Annals of Internal Medicine䊛 In the Clinic®
Deep Venous Thrombosis
V
enous thromboembolism (VTE) is a relatively common and potentially lifethreatening condition. In the United States, it affects approximately 100 out of 100 000 persons per year, leading to 900 000 events annually (1). About one third of patients with VTE present with features of pulmonary embolism (PE), and two thirds present with features of deep venous thrombosis (DVT). Treated DVT has an excellent prognosis, with a probability over 3 to 6 months for fatal PE of 0.4% and 3.8% for recurrent DVT or nonfatal PE (2). The most common complications of VTE are the postthrombotic syndrome (PTS) and venous ulcer, with an overall U.S. incidence of 76.1 and 18.0 per 100 000 person-years, respectively (1).
The CME quiz is available at www.annals.org/intheclinic.aspx. Complete the quiz to earn up to 1.5 CME credits.
Physician Writers John Spandorfer Taki Galanis
CME Objective: To review current evidence for prevention, diagnosis, treatment, and practice improvement for deep venous thrombosis. Funding Source: American College of Physicians. Disclosures: Drs. Spandorfer and Galanis, ACP Contributing Authors, have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje /ConflictOfInterestForms.do?msNum=M14-2553. © 2015 American College of Physicians
Downloaded From: http://annals.org/ by a Scott Memorial Library User on 05/13/2015
Prevention Diagnosis Treatment Practice Improvement Tool Kit Patient Information
1. Heit JA. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol. 2008;28:370-2. [PMID: 18296591] 2. Douketis JD, Kearon C, Bates S, Duku EK, Ginsberg JS. Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA. 1998;279:458-62. [PMID: 9466640] 3. Goldhaber SZ. Risk factors for venous thromboembolism. J Am Coll Cardiol. 2010;56:1-7. [PMID: 20620709] 4. Cohoon KP, Heit JA. Inherited and secondary thrombophilia. Circulation. 2014;129:254-7. [PMID: 24421360] 5. Ageno W, Becattini C, Brighton T, Selby R, Kamphuisen PW. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation. 2008;117:93-102. [PMID: 18086925] 6. Wattanakit K, Lutsey PL, Bell EJ, et al. Association between cardiovascular disease risk factors and occurrence of venous thromboembolism. A time-dependent analysis. Thromb Haemost. 2012; 108:508-15. [PMID: 22782466] 7. Heit JA, Silverstein MD, Mohr DN, et al. Risk factors for deep vein thrombosis and pulmonary embolism: a populationbased case-control study. Arch Intern Med. 2000; 160:809-15. [PMID: 10737280] 8. Spencer FA, Emery C, Lessard D, et al. The Worcester Venous Thromboembolism study: a population-based study of the clinical epidemiology of venous thromboembolism. J Gen Intern Med. 2006;21:722-7. [PMID: 16808773] 9. Lijfering WM, Rosendaal FR, Cannegieter SC. Risk factors for venous thrombosis - current understanding from an epidemiological point of view. Br J Haematol. 2010;149:82433. [PMID: 20456358] 10. Kahn SR, Lim W, Dunn AS, Cushman M, Dentali F, Akl EA, et al; American College of Chest Physicians. Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis. Chest. 2012;141: e195S-226S. [PMID: 22315261] 11. Dermody M, AlessiChinetti J, Iafrati MD, Estes JM. The utility of screening for deep venous thrombosis in asymptomatic, nonambulatory neurosurgical patients. J Vasc Surg. 2011;53:1309-15. [PMID: 21215569]
Prevention What factors increase the risk for VTE? The main risk factors for VTE are recent surgery, major trauma, congestive heart or respiratory failure, malignant conditions (especially from the lung, pancreas, colon and rectum, kidney, and prostate), chronic kidney disease, the nephrotic syndrome, inflammatory bowel disease, pregnancy, hormone replacement, estrogen-containing oral contraceptive therapy, previous VTE, hereditary thrombophilia, increasing age, immobility, and extended air travel (3). The most common forms of genetic risk factors for VTE are the non–O blood type and the heterozy– gous gene mutations for factor V Leiden and prothrombin (4). Many of the risk factors for cardiovascular disease, such as obesity, smoking, hypertension, diabetes, and hypercholesterolemia, have been shown in a metaanalysis to increase the risk for VTE (5), although more recent data suggest that this risk may only be present for obesity and smoking (6). Hospitalization is independently associated with an 8-fold increase in the relative risk for VTE (7). Among outpatients who developed VTE, 23% had undergone surgery and 37% had been hospitalized in the preceding 3 months (8). Frequently, VTE is a result of multiple risk factors that, when combined, exceed the “thrombosis threshold” that leads to VTE (9). Fifty-three percent of patients with VTE in a populationbased study had 3 or more identifiable risk factors for VTE (8).
Should clinicians screen specific types of patients for DVT? Ultrasound screening for DVT in hospitalized medical patients has
姝 2015 American College of Physicians ITC2 In the Clinic Downloaded From: http://annals.org/ by a Scott Memorial Library User on 05/13/2015
not been systematically studied, and there is no evidence to support its use in this population (10). Data on use in hospitalized orthopedic surgery patients are also lacking. There is, however, limited evidence for screening ultrasonography in asymptomatic nonambulatory neurosurgery patients who were given unspecified mechanical prophylaxis (11).
Which hospitalized medical patients should receive prophylaxis, and what should be used? Clinicians should consider both whether the patient is at high risk for DVT and at risk for bleeding. For hospitalized medical patients, the Padua Prediction Score provides a risk estimate for DVT (12) (Table 1). Gastroduodenal ulcer bleeding within 3 months of admission and a platelet count below 50 000 per microliter are two major independent risk factors for bleeding (13). One risk model for assessing bleeding risk, the IMPROVE model, includes those risks as well as any prior bleeding within 3 months, hepatic failure, renal failure, cardiovascular catheterization, intensive care unit or critical care unit stay, rheumatic disease, current cancer, age, and sex (13). Unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and fondaparinux all reduce the risk for DVT. Use of any of these agents is recommended for patients at increased risk for DVT but not at high risk for bleeding (10). Although twice-daily UFH dosing causes fewer major bleeding episodes, thrice-daily dosing offers somewhat better efficacy in preventing clinically relevant thrombotic events (14).
Annals of Internal Medicine
5 May 2015
In a recent meta-analysis, LMWH was favored over UFH, with a reduced risk for both DVT and bleeding (15). Although there is limited evidence that mechanical prophylaxis is effective in medical inpatients, for patients who are at increased risk for DVT and bleeding, expert guidelines recommend mechanical prophylaxis with graduated compression stockings or intermittent pneumatic compression (IPC) (10). A recent study showed that IPC reduced the risk for DVT among patients who have had stroke (16). For patients at low risk for DVT, no prophylaxis is indicated.
Which hospitalized surgical patients should receive prophylaxis, and what should be used? Clinicians should first consider the patient's risk for DVT related to both the type of surgery and the patient-related risk factors. The Caprini Risk Assessment Model is the most widely used tool to assess levels of thromboembolic risk (Table 2) (17). The American College of Chest Physicians (ACCP) makes the following recommendations for general and abdominal-pelvic surgery: for patients at very low risk (Caprini score 0), no prophylaxis other than early ambulation; for patients at low risk (Caprini score 1-2), IPC; for patients at moderate risk (Caprini score 3-4), LMWH, low-dose UFH, or IPC; for patients at high risk (Caprini score ≥ 5), LMWH or low-dose UFH (18). For patients at increased risk for bleeding or at risk for severe consequences of bleeding should it occur (including patients undergoing spinal surgery and craniotomy), the ACCP recommends IPC. For patients having craniotomy or spinal surgery at very high risk for DVT, pharmacologic prophylaxis, such as LMWH or UFH, can be
added once adequate hemostasis is achieved and the risk for bleeding decreases. For patients undergoing total hip or knee arthroplasty, LMWH, fondaparinux, rivaroxaban, apixaban, or warfarin are recommended for 10 –14 days. Additional benefit may arise from extending the treatment for up to 35 days from the day of surgery (19 –20). Aspirin 81 mg daily, started after 10 –14 days of LMWH and continued for 28 days, may be an alternative for the extended prophylaxis regimen in hip replacement patients (21).
Which pregnant patients should receive prophylaxis, and what methods should be used? The ACCP and the American College of Obstetrics and Gynecology have made recommendations regarding VTE prevention in pregnant patients who have had prior VTE or who may be at increased risk for VTE. In general, women with previous idiopathic VTE or VTE related to pregnancy, estrogen therapy, or thrombophilia are at higher risk than those with previous VTE related to a temporary risk factor. Screening for thrombophilia may be considered when a patient had VTE unrelated to a known risk factor or when a first-degree relative has a known high-risk thrombophilia (22–23). Pharmacologic DVT prevention is suggested in certain patients based on personal and family (first-degree relative) history of DVT and whether the patient has a known thrombophilia (Table 3) (22, 24). A recent report concluded that any recommendations concerning VTE prophylaxis in pregnancy were made from trials that were not of high methodological quality (25).
5 May 2015 Annals of Internal Medicine In the Clinic Downloaded From: http://annals.org/ by a Scott Memorial Library User on 05/13/2015
ITC3
Table 1. Risk Factor Guide for VTE in Hospitalized Medical Patients* Risk Factor
Points
Active cancer Previous VTE with exclusion of superficial vein thrombosis Reduced mobility Already known thrombophilic condition, defects of antithrombin, protein C or S, factor V Leiden, the antiphospholipid syndrome Recent (70 y) Heart and/or respiratory failure Acute myocardial infarction or ischemic stroke Acute infection or rheumatologic disorder Obesity (BMI >30 mg/k2) Ongoing hormonal treatment
3 3
3 3
2 1 1 1 1 1 1
BMI = body mass index; VTE = venous thromboembolism. * From reference 12. High risk for VTE is defined by a cumulative score ≥4 and low risk 25 kg/m2
Age 61–74 y Arthroscopic surgery Major open surgery (≥45 min) Laparoscopic surgery (>45 min) Cancer (past or present)
Age ≥75 y History of VTE Family history of VTE
Stroke (3 d or major surgery within 12 wk requiring general or regional anesthesia Localized tenderness along the distribution of the deep venous system Entire leg swollen Calf swelling 3 cm larger than asymptomatic side (measured 10 cm below the tibial tuberosity) Pitting edema confined to the symptomatic leg Collateral superficial veins (nonvaricose) Previously documented DVT Alternative diagnosis at least as likely as DVT DVT unlikely (score ≤1) or DVT likely (score ≥2)
Score 1
1
1
1
1 1
1 1 1 –2
Primary Care Rule† Male Use of hormonal contraceptives Active cancer in past 6 mo Surgery in previous month Absence of leg trauma Distention of collateral leg veins Difference in calf circumference ≥3 cm Abnormal D-dimer assay result Very low risk (score ≤3) or increased risk (score ≥4) DVT = deep venous thrombosis. * From Wells PS, Anderson DR, Rodger M, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med. 2003;349: 1227-35. † From Toll DB, Oudega R, Vergouwe Y, Moons KG, Hoes AW. A new diagnostic rule for deep vein thrombosis: safety and efficiency in clinically relevant subgroups. Fam Pract. 2008;25:3-8.
1 1 1 1 1 1
An alternative prediction score, termed the Primary Care Rule, was derived and validated in primary care patients presenting with symptoms of DVT (31) (Table 4). This rule has also been shown to be effective regardless of patient age, sex, and history of VTE. No matter which is used, a clinical prediction score should not be the sole criterion for diagnosing DVT and must be calculated in conjunction with D-dimer testing to determine whether additional studies are necessary.
What is the role of D-dimer testing? A meta-analysis showed that the 3-month incidence of VTE was 0.4% among patients with a low or intermediate clinical probability of VTE and a normal highly sensitive D-dimer test result (32).
Enzyme-linked immunoassay D-dimer tests have higher sensitivity and lower specificity, whereas whole-blood agglutination assays have lower sensitivity and higher specificity (33). Point-of-care testing is also available and can be used to rule out DVT in the emergency department or in outpatient practice.
2 6
A diagnostic meta-analysis of point-of-care D-dimer assays showed that quantitative assays had better sensitivity than qualitative assays. In this analysis, the most sensitive test had a sensitivity of 0.96 and a posttest probability of DVT of 0.9% in low-risk patients (34).
The sensitivity and specificity of D-dimer assays are suboptimal in pregnant women; patients receiving anticoagulation therapy; and those with prolonged clinical symptoms of DVT, prior DVT, or cancer. D-dimer levels also normally increase with age; however, the combination of a negative D-dimer assay along with a low pretest clinical probability has been shown to be associated with an acceptable negative pre-
姝 2015 American College of Physicians ITC6 In the Clinic Downloaded From: http://annals.org/ by a Scott Memorial Library User on 05/13/2015
dictive value in the elderly. D-dimer testing must be combined with an assessment of pretest probability to safely exclude DVT.
What is the role of venous ultrasonography? Figure 1 outlines the role of ultrasonography in the diagnosis of DVT. A meta-analysis of 100 cohort studies showed that venous ultrasonography has 94% sensitivity for detecting proximal venous thrombosis, 63% sensitivity for distal DVT, and 94% specificity for both (35).
Whereas one ultrasound method involves interrogation of only the common and popliteal veins (proximal ultrasonography), the other examines the entire deep vein system, including the calf veins (whole-leg ultrasonography). These methods have been investigated in prospective cohort and randomized studies and have been shown to be associated with an acceptable 3-month incidence of VTE after negative results. A meta-analysis of randomized and prospective cohort studies investigating the risk for VTE after a single negative, whole-leg ultrasound showed that this technique was associated with a low 3-month incidence of VTE (pooled incidence, 0.57%) (36).
The potential advantage of whole-leg ultrasonography is to avoid repeated testing. However, it may identify more patients with isolated, calf vein DVT, which has an uncertain clinical significance. In the meta-analysis, 52.1% of all DVTs diagnosed on the initial study were isolated calf vein thrombi (36).
What is the role of other types of testing? The role of other testing, such as computed tomography (CT) venography and magnetic resonance imaging (MRI), in diagnosing DVT is uncertain.
Annals of Internal Medicine
5 May 2015
Figure 1. DVT treatment algorithm.
Wells Score and Primary Care Rule
DVT unlikely
DVT likely
Sensitive D-dimer
Whole-leg ultrasonography
Negative
Positive
No further evaluation
Whole-leg ultrasonography
Negative
Positive Sensitive D-dimer
Isolated calf vein DVT
Negative
Proximal vein DVT
Treat
Do not treat
Symptomatic or high risk for propagation
High bleeding risk or low risk for propagation
Consider treatment
Repeat ultrasonography in 1 wk
Positive
Repeat ultrasonography in 1 wk
Negative
Do not treat
DVT = deep venous thrombosis.
Two separate meta-analyses of CT and MRI for the diagnosis of DVT showed high pooled sensitivity and specificity compared with a reference standard, which was most often ultrasonography for the CT studies and venography for the MRI investigations. However, the individual studies in both analyses had significant heterogeneity (37–38).
There are no management studies that have shown an acceptably low 3-month rate of VTE after negative results on CT or MRI, as has been shown with ultrasonography. Consequently, these methods are not recommended as first-line diagnostic tests, except in cases when ultrasonography cannot be performed (i.e., lower-extremity casting or severe edema precluding the ability to adequately visualize and compress vessels) (39).
How should a pregnant patient be evaluated for suspected DVT? Clinical prediction rules have not been formally validated in pregnant patients. Furthermore, D-dimer assays are associated with poor specificity, as most pregnant women have positive results on D-dimer testing by the third trimester. Compression ultrasonography is thus recommended as the initial test in this patient population, and follow-up ultrasonography is suggested in patients with an initial normal ultrasound. Patients with symptoms suggestive of iliac venous thrombosis (whole-leg edema or discomfort in the flank, back, or buttock) should have the pelvic vessels
5 May 2015 Annals of Internal Medicine In the Clinic Downloaded From: http://annals.org/ by a Scott Memorial Library User on 05/13/2015
ITC7
28. Kuipers S, Venemans A, Middeldorp S, et al. The risk of venous thrombosis after air travel: contribution of clinical risk factors [Letter]. Br J Haematol. 2014;165: 412-3. [PMID: 24428564] 29. Goodacre S, Sutton AJ, Sampson FC. Meta-analysis: the value of clinical assessment in the diagnosis of deep venous thrombosis. Ann Intern Med. 2005;143:129-39. [PMID: 16027455] 30. Geersing GJ, Zuithoff NP, Kearon C, et al. Exclusion of deep vein thrombosis using the Wells rule in clinically important subgroups: individual patient data meta-analysis. BMJ. 2014;348:g1340. [PMID: 24615063] 31. Oudega R, Moons KG, Hoes AW. Ruling out deep venous thrombosis in primary care. A simple diagnostic algorithm including D-dimer testing. Thromb Haemost. 2005;94:200-5. [PMID: 16113804] 32. Fancher TL, White RH, Kravitz RL. Combined use of rapid D-dimer testing and estimation of clinical probability in the diagnosis of deep vein thrombosis: systematic review. BMJ. 2004;329: 821. [PMID: 15383452] 33. Di Nisio M, Squizzato A, Rutjes AW, et al. Diagnostic accuracy of D-dimer test for exclusion of venous thromboembolism: a systematic review. J Thromb Haemost. 2007;5:296-304. [PMID: 17155963] 34. Geersing GJ, Janssen KJ, Oudega R, et al. Excluding venous thromboembolism using point of care D-dimer tests in outpatients: a diagnostic meta-analysis. BMJ. 2009;339:b2990. [PMID: 19684102] 35. Goodacre S, Sampson F, Thomas S, van Beek E, Sutton A. Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis. BMC Med Imaging. 2005;5:6. [PMID: 16202135] 36. Johnson SA, Stevens SM, Woller SC, et al. Risk of deep vein thrombosis following a single negative whole-leg compression ultrasound: a systematic review and metaanalysis. JAMA. 2010; 303:438-45. [PMID: 20124539]
姝 2015 American College of Physicians
Table 5. Differential Diagnosis of DVT Disease
Characteristics
Notes
Venous insufficiency (venous reflux)
Usually due to venous hypertension from such causes as venous reflux or obesity Firm, tender, varicose vein
Obtain ultrasonography of venous reflux
Superficial thrombophlebitis Muscle strain, tear, or trauma
Leg swelling in a paralyzed limb Baker cyst Cellulitis Lymphedema
Pain occurring with a range of motion more characteristic of orthopedic problem due to trauma; usually a history of leg injury History of paraplegia Pain localized to popliteal region of leg Skin erythema and warmth Toe edema is more characteristic of lymphedema than of venous edema
Superficial thrombosis is rarely associated with DVT Perform the appropriate orthopedic evaluation
Patients with paralyzed limb may develop edema without DVT Seen on ultrasonography Consider antibiotic treatment Lymphedema can occur in 1 or both legs
DVT = deep venous thrombosis.
evaluated with ultrasonography and/or MRI (24).
37. Thomas SM, Goodacre SW, Sampson FC, van Beek EJ. Diagnostic value of CT for deep vein thrombosis: results of a systematic review and meta-analysis. Clin Radiol. 2008;63:299-304. [PMID: 18275870] 38. Sampson FC, Goodacre SW, Thomas SM, van Beek EJ. The accuracy of MRI in diagnosis of suspected deep vein thrombosis: systematic review and meta-analysis. Eur Radiol. 2007;17:175-81. [PMID: 16628439] 39. Kearon C, Akl EA, Comerota AJ, et al; American College of Chest Physicians. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis. Chest. 2012;141: e419S-94S. [PMID: 22315268] 40. Kahn SR, Ginsberg JS. Relationship between deep venous thrombosis and the postthrombotic syndrome. Arch Intern Med. 2004;164:17-26. [PMID: 14718318] 41. Carrier M, Le Gal G, Wells PS, et al. Systematic review: the Trousseau syndrome revisited: should we screen extensively for cancer in patients with venous thromboembolism? Ann Intern Med. 2008;149: 323-33. [PMID: 18765702] 42. Cohn DM, Vansenne F, de Borgie CA, Middeldorp S. Thrombophilia testing for prevention of recurrent venous thromboembolism. Cochrane Database Syst Rev. 2012; 12:CD007069. [PMID: 23235639]
What other diagnoses should clinicians consider? The differential diagnosis of suspected DVT is extensive. Table 5 outlines the main alternative considerations. Such conditions as tendinitis, calf hematoma, PTS, advanced venous insufficiency, and arthritis should also be considered. When should clinicians consider consulting a specialist for diagnosing DVT? PTS occurs in 20%–50% of patients diagnosed with symptomatic DVT (40). Differentiating this condition from recurrent DVT can be challenging. Few welldesigned studies have investigated strategies to diagnose recurrent DVT. Furthermore, guidelines differ on which strategy should be used in suspected recurrent cases. Residual abnormalities on ultrasonography are common. Specific, well-defined criteria for diagnosing recurrent DVT, especially in venous segments with residual abnormalities, are lacking. For patients with recurrent DVT (particularly if the recurrence is questionable), a clinician should thus consider consulting a specialist. A referral should also be considered if im-
姝 2015 American College of Physicians ITC8 In the Clinic Downloaded From: http://annals.org/ by a Scott Memorial Library User on 05/13/2015
aging is nondiagnostic or if suspicion for DVT remains high despite negative testing.
What other underlying conditions and clinical manifestations should clinicians look for? Within 12 months of a VTE diagnosis, 3.5%–10% of patients will be diagnosed with cancer (41), and this risk seems to be higher in patients with an unprovoked thrombosis. Although a systematic review showed that an extensive screening strategy significantly increased the proportion of patients diagnosed with cancer, there are no randomized, controlled trials that have shown a mortality benefit of an extensive screening protocol. Other factors, such as patient anxiety, radiation exposure, and risks of additional diagnostic procedures, have not been formally investigated. Cancer screening that is tailored according to the patient's age, symptoms, and risk factors is thus suggested in patients who are diagnosed with DVT. The role of thrombophilia testing is also uncertain. There are no randomized, controlled clinical trials that have investigated the role of such testing to assess the risk for recurrent VTE (42). Consequently, there is no consensus
Annals of Internal Medicine
5 May 2015
among the guidelines regarding which, if any, patients should be tested. Some societies advocate
testing young patients with a family history of DVT, whereas others do not.
Diagnosis... Individual clinical features have little predictive value in diagnosing DVT. Clinicians should consider using a clinical prediction rule that incorporates a sensitive D-dimer assay to stratify a patient's risk for thrombosis. Various clinical scores exist, of which the Wells score is the most studied. An alternative is the Primary Care Rule, which has also been shown to be effective in ruling out DVT in the primary care setting. Whole-leg ultrasonography may limit the need for repeated testing but will identify more patients with isolated calf vein thrombi. The use of an extensive cancer screening and thrombophilia testing strategy is controversial in patients who are diagnosed with DVT. Clinicians should consider consulting a specialist for patients with a possible recurrent DVT or in situations where the imaging studies are nondiagnostic or negative, particularly if suspicion for thrombosis is high.
CLINICAL BOTTOM LINE
Treatment As shown in Figure 2, DVT treatment is divided into several phases. Some of the novel oral anticoagulants (NOACs), such as rivaroxaban and apixaban, can be used immediately during the initial phase of treatment, whereas others, such as dabigatran etexilate and edoxaban, should not be used until the patient has been treated with a parenteral anticoagulant, such as UFH or LMWH, for at least 5 days. Table 6 summarizes the dosing regimens, mechanisms of action, and side effects of the available anticoagulants; as the table shows, a reduced dose of apixaban (2.5 mg twice daily) has also been approved for DVT treatment during the extended phase of therapy.
How should clinicians decide whether to treat patients on an outpatient or inpatient basis? Most patients with DVT can be safely treated with LMWH as outpatients. Several systematic reviews comparing patients with VTE treated with LMWH administered at home with those treated in the hospital found
no difference in outcomes (43). Furthermore, outpatient treatment of patients with PE at low risk for adverse events (as measured by a clinical prediction rule) has been shown to be safe and effective in several randomized, controlled trials and a systematic review (44).
A recent registry of more than 13 000 patients found that home treatment was associated with a better outcome than hospital treatment (45). However, clinicians should consider admitting patients who have difficulty managing their outpatient treatment.
What local measures should clinicians recommend? Data regarding the efficacy of compression therapy in reducing the risk for PTS conflict. For example, elastic compression stockings did not prevent PTS in a recent randomized, placebocontrolled trial (46). However, the clinician should consider early ambulation because it has not been shown to be associated with increased risk for PE in patients with acute DVT, and it may lead to more rapid resolution of limb pain (47). Early ambulation also has the potential to decrease PTS (39).
5 May 2015 Annals of Internal Medicine In the Clinic Downloaded From: http://annals.org/ by a Scott Memorial Library User on 05/13/2015
ITC9
43. Segal JB, Streiff MB, Hofmann LV, et al. Management of venous thromboembolism: a systematic review for a practice guideline. Ann Intern Med. 2007;146: 211-22. [PMID: 17261856] 44. Squizzato A, Galli M, Dentali F, Ageno W. Outpatient treatment and early discharge of symptomatic pulmonary embolism: a systematic review. Eur Respir J. 2009;33:1148-55. [PMID: 19407049] 45. Lozano F, Trujillo-Santos J, Barro´n M, et al; RIETE Investigators. Home versus in-hospital treatment of outpatients with acute deep venous thrombosis of the lower limbs. J Vasc Surg. 2014;59:1362-7.e1. [PMID: 24439322] 46. Kahn SR, Shapiro S, Wells PS, et al; SOX trial investigators. Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet. 2014;383:880-8. [PMID: 24315521] 47. Kahn SR, Shrier I, Kearon C. Physical activity in patients with deep venous thrombosis: a systematic review. Thromb Res. 2008;122:763-73. [PMID: 18078981]
姝 2015 American College of Physicians
Figure 2. Phases of anticoagulation treatment.
Long-Term
Initial
IV heparin SC heparin LMWH Fondaparinux Rivaroxaban Apixaban
0–10 d
Extended
Vitamin K antagonist Rivaroxaban Dabigatran LMWH* Apixaban Edoxaban
10 d–3 mo
3 mo–Indefinite
IV = intravenous; LMWH = low-molecular-weight heparin; SC = subcutaneous. * Preferred in patients with cancer.
48. Agnelli G, Buller HR, Cohen A, et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799808. [PMID: 23808982] 49. Castellucci LA, Cameron C, Le Gal G, et al. Clinical and safety outcomes associated with treatment of acute venous thromboembolism: a systematic review and meta-analysis. JAMA. 2014;312:1122-35. [PMID: 25226478] 50. van der Hulle T, Kooiman J, den Exter PL, et al. Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost. 2014;12: 320-8. [PMID: 24330006] 51. Schulman S, Kakkar AK, Goldhaber SZ, et al; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129:764-72. [PMID: 24344086] 52. Prins MH, Lensing AW, Bauersachs R, et al; EINSTEIN Investigators. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J. 2013;11:21. [PMID: 24053656]
When should clinicians start anticoagulants? There are no randomized studies investigating the timing of anticoagulation therapy initiation in patients with suspected DVT. In patients with a high pretest probability of DVT and a low risk for bleeding, it is reasonable to initiate a short-acting anticoagulant while awaiting the results of the diagnostic work-up, particularly if there is a delay in testing. In patients who are diagnosed with acute proximal DVT, the clinician should initiate anticoagulation with either a parental anticoagulant or apixaban or rivaroxaban immediately unless contraindicated. If a vitamin k antagonist (VKA) is chosen for the long-term phase of therapy, it should be started on the same day as the parental anticoagulant. Robust evidence on the treatment of an isolated calf vein thrombosis is lacking. Immediate initiation of anticoagulation is preferred in patients whose symptoms (particularly if severe) are probably related to calf vein thrombosis or if the patient has a high risk for thrombus propagation (i.e., active cancer, large thrombus burden, location of
姝 2015 American College of Physicians ITC10 In the Clinic Downloaded From: http://annals.org/ by a Scott Memorial Library User on 05/13/2015
thrombus close to the popliteal junction, or history of DVT), particularly if the bleeding risk is low (39). Weekly surveillance ultrasonography for two weeks is preferred in other patients (31).
Which anticoagulants should clinicians use? Figure 2 summarizes the treatment options for each phase of anticoagulation therapy. Several of the NOACs have been studied for the treatment of VTE and have been shown to be effective and safe (48). Table 6 outlines the anticoagulant regimens that can be used for DVT. Subcutaneous heparin (either with monitored or unmonitored activated partial thromboplastin time [aPTT]) is an alternative to intravenous heparin in patients with renal insufficiency, those with poor intravenous access, or pregnant patients beyond 36 weeks of gestation. A meta-analysis comparing the efficacy and safety of various anticoagulation options showed that the combination of UFH and VKAs was associated with a higher risk for recurrent VTE than the combination of low-molecular-weight heparin (LMWH) and VKAs. All of the NOACs were found to be as effective as standard therapy. Rivaroxaban and apixaban were associated with a lower
Annals of Internal Medicine
5 May 2015
Table 6. Drug Treatment for DVT Drug, Dosage
Mechanism of Action
Side Effects
LMWH Dalteparin, 200 IU/kg SC once daily Enoxaparin, 1 mg/kg SC every 12 h or 1.5 mg/kg every 24 h Tinzaparin, 175 IU/kg SC once daily IV or SC UFH to keep aPTT ≥1.5 times control value
Direct anti-factor Xa effect; also inhibits thrombin via antithrombin activation
Bleeding, thrombocytopenia, hypersensitivity, osteoporosis, HIT
Enhances antithrombin activity, thereby inhibiting thrombin activation (and to a lesser extent factor Xa activity) Inhibits factor Xa
Bleeding, thrombocytopenia, hypersensitivity, osteoporosis, elevation of liver enzymes, hyperkalemia, HIT
Fondaparinux 100 kg, 10 mg SC daily Coumarin derivatives Overlap UFH, LMWH, or fondaparinux for at least 5 d and until INR 2–3 for 24 h Apixaban Acute phase*: 10 mg twice daily × 7 d followed by 5 mg twice daily Extended phase†: 2.5 mg twice daily Rivaroxaban Acute phase*: 15 mg twice daily for 21 d followed by 20 mg daily Extended phase‡: 20 mg daily IV direct thrombin inhibitors Lepirudin, 0.1 mg/kg/h Bivalirudin, 0.75mg/kg IV loading; then 1.75 mg/kg/h Argatroban, 2 μg/kg/min Consider dose reduction in critically ill Oral direct thrombin inhibitor Dabigatran etexilate Acute phase: 150 mg twice daily after at least 5 d of parenteral anticoagulation Extended phase: 150 mg twice daily
Inhibits generation of vitamin k–dependent coagulation factors II, VII, IX, and X Direct anti-Xa effect
Bleeding, purpura, anemia
Hypercoagulability during first few days of treatment, bleeding, hypersensitivity, teratogenicity, drug interactions, skin necrosis, osteoporosis Bleeding, hypersensitivity, interaction with p-GP or cytochrome p450 inducers/inhibitors
Direct anti-Xa effect
Bleeding, hypersensitivity, case reports of possible liver toxicity, interaction with p-GP or cytochrome p450 inducers/inhibitors
Directly inhibits thrombin activity
Bleeding, hypersensitivity, injection-site reactions
Bleeding, hypersensitivity, dyspepsia, possible increased risk for ACS compared with VKA, interaction with p-GP inducers/inhibitors
ACS = acute coronary syndrome; aPTT = activated partial thromboplastin time; DVT = deep venous thrombosis; HIT = heparininduced thrombocytopenia; INR = international normalized ratio; IV = intravenous; LMWH = low-molecular-weight heparin; p-GP = p-glycoprotein; SC = subcutaneous; UFH = unfractionated heparin; VKA = vitamin k antagonist. * Acute phase = first 5–10 d of treatment for acute DVT. † Extended phase = period after first 6 mo of treatment. ‡ Extended phase = period after first 21 d of treatment.
risk for major bleeding than either the UFH- or the LMWH-VKA combination in this analysis (49). In a separate meta-analysis, the NOACs were found to be as effective as the VKAs and were associated with a lower risk for bleeding complications (50).
All of the NOACs as well as the LMWHs undergo renal excretion. UFH and VKAs thus remain the anticoagulants of choice in patients with renal insufficiency. The elderly and patients with active cancer or underlying thrombophilia were underrepresented in the NOAC clinical trials. In a
pooled analysis, clinically relevant bleeding occurred more often in patients older than 85 years who were treated with dabigatran for VTE than in those who received warfarin. However, sex, creatinine clearance, ethnicity, and body mass index did not influence bleeding outcomes. In this analysis, there was no difference in efficacy between dabigatran and standard therapy in patients with cancer or those who presented with a symptomatic PE (51). In a pooled analysis of the rivaroxaban
trials, fragility (age >75 years, creatinine clearance
Deep Venous Thrombosis
V
enous thromboembolism (VTE) is a relatively common and potentially lifethreatening condition. In the United States, it affects approximately 100 out of 100 000 persons per year, leading to 900 000 events annually (1). About one third of patients with VTE present with features of pulmonary embolism (PE), and two thirds present with features of deep venous thrombosis (DVT). Treated DVT has an excellent prognosis, with a probability over 3 to 6 months for fatal PE of 0.4% and 3.8% for recurrent DVT or nonfatal PE (2). The most common complications of VTE are the postthrombotic syndrome (PTS) and venous ulcer, with an overall U.S. incidence of 76.1 and 18.0 per 100 000 person-years, respectively (1).
The CME quiz is available at www.annals.org/intheclinic.aspx. Complete the quiz to earn up to 1.5 CME credits.
Physician Writers John Spandorfer Taki Galanis
CME Objective: To review current evidence for prevention, diagnosis, treatment, and practice improvement for deep venous thrombosis. Funding Source: American College of Physicians. Disclosures: Drs. Spandorfer and Galanis, ACP Contributing Authors, have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje /ConflictOfInterestForms.do?msNum=M14-2553. © 2015 American College of Physicians
Downloaded From: http://annals.org/ by a Scott Memorial Library User on 05/13/2015
Prevention Diagnosis Treatment Practice Improvement Tool Kit Patient Information
1. Heit JA. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol. 2008;28:370-2. [PMID: 18296591] 2. Douketis JD, Kearon C, Bates S, Duku EK, Ginsberg JS. Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA. 1998;279:458-62. [PMID: 9466640] 3. Goldhaber SZ. Risk factors for venous thromboembolism. J Am Coll Cardiol. 2010;56:1-7. [PMID: 20620709] 4. Cohoon KP, Heit JA. Inherited and secondary thrombophilia. Circulation. 2014;129:254-7. [PMID: 24421360] 5. Ageno W, Becattini C, Brighton T, Selby R, Kamphuisen PW. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation. 2008;117:93-102. [PMID: 18086925] 6. Wattanakit K, Lutsey PL, Bell EJ, et al. Association between cardiovascular disease risk factors and occurrence of venous thromboembolism. A time-dependent analysis. Thromb Haemost. 2012; 108:508-15. [PMID: 22782466] 7. Heit JA, Silverstein MD, Mohr DN, et al. Risk factors for deep vein thrombosis and pulmonary embolism: a populationbased case-control study. Arch Intern Med. 2000; 160:809-15. [PMID: 10737280] 8. Spencer FA, Emery C, Lessard D, et al. The Worcester Venous Thromboembolism study: a population-based study of the clinical epidemiology of venous thromboembolism. J Gen Intern Med. 2006;21:722-7. [PMID: 16808773] 9. Lijfering WM, Rosendaal FR, Cannegieter SC. Risk factors for venous thrombosis - current understanding from an epidemiological point of view. Br J Haematol. 2010;149:82433. [PMID: 20456358] 10. Kahn SR, Lim W, Dunn AS, Cushman M, Dentali F, Akl EA, et al; American College of Chest Physicians. Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis. Chest. 2012;141: e195S-226S. [PMID: 22315261] 11. Dermody M, AlessiChinetti J, Iafrati MD, Estes JM. The utility of screening for deep venous thrombosis in asymptomatic, nonambulatory neurosurgical patients. J Vasc Surg. 2011;53:1309-15. [PMID: 21215569]
Prevention What factors increase the risk for VTE? The main risk factors for VTE are recent surgery, major trauma, congestive heart or respiratory failure, malignant conditions (especially from the lung, pancreas, colon and rectum, kidney, and prostate), chronic kidney disease, the nephrotic syndrome, inflammatory bowel disease, pregnancy, hormone replacement, estrogen-containing oral contraceptive therapy, previous VTE, hereditary thrombophilia, increasing age, immobility, and extended air travel (3). The most common forms of genetic risk factors for VTE are the non–O blood type and the heterozy– gous gene mutations for factor V Leiden and prothrombin (4). Many of the risk factors for cardiovascular disease, such as obesity, smoking, hypertension, diabetes, and hypercholesterolemia, have been shown in a metaanalysis to increase the risk for VTE (5), although more recent data suggest that this risk may only be present for obesity and smoking (6). Hospitalization is independently associated with an 8-fold increase in the relative risk for VTE (7). Among outpatients who developed VTE, 23% had undergone surgery and 37% had been hospitalized in the preceding 3 months (8). Frequently, VTE is a result of multiple risk factors that, when combined, exceed the “thrombosis threshold” that leads to VTE (9). Fifty-three percent of patients with VTE in a populationbased study had 3 or more identifiable risk factors for VTE (8).
Should clinicians screen specific types of patients for DVT? Ultrasound screening for DVT in hospitalized medical patients has
姝 2015 American College of Physicians ITC2 In the Clinic Downloaded From: http://annals.org/ by a Scott Memorial Library User on 05/13/2015
not been systematically studied, and there is no evidence to support its use in this population (10). Data on use in hospitalized orthopedic surgery patients are also lacking. There is, however, limited evidence for screening ultrasonography in asymptomatic nonambulatory neurosurgery patients who were given unspecified mechanical prophylaxis (11).
Which hospitalized medical patients should receive prophylaxis, and what should be used? Clinicians should consider both whether the patient is at high risk for DVT and at risk for bleeding. For hospitalized medical patients, the Padua Prediction Score provides a risk estimate for DVT (12) (Table 1). Gastroduodenal ulcer bleeding within 3 months of admission and a platelet count below 50 000 per microliter are two major independent risk factors for bleeding (13). One risk model for assessing bleeding risk, the IMPROVE model, includes those risks as well as any prior bleeding within 3 months, hepatic failure, renal failure, cardiovascular catheterization, intensive care unit or critical care unit stay, rheumatic disease, current cancer, age, and sex (13). Unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and fondaparinux all reduce the risk for DVT. Use of any of these agents is recommended for patients at increased risk for DVT but not at high risk for bleeding (10). Although twice-daily UFH dosing causes fewer major bleeding episodes, thrice-daily dosing offers somewhat better efficacy in preventing clinically relevant thrombotic events (14).
Annals of Internal Medicine
5 May 2015
In a recent meta-analysis, LMWH was favored over UFH, with a reduced risk for both DVT and bleeding (15). Although there is limited evidence that mechanical prophylaxis is effective in medical inpatients, for patients who are at increased risk for DVT and bleeding, expert guidelines recommend mechanical prophylaxis with graduated compression stockings or intermittent pneumatic compression (IPC) (10). A recent study showed that IPC reduced the risk for DVT among patients who have had stroke (16). For patients at low risk for DVT, no prophylaxis is indicated.
Which hospitalized surgical patients should receive prophylaxis, and what should be used? Clinicians should first consider the patient's risk for DVT related to both the type of surgery and the patient-related risk factors. The Caprini Risk Assessment Model is the most widely used tool to assess levels of thromboembolic risk (Table 2) (17). The American College of Chest Physicians (ACCP) makes the following recommendations for general and abdominal-pelvic surgery: for patients at very low risk (Caprini score 0), no prophylaxis other than early ambulation; for patients at low risk (Caprini score 1-2), IPC; for patients at moderate risk (Caprini score 3-4), LMWH, low-dose UFH, or IPC; for patients at high risk (Caprini score ≥ 5), LMWH or low-dose UFH (18). For patients at increased risk for bleeding or at risk for severe consequences of bleeding should it occur (including patients undergoing spinal surgery and craniotomy), the ACCP recommends IPC. For patients having craniotomy or spinal surgery at very high risk for DVT, pharmacologic prophylaxis, such as LMWH or UFH, can be
added once adequate hemostasis is achieved and the risk for bleeding decreases. For patients undergoing total hip or knee arthroplasty, LMWH, fondaparinux, rivaroxaban, apixaban, or warfarin are recommended for 10 –14 days. Additional benefit may arise from extending the treatment for up to 35 days from the day of surgery (19 –20). Aspirin 81 mg daily, started after 10 –14 days of LMWH and continued for 28 days, may be an alternative for the extended prophylaxis regimen in hip replacement patients (21).
Which pregnant patients should receive prophylaxis, and what methods should be used? The ACCP and the American College of Obstetrics and Gynecology have made recommendations regarding VTE prevention in pregnant patients who have had prior VTE or who may be at increased risk for VTE. In general, women with previous idiopathic VTE or VTE related to pregnancy, estrogen therapy, or thrombophilia are at higher risk than those with previous VTE related to a temporary risk factor. Screening for thrombophilia may be considered when a patient had VTE unrelated to a known risk factor or when a first-degree relative has a known high-risk thrombophilia (22–23). Pharmacologic DVT prevention is suggested in certain patients based on personal and family (first-degree relative) history of DVT and whether the patient has a known thrombophilia (Table 3) (22, 24). A recent report concluded that any recommendations concerning VTE prophylaxis in pregnancy were made from trials that were not of high methodological quality (25).
5 May 2015 Annals of Internal Medicine In the Clinic Downloaded From: http://annals.org/ by a Scott Memorial Library User on 05/13/2015
ITC3
Table 1. Risk Factor Guide for VTE in Hospitalized Medical Patients* Risk Factor
Points
Active cancer Previous VTE with exclusion of superficial vein thrombosis Reduced mobility Already known thrombophilic condition, defects of antithrombin, protein C or S, factor V Leiden, the antiphospholipid syndrome Recent (70 y) Heart and/or respiratory failure Acute myocardial infarction or ischemic stroke Acute infection or rheumatologic disorder Obesity (BMI >30 mg/k2) Ongoing hormonal treatment
3 3
3 3
2 1 1 1 1 1 1
BMI = body mass index; VTE = venous thromboembolism. * From reference 12. High risk for VTE is defined by a cumulative score ≥4 and low risk 25 kg/m2
Age 61–74 y Arthroscopic surgery Major open surgery (≥45 min) Laparoscopic surgery (>45 min) Cancer (past or present)
Age ≥75 y History of VTE Family history of VTE
Stroke (3 d or major surgery within 12 wk requiring general or regional anesthesia Localized tenderness along the distribution of the deep venous system Entire leg swollen Calf swelling 3 cm larger than asymptomatic side (measured 10 cm below the tibial tuberosity) Pitting edema confined to the symptomatic leg Collateral superficial veins (nonvaricose) Previously documented DVT Alternative diagnosis at least as likely as DVT DVT unlikely (score ≤1) or DVT likely (score ≥2)
Score 1
1
1
1
1 1
1 1 1 –2
Primary Care Rule† Male Use of hormonal contraceptives Active cancer in past 6 mo Surgery in previous month Absence of leg trauma Distention of collateral leg veins Difference in calf circumference ≥3 cm Abnormal D-dimer assay result Very low risk (score ≤3) or increased risk (score ≥4) DVT = deep venous thrombosis. * From Wells PS, Anderson DR, Rodger M, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med. 2003;349: 1227-35. † From Toll DB, Oudega R, Vergouwe Y, Moons KG, Hoes AW. A new diagnostic rule for deep vein thrombosis: safety and efficiency in clinically relevant subgroups. Fam Pract. 2008;25:3-8.
1 1 1 1 1 1
An alternative prediction score, termed the Primary Care Rule, was derived and validated in primary care patients presenting with symptoms of DVT (31) (Table 4). This rule has also been shown to be effective regardless of patient age, sex, and history of VTE. No matter which is used, a clinical prediction score should not be the sole criterion for diagnosing DVT and must be calculated in conjunction with D-dimer testing to determine whether additional studies are necessary.
What is the role of D-dimer testing? A meta-analysis showed that the 3-month incidence of VTE was 0.4% among patients with a low or intermediate clinical probability of VTE and a normal highly sensitive D-dimer test result (32).
Enzyme-linked immunoassay D-dimer tests have higher sensitivity and lower specificity, whereas whole-blood agglutination assays have lower sensitivity and higher specificity (33). Point-of-care testing is also available and can be used to rule out DVT in the emergency department or in outpatient practice.
2 6
A diagnostic meta-analysis of point-of-care D-dimer assays showed that quantitative assays had better sensitivity than qualitative assays. In this analysis, the most sensitive test had a sensitivity of 0.96 and a posttest probability of DVT of 0.9% in low-risk patients (34).
The sensitivity and specificity of D-dimer assays are suboptimal in pregnant women; patients receiving anticoagulation therapy; and those with prolonged clinical symptoms of DVT, prior DVT, or cancer. D-dimer levels also normally increase with age; however, the combination of a negative D-dimer assay along with a low pretest clinical probability has been shown to be associated with an acceptable negative pre-
姝 2015 American College of Physicians ITC6 In the Clinic Downloaded From: http://annals.org/ by a Scott Memorial Library User on 05/13/2015
dictive value in the elderly. D-dimer testing must be combined with an assessment of pretest probability to safely exclude DVT.
What is the role of venous ultrasonography? Figure 1 outlines the role of ultrasonography in the diagnosis of DVT. A meta-analysis of 100 cohort studies showed that venous ultrasonography has 94% sensitivity for detecting proximal venous thrombosis, 63% sensitivity for distal DVT, and 94% specificity for both (35).
Whereas one ultrasound method involves interrogation of only the common and popliteal veins (proximal ultrasonography), the other examines the entire deep vein system, including the calf veins (whole-leg ultrasonography). These methods have been investigated in prospective cohort and randomized studies and have been shown to be associated with an acceptable 3-month incidence of VTE after negative results. A meta-analysis of randomized and prospective cohort studies investigating the risk for VTE after a single negative, whole-leg ultrasound showed that this technique was associated with a low 3-month incidence of VTE (pooled incidence, 0.57%) (36).
The potential advantage of whole-leg ultrasonography is to avoid repeated testing. However, it may identify more patients with isolated, calf vein DVT, which has an uncertain clinical significance. In the meta-analysis, 52.1% of all DVTs diagnosed on the initial study were isolated calf vein thrombi (36).
What is the role of other types of testing? The role of other testing, such as computed tomography (CT) venography and magnetic resonance imaging (MRI), in diagnosing DVT is uncertain.
Annals of Internal Medicine
5 May 2015
Figure 1. DVT treatment algorithm.
Wells Score and Primary Care Rule
DVT unlikely
DVT likely
Sensitive D-dimer
Whole-leg ultrasonography
Negative
Positive
No further evaluation
Whole-leg ultrasonography
Negative
Positive Sensitive D-dimer
Isolated calf vein DVT
Negative
Proximal vein DVT
Treat
Do not treat
Symptomatic or high risk for propagation
High bleeding risk or low risk for propagation
Consider treatment
Repeat ultrasonography in 1 wk
Positive
Repeat ultrasonography in 1 wk
Negative
Do not treat
DVT = deep venous thrombosis.
Two separate meta-analyses of CT and MRI for the diagnosis of DVT showed high pooled sensitivity and specificity compared with a reference standard, which was most often ultrasonography for the CT studies and venography for the MRI investigations. However, the individual studies in both analyses had significant heterogeneity (37–38).
There are no management studies that have shown an acceptably low 3-month rate of VTE after negative results on CT or MRI, as has been shown with ultrasonography. Consequently, these methods are not recommended as first-line diagnostic tests, except in cases when ultrasonography cannot be performed (i.e., lower-extremity casting or severe edema precluding the ability to adequately visualize and compress vessels) (39).
How should a pregnant patient be evaluated for suspected DVT? Clinical prediction rules have not been formally validated in pregnant patients. Furthermore, D-dimer assays are associated with poor specificity, as most pregnant women have positive results on D-dimer testing by the third trimester. Compression ultrasonography is thus recommended as the initial test in this patient population, and follow-up ultrasonography is suggested in patients with an initial normal ultrasound. Patients with symptoms suggestive of iliac venous thrombosis (whole-leg edema or discomfort in the flank, back, or buttock) should have the pelvic vessels
5 May 2015 Annals of Internal Medicine In the Clinic Downloaded From: http://annals.org/ by a Scott Memorial Library User on 05/13/2015
ITC7
28. Kuipers S, Venemans A, Middeldorp S, et al. The risk of venous thrombosis after air travel: contribution of clinical risk factors [Letter]. Br J Haematol. 2014;165: 412-3. [PMID: 24428564] 29. Goodacre S, Sutton AJ, Sampson FC. Meta-analysis: the value of clinical assessment in the diagnosis of deep venous thrombosis. Ann Intern Med. 2005;143:129-39. [PMID: 16027455] 30. Geersing GJ, Zuithoff NP, Kearon C, et al. Exclusion of deep vein thrombosis using the Wells rule in clinically important subgroups: individual patient data meta-analysis. BMJ. 2014;348:g1340. [PMID: 24615063] 31. Oudega R, Moons KG, Hoes AW. Ruling out deep venous thrombosis in primary care. A simple diagnostic algorithm including D-dimer testing. Thromb Haemost. 2005;94:200-5. [PMID: 16113804] 32. Fancher TL, White RH, Kravitz RL. Combined use of rapid D-dimer testing and estimation of clinical probability in the diagnosis of deep vein thrombosis: systematic review. BMJ. 2004;329: 821. [PMID: 15383452] 33. Di Nisio M, Squizzato A, Rutjes AW, et al. Diagnostic accuracy of D-dimer test for exclusion of venous thromboembolism: a systematic review. J Thromb Haemost. 2007;5:296-304. [PMID: 17155963] 34. Geersing GJ, Janssen KJ, Oudega R, et al. Excluding venous thromboembolism using point of care D-dimer tests in outpatients: a diagnostic meta-analysis. BMJ. 2009;339:b2990. [PMID: 19684102] 35. Goodacre S, Sampson F, Thomas S, van Beek E, Sutton A. Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis. BMC Med Imaging. 2005;5:6. [PMID: 16202135] 36. Johnson SA, Stevens SM, Woller SC, et al. Risk of deep vein thrombosis following a single negative whole-leg compression ultrasound: a systematic review and metaanalysis. JAMA. 2010; 303:438-45. [PMID: 20124539]
姝 2015 American College of Physicians
Table 5. Differential Diagnosis of DVT Disease
Characteristics
Notes
Venous insufficiency (venous reflux)
Usually due to venous hypertension from such causes as venous reflux or obesity Firm, tender, varicose vein
Obtain ultrasonography of venous reflux
Superficial thrombophlebitis Muscle strain, tear, or trauma
Leg swelling in a paralyzed limb Baker cyst Cellulitis Lymphedema
Pain occurring with a range of motion more characteristic of orthopedic problem due to trauma; usually a history of leg injury History of paraplegia Pain localized to popliteal region of leg Skin erythema and warmth Toe edema is more characteristic of lymphedema than of venous edema
Superficial thrombosis is rarely associated with DVT Perform the appropriate orthopedic evaluation
Patients with paralyzed limb may develop edema without DVT Seen on ultrasonography Consider antibiotic treatment Lymphedema can occur in 1 or both legs
DVT = deep venous thrombosis.
evaluated with ultrasonography and/or MRI (24).
37. Thomas SM, Goodacre SW, Sampson FC, van Beek EJ. Diagnostic value of CT for deep vein thrombosis: results of a systematic review and meta-analysis. Clin Radiol. 2008;63:299-304. [PMID: 18275870] 38. Sampson FC, Goodacre SW, Thomas SM, van Beek EJ. The accuracy of MRI in diagnosis of suspected deep vein thrombosis: systematic review and meta-analysis. Eur Radiol. 2007;17:175-81. [PMID: 16628439] 39. Kearon C, Akl EA, Comerota AJ, et al; American College of Chest Physicians. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis. Chest. 2012;141: e419S-94S. [PMID: 22315268] 40. Kahn SR, Ginsberg JS. Relationship between deep venous thrombosis and the postthrombotic syndrome. Arch Intern Med. 2004;164:17-26. [PMID: 14718318] 41. Carrier M, Le Gal G, Wells PS, et al. Systematic review: the Trousseau syndrome revisited: should we screen extensively for cancer in patients with venous thromboembolism? Ann Intern Med. 2008;149: 323-33. [PMID: 18765702] 42. Cohn DM, Vansenne F, de Borgie CA, Middeldorp S. Thrombophilia testing for prevention of recurrent venous thromboembolism. Cochrane Database Syst Rev. 2012; 12:CD007069. [PMID: 23235639]
What other diagnoses should clinicians consider? The differential diagnosis of suspected DVT is extensive. Table 5 outlines the main alternative considerations. Such conditions as tendinitis, calf hematoma, PTS, advanced venous insufficiency, and arthritis should also be considered. When should clinicians consider consulting a specialist for diagnosing DVT? PTS occurs in 20%–50% of patients diagnosed with symptomatic DVT (40). Differentiating this condition from recurrent DVT can be challenging. Few welldesigned studies have investigated strategies to diagnose recurrent DVT. Furthermore, guidelines differ on which strategy should be used in suspected recurrent cases. Residual abnormalities on ultrasonography are common. Specific, well-defined criteria for diagnosing recurrent DVT, especially in venous segments with residual abnormalities, are lacking. For patients with recurrent DVT (particularly if the recurrence is questionable), a clinician should thus consider consulting a specialist. A referral should also be considered if im-
姝 2015 American College of Physicians ITC8 In the Clinic Downloaded From: http://annals.org/ by a Scott Memorial Library User on 05/13/2015
aging is nondiagnostic or if suspicion for DVT remains high despite negative testing.
What other underlying conditions and clinical manifestations should clinicians look for? Within 12 months of a VTE diagnosis, 3.5%–10% of patients will be diagnosed with cancer (41), and this risk seems to be higher in patients with an unprovoked thrombosis. Although a systematic review showed that an extensive screening strategy significantly increased the proportion of patients diagnosed with cancer, there are no randomized, controlled trials that have shown a mortality benefit of an extensive screening protocol. Other factors, such as patient anxiety, radiation exposure, and risks of additional diagnostic procedures, have not been formally investigated. Cancer screening that is tailored according to the patient's age, symptoms, and risk factors is thus suggested in patients who are diagnosed with DVT. The role of thrombophilia testing is also uncertain. There are no randomized, controlled clinical trials that have investigated the role of such testing to assess the risk for recurrent VTE (42). Consequently, there is no consensus
Annals of Internal Medicine
5 May 2015
among the guidelines regarding which, if any, patients should be tested. Some societies advocate
testing young patients with a family history of DVT, whereas others do not.
Diagnosis... Individual clinical features have little predictive value in diagnosing DVT. Clinicians should consider using a clinical prediction rule that incorporates a sensitive D-dimer assay to stratify a patient's risk for thrombosis. Various clinical scores exist, of which the Wells score is the most studied. An alternative is the Primary Care Rule, which has also been shown to be effective in ruling out DVT in the primary care setting. Whole-leg ultrasonography may limit the need for repeated testing but will identify more patients with isolated calf vein thrombi. The use of an extensive cancer screening and thrombophilia testing strategy is controversial in patients who are diagnosed with DVT. Clinicians should consider consulting a specialist for patients with a possible recurrent DVT or in situations where the imaging studies are nondiagnostic or negative, particularly if suspicion for thrombosis is high.
CLINICAL BOTTOM LINE
Treatment As shown in Figure 2, DVT treatment is divided into several phases. Some of the novel oral anticoagulants (NOACs), such as rivaroxaban and apixaban, can be used immediately during the initial phase of treatment, whereas others, such as dabigatran etexilate and edoxaban, should not be used until the patient has been treated with a parenteral anticoagulant, such as UFH or LMWH, for at least 5 days. Table 6 summarizes the dosing regimens, mechanisms of action, and side effects of the available anticoagulants; as the table shows, a reduced dose of apixaban (2.5 mg twice daily) has also been approved for DVT treatment during the extended phase of therapy.
How should clinicians decide whether to treat patients on an outpatient or inpatient basis? Most patients with DVT can be safely treated with LMWH as outpatients. Several systematic reviews comparing patients with VTE treated with LMWH administered at home with those treated in the hospital found
no difference in outcomes (43). Furthermore, outpatient treatment of patients with PE at low risk for adverse events (as measured by a clinical prediction rule) has been shown to be safe and effective in several randomized, controlled trials and a systematic review (44).
A recent registry of more than 13 000 patients found that home treatment was associated with a better outcome than hospital treatment (45). However, clinicians should consider admitting patients who have difficulty managing their outpatient treatment.
What local measures should clinicians recommend? Data regarding the efficacy of compression therapy in reducing the risk for PTS conflict. For example, elastic compression stockings did not prevent PTS in a recent randomized, placebocontrolled trial (46). However, the clinician should consider early ambulation because it has not been shown to be associated with increased risk for PE in patients with acute DVT, and it may lead to more rapid resolution of limb pain (47). Early ambulation also has the potential to decrease PTS (39).
5 May 2015 Annals of Internal Medicine In the Clinic Downloaded From: http://annals.org/ by a Scott Memorial Library User on 05/13/2015
ITC9
43. Segal JB, Streiff MB, Hofmann LV, et al. Management of venous thromboembolism: a systematic review for a practice guideline. Ann Intern Med. 2007;146: 211-22. [PMID: 17261856] 44. Squizzato A, Galli M, Dentali F, Ageno W. Outpatient treatment and early discharge of symptomatic pulmonary embolism: a systematic review. Eur Respir J. 2009;33:1148-55. [PMID: 19407049] 45. Lozano F, Trujillo-Santos J, Barro´n M, et al; RIETE Investigators. Home versus in-hospital treatment of outpatients with acute deep venous thrombosis of the lower limbs. J Vasc Surg. 2014;59:1362-7.e1. [PMID: 24439322] 46. Kahn SR, Shapiro S, Wells PS, et al; SOX trial investigators. Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet. 2014;383:880-8. [PMID: 24315521] 47. Kahn SR, Shrier I, Kearon C. Physical activity in patients with deep venous thrombosis: a systematic review. Thromb Res. 2008;122:763-73. [PMID: 18078981]
姝 2015 American College of Physicians
Figure 2. Phases of anticoagulation treatment.
Long-Term
Initial
IV heparin SC heparin LMWH Fondaparinux Rivaroxaban Apixaban
0–10 d
Extended
Vitamin K antagonist Rivaroxaban Dabigatran LMWH* Apixaban Edoxaban
10 d–3 mo
3 mo–Indefinite
IV = intravenous; LMWH = low-molecular-weight heparin; SC = subcutaneous. * Preferred in patients with cancer.
48. Agnelli G, Buller HR, Cohen A, et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799808. [PMID: 23808982] 49. Castellucci LA, Cameron C, Le Gal G, et al. Clinical and safety outcomes associated with treatment of acute venous thromboembolism: a systematic review and meta-analysis. JAMA. 2014;312:1122-35. [PMID: 25226478] 50. van der Hulle T, Kooiman J, den Exter PL, et al. Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost. 2014;12: 320-8. [PMID: 24330006] 51. Schulman S, Kakkar AK, Goldhaber SZ, et al; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129:764-72. [PMID: 24344086] 52. Prins MH, Lensing AW, Bauersachs R, et al; EINSTEIN Investigators. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J. 2013;11:21. [PMID: 24053656]
When should clinicians start anticoagulants? There are no randomized studies investigating the timing of anticoagulation therapy initiation in patients with suspected DVT. In patients with a high pretest probability of DVT and a low risk for bleeding, it is reasonable to initiate a short-acting anticoagulant while awaiting the results of the diagnostