respiratory disease or who is confined to bed and has one or more additional risk factors (including active cancer, previous VTE, sepsis, acute neurologic disease, or inflammatory bowel disease) should receive DVT prophylaxis with the following agents: • Unfractionated heparin: 5000 U subcutaneously (SC) every 8 or 12 hours • LMWH: Dalteparin 5000 IU SC every 24 hours or enoxaparin 40 mg SC every 24 hours • Fondaparinux: 2.5 mg SC every 24 hours 10. Should patients undergoing surgery receive deep vein thrombosis prophylaxis based on specific recommendations for each respective procedure? Yes. Most surgical procedures have defined recommendations for preventing DVT in the postoperative period if age and other clinical comorbidities demonstrate an elevated risk based upon risk assessment models such as that of the Rogers or Caprini score. The various prophylaxis regimens for different surgical procedures are listed in Table 60.2. 11. Are there specific surgical groups that require extended deep vein thrombosis prophylaxis following hospital discharge? • For a patient undergoing total hip replacement, total knee replacement, and hip fracture surgery, extended DVT prophylaxis is recommended for up to 35 days after surgery with LMWH, unfractionated heparin, fondaparinux, warfarin, rivaroxaban, apixaban, dabigatran, or acetylsalicylic acid (ASA). • For selected high-risk general surgery patients undergoing major cancer surgery or who have previously had venous thromboembolism, it is recommended that DVT prophylaxis be continued with LMWH: enoxaparin 40 mg SC every 24 hours or dalteparin 5000 IU SC every 24 hours for 35 days. 12. What treatment regimens are available for the treatment of deep vein thrombosis? Several treatment regimens using unfractionated heparin (UFH), an LMWH, or a direct oral anticoagulant (DOAC) are available for the treatment of DVT. These are listed in Table 60.3. 13. Which low-molecular-weight heparins are renally excreted? All the LMWHs are renally excreted. Enoxaparin is the only LMWH that has a recommended dose for creatinine clearance less than 30 mL/min (1 mg/kg SC every 24 hours). All other LMWHs listed here should not be used with creatinine clearance less than 30 mL/min. 14. When should warfarin be started in the treatment regimens for deep vein thrombosis listed earlier? Older dosing protocols proposed a delay in warfarin administration, but this only prolongs the therapeutic onset of warfarin and may extend the hospitalization. Given the long period until therapeutic benefit, warfarin should be given on the first day of treatment with UFH or an LMWH
Chapter 60 DEEP VEIN THROMBOSIS: PROPHYLAXIS AND TREATMENT 517 Table 60.2. Deep Vein Thrombosis Prophylaxis Regimens for Various Surgeries General/Urologic/Gastrointestinal/Gynecologic/Bariatric/Vascular/Plastic/ Reconstructive Surgery The following regimens are for patients undergoing major surgical procedures for benign or malignant disease and associated DVT risk factors: • Unfractionated heparin: 5000 U SC q8h • LMWH: Enoxaparin 40 mg SC q24h, dalteparin 5000 IU SC q24h • External pneumatic compression sleeves plus one of the above regimens • Fondaparinux 2.5 mg SC q24h can be considered for patients with a history of heparin-associated thrombocytopenia. • Roux-en-Y gastric bypass: BMI <50 kg/m2 40 mg SC q12h,BMI >50 kg/m2 60 mg SC q12h Orthopedic Surgery The following regimens are for patients undergoing orthopedic surgery: Total Hip/Knee Surgery • LMWH: Enoxaparin SC 40 mg qday as dose option, enoxaparin 30 mg SC q12h, dalteparin 5000 IU SC q24h • Unfractionated heparin: 5000 U SC q8h • Fondaparinux 2.5 mg SC q24h • Rivaroxaban 10 mg q24h Dabigatran 220 mg every 24 h (initiation of first dose 24 h postoperatively)— approved in the United States only for total hip arthroplasty • Aspirin (optimal dosing not universally agreed upon) • Warfarin 5 mg on the evening of surgery, then adjust dose to achieve an INR of 2 to 3 • Intermittent pneumatic compression devices Hip Fracture • LMWH: Enoxaparin 40 mg SC qday as dose option, enoxaparin 30 mg SC q12h, dalteparin 5000 IU SC q24h • Unfractionated heparin: 5000 U SC q8h • Fondaparinux 2.5 mg SC q24h • Αspirin (optimal dosing not universally agreed upon) • Warfarin 5 mg on the evening of surgery, then adjust dose to achieve an INR of 2 to 3 • Intermittent pneumatic compression devices Neurosurgery The following regimens are for patients undergoing neurosurgery: • External pneumatic compression sleeves are the prophylaxis of choice. • Combination therapy with either unfractionated heparin (5000 U SC q8h or q12h) or LMWH (enoxaparin 40 mg SC q24h) can be used, Coronary Artery Bypass Surgery The following regimens are for patients undergoing coronary artery bypass surgery: • LMWH (preferred over unfractionated heparin): enoxaparin 40 mg SC q24h or dalteparin 5000 IU SC q24h • Unfractionated heparin: 5000 U SC q8h • Fondaparinux 2.5 mg SC q24h for patients with history of heparin-induced thrombocytopenia • External pneumatic compression sleeves for high-bleeding-risk patients DVT, Deep vein thrombosis; INR, international normalized ratio; LMWH, low-molecular-weight heparin.
to minimize the period of bridging anticoagulation. Warfarin dosing need not wait until the day of discharge, as this may mean costly bridging therapy for the patient as an outpatient. The usual dose is 5 to 10 mg daily. 15. Can the international normalized ratio in patients treated with warfarin be influenced by food and drug intake? Yes. Warfarin is influenced by numerous medications and dietary components. INR monitoring must be vigilant when medication and dietary changes occur. Foods rich in vitamin K, such as leafy green
518 PART IX VENOUS THROMBOEMBOLIC DISEASE Table 60.3. Regimens for the Treatment of Deep Vein Thrombosis Unfractionated Heparin • Administer intravenous bolus of UFH (80 U/kg or 5000 U) followed by continuous infusion of 18 U/kg per hour or 1300 U/h. The activated partial thromboplastin time (APTT) is checked q6h to adjust the infusion to achieve the therapeutic aPTT of the hospital laboratory. • Subcutaneous UFH at 333 U/kg is the initial dose, followed in 12 h by 250 U/kg SC q12h. Monitoring of the APTT is not necessary. Low-Molecular-Weight Heparin • Enoxaparin 1 mg/kg SC q12 h or 1.5 mg/kg SC q24h • Dalteparin 200 IU/kg SC q24h • Tinzaparin 175 IU/kg SC q24h Fondaparinux • Fondaparinux dosed by weight range: Less than 50 kg, 5 mg SC; 50 to 100 kg, 7.5 mg SC q24h; more than 100 kg, 10 mg SC q24h Oral Anti-Xa Inhibitors • Rivaroxaban 15 mg q12h for 21 days; then 20 mg/d to complete 3 or 6 months of treatment • Apixaban 10 mg q12h for 7 days; then 5 mg q12h to complete 3 to 6 months of treatment • Edoxaban: This agent is initiated only after 5 to 10 days of therapeutic LMWH or IV UFH at the following schedule: 60 mg q24h for 3 to 6 months. Do not use this agent if the creatinine clearance is greater than 95 mL/min. Oral Anti-IIa Inhibitor • Dabigatran 150 mg q12h for 3 to 6 months. This agent is initiated only after 5 to 10 days of therapeutic LMWH or IV UFH at the following schedule: 150 mg q12h for 3 to 6 months. aPTT, Activated partial thromboplastin time.
vegetables, will lower the INR level and diminish the anticoagulant effect of warfarin. Medications such as erythromycin and phenytoin may increase the serum concentration of warfarin, which can increase bleeding risk. Substances such as ginkgo biloba and cranberry juice may also increase the risk of bleeding in combination with warfarin. A full medication inventory including that of supplements is essential to reducing complications associated with the use of vitamin K antagonists (VKAs). Antiplatelet agents have an anticoagulant effect that enhances the bleeding risk associated with warfarin use. 16. When should these therapeutic regimens for treating deep vein thrombosis be discontinued and warfarin remain as the sole therapy? These therapies must be used for at least 5 days and until the INR is between 2 and 3 for 2 consecutive days. 17. What is the target international normalized ratio for treating patients with deep vein thrombosis? The target INR for the treatment of DVT to prevent recurrent disease is 2 to 3. 18. How long should patients with acute deep vein thrombosis be treated with warfarin? For patients with DVT secondary to a transient risk factor, 3 months of warfarin is appropriate. Unprovoked (previously called “idiopathic”) proximal DVT in patients without risk factors for bleeding should receive long-term warfarin therapy with a target INR of 2 to 3. Patients with DVT and cancer should receive LMWH for 3 to 6 months as the initial approach to management and long-term treatment with either warfarin or LMWH until the cancer is resolved or in remission. 19. Does thrombosis of the great saphenous vein usually require full-dose anticoagulation? The great saphenous vein is a superficial vein, not a deep vein. Full-dose anticoagulation is usually not required if the area of superficial phlebitis is not near the common femoral junction. The American College of Chest Physicians (ACCP) has recommended that greater saphenous vein thrombosis that is
Chapter 60 DEEP VEIN THROMBOSIS: PROPHYLAXIS AND TREATMENT 519 greater than 5 cm in length should receive treatment with fondaparinux 2.5 mg daily, enoxaparin 40 mg daily, or dalteparin 5000 U daily for 6 weeks. 20. What is the currently preferred name for the superficial femoral vein? The femoral vein. The superficial femoral vein has been reclassified as the femoral vein because of how often with its former name it was mistakenly thought to be a superficial vein. 21. When can patients with acute deep vein thrombosis ambulate? Patients can ambulate with acute DVT and should not be placed on bed rest unless the lower extremity is painful and cannot bear weight. 22. Can patients with acute deep vein thrombosis be treated as outpatients? Yes. The LMWH and DOAC regimens listed here can be used to treat patients in the outpatient setting. The same principles of management should be followed using these agents as with inpatient treatment. 23. When should catheter-directed thrombolysis be used to treat acute deep vein thrombosis? In selected patients with extensive acute proximal iliofemoral DVT where symptoms have been present for less than 14 days—patients who are functionally active and who have a low bleeding risk—the use of pharmacomechanical thrombolysis is recommended if the appropriate expertise and resources are available. 24. Are inferior vena caval filters indicated for the initial treatment of acute deep vein thrombosis? No. Vena caval filters are indicated when the patient cannot receive anticoagulation for the treatment of acute DVT. In certain cases (temporary contraindication to anticoagulant therapy), retrievable vena caval filters have been placed, with the intention of removing them within a defined time (based on the specific filter), after which anticoagulation therapy could be reinstituted. 25. When are gradient elastic stockings recommended as part of the treatment of acute deep vein thrombosis? For patients with symptomatic DVT the use of gradient elastic stockings with an ankle pressure of 30 to 40 mm Hg is recommended. The pressure may not be tolerated because of the degree of lower extremity edema. Elastic bandages may be used because they can be adjusted to control swelling and the pain associated with increased external pressure. The elastic bandages can be used initially, but as the swelling recedes, gradient elastic stockings at 20 to 30 or 30 to 40 mm Hg may be applied. 26. When is a low-intensity international normalized ratio indicated for the treatment of deep vein thrombosis? For patients with idiopathic (unprovoked) DVT who have a strong preference for less frequent INR testing to monitor their therapy, it is recommended that after the first 3 months of therapy lowintensity therapy at an INR of 1.5 to 1.9 with less frequent INR monitoring be employed instead of stopping warfarin anticoagulation. 27. Can direct oral anticoagulants be used for extended treatment of deep vein thrombosis? Yes. The following DOACs have been approved for extended treatment of DVT after the initial 3 to 6 months of therapy: • Rivaroxaban 20 mg every day • Apixaban 2.5 mg every 12 hours • Dabigatran 150 mg every 12 hours Recommendations on short- and long-term DVT treatment from the ACCP are summarized in Table 60.4. 28. Should compression ultrasound be used at the time of discharge as routine screening in the patient who has undergone total joint replacement surgery? Asymptomatic patients who have undergone joint replacement surgery should not have compression ultrasound on discharge as a screening test for DVT because the ultrasound is not as sensitive and specific in asymptomatic patients. Appropriate DVT prophylaxis should be the approach to management.
520 PART IX VENOUS THROMBOEMBOLIC DISEASE Table 60.4. Summary of the 2016 American College of Clinical Pharmacy Recommendations on Antithrombotic Therapy for Venous Thromboembolism Choice of Long-Term (First 3 Months) and Extended (No Scheduled Stop Date) Anticoagulant Treatment • In patients with proximal DVT or PE, we recommend long-term (3-month) anticoagulant therapy over no such therapy. • In patients with DVT of the leg and no cancer, we suggest dabigatran, rivaroxaban, apixaban, or edoxaban as long-term (first 3 months) anticoagulant therapy over VKA therapy. • For patients with DVT of the leg or PE and no cancer who are not treated with dabigatran, rivaroxaban, apixaban, or edoxaban, we suggest VKA therapy over LMWH. • In patients with DVT of the leg or PE and cancer (“cancer-associated thrombosis”), we suggest LMWH as long-term (first 3 months) anticoagulant therapy over VKA therapy, dabigatran, rivaroxaban, apixaban, or edoxaban. • In patients with DVT of the leg or PE who receive extended therapy, we suggest that there is no need to change the choice of anticoagulant after the first 3 months. Duration of Anticoagulant Therapy • In patients with a proximal DVT of the leg or PE provoked by surgery, we recommend treatment with anticoagulation for 3 months over (i) treatment for a shorter period (grade 1B), (ii) treatment for a longer time-limited period (e.g., 6, 12, or 24 months), or (iii) extended therapy (no scheduled stop date). • In patients with a proximal DVT of the leg or PE provoked by a nonsurgical transient risk factor, we recommend treatment with anticoagulation for 3 months over (i) treatment for a shorter period (grade 1B) or (ii) treatment for a longer time-limited period (e.g., 6, 12, or 24 months) (grade 1B). We suggest treatment with anticoagulation for 3 months over extended therapy if there is a low or moderate bleeding risk (grade 2B) and recommend treatment for 3 months over extended therapy if there is a high risk of bleeding. • In patients with an isolated distal DVT of the leg provoked by surgery or by a nonsurgical transient risk factor, we suggest treatment with anticoagulation for 3 months over treatment for a shorter period (grade 2C). We recommend treatment with anticoagulation for 3 months over treatment for a longer time-limited period (e.g., 6, 12, or 24 months) (grade 1B), and we recommend treatment with anticoagulation for 3 months over extended therapy (no scheduled stop date). • In patients with an unprovoked DVT of the leg (isolated distal or proximal) or PE, we recommend treatment with anticoagulation for at least 3 months over treatment for a shorter period (grade 1B), and we recommend treatment with anticoagulation for 3 months over treatment of a longer timelimited period (e.g., 6, 12, or 24 months). • In patients with a first VTE that is an unprovoked proximal DVT of the leg or PE and who have a (i) low or moderate bleeding risk (see the text), we suggest extended anticoagulant therapy (no scheduled stop date) for 3 months (grade 2B). For patients with a (ii) high bleeding risk (see the text), we recommend 3 months of anticoagulant therapy over extended therapy (no scheduled stop date). • For patients with a second unprovoked VTE who have a (i) low bleeding risk (see the text), we recommend extended anticoagulant therapy (no scheduled stop date) for 3 months (grade 1B); for those with a (ii) moderate bleeding risk (see the text), we suggest extended anticoagulant therapy for 3 months (grade 2B); and for patients with a (iii) high bleeding risk (see the text), we suggest 3 months of anticoagulant therapy over extended therapy (no scheduled stop date). • For patients with DVT of the leg or PE and active cancer (“cancer-associated thrombosis”) who (i) do not have a high bleeding risk, we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months (grade 1B) or those who (ii) have a high bleeding risk, we suggest extended anticoagulant therapy (no scheduled stop date) for 3 months. DVT, Deep vein thrombosis; LMWH, low-molecular-weight heparin; PE, pulmonary embolism; VKA, vitamin K antagonist; VTE, venous thromboembolic. Adapted from Kearon, C., Akl, E. A., Ornelas, J., Blaivas, A., Jimenez, D., Bounameaux, H., et al. (2016). Antithrombotic therapy for VTE disease CHEST guideline and expert panel report. Chest, 149(2),315–352.
Chapter 60 DEEP VEIN THROMBOSIS: PROPHYLAXIS AND TREATMENT 521 Bibliography, Suggested Readings, and Websites British Thoracic Society Standards of Care Committee Pulmonary Embolism Guideline Development Group. (2003). British Thoracic Society guidelines for the management of suspected acute pulmonary embolism. Thorax, 58 (6), 470–483. Decousus, H., Leizorovicz, A., Parent, F., Page, Y., Tardy, B., Girard, P., et al. (1998). A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. New England Journal of Medicine, 338, 409–415. Falck-Ytter, Y., Francis, C. W., Johanson, N. A., Curley, C., Dahl, O. E., Schulman, S., et al. (2012). 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, 141(Suppl. 2), e278S–e325S. Gould, M. K., Garcia, D. A., Wren, S. M., Karanicolas, P. J., Arcelus, J. I., Heit, J. A., et al. (2012). 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, 141 (Suppl. 2), e227S–e277S. Kahn, S. R., Lim, W., Dunn, A. S., Cushman, M., Dentali, F., Akl, E. A., et al. (2012). 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, 141(Suppl. 2), e195S–e226S. Kearon, C., Akl, E. A., Ornelas, J., Blaivas, A., Jimenez, D., Bounameaux, H., et al. (2016). Antithrombotic therapy for VTE disease CHEST guideline and expert panel report. Chest, 149(2), 315–352. Kearon, C., Ginsberg, J. S., Julian, J. A., Douketis, J., Solymoss, S., Ockelford, P., et al. (2006). Comparison of fixed-dose weight adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. Journal of the American Medical Association, 296, 935–942. Koopman, M. M., Prandoni, P., Piovella, F., Ockelford, P. A., Brandjes, D. P., van der Meer, J., et al. (1996). Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. New England Journal of Medicine, 334, 682–687. Levine, M., Gent, M., Hirsh, J., Leclerc, J., Anderson, D., Weitz, J., et al. (1996). A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep vein thrombosis. New England Journal of Medicine, 334, 677–681. Mechanick, J. I., Youdim, A., Jones, D., et al. (2013). Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric patient—2013 update. Obesity, 21(Suppl.), S1–S27. Merli, G. J. (2008). Pathophysiology of venous thrombosis and the diagnosis of deep vein thrombosis-pulmonary embolism in the elderly. Cardiology Clinics, 26, 203–219. Merli, G., Spiro, T., Olsson, C. G., Abildgaard, U., Davidson, B. L., Eldor, A., et al. (2001). Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. Annals of Internal Medicine, 134, 191–202. Nicolaides, A. N., Fareed, J., Kakkar, A. K., & Breddin, H. K. (2006). Prevention and treatment of venous thromboembolism. International consensus statement (guidelines according to scientific evidence). International Angiology, 25 (2), 101–161. Snow, V., Qaseem, A., Barry, P., Hornbake, E. R., Rodnick, J. E., Tobolic, T., et al. (2007). Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Annals of Internal Medicine, 146 (3), 204–210. The Matisse Investigators. (2003). Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. New England Journal of Medicine, 349, 1695–1702. Wells, P. S., Anderson, D. R., Rodger, M. A., Forgie, M. A., Florack, P., Touchie, D., et al. (2005). A randomized trial comparing two low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism. Archives of Internal Medicine, 165, 733–738.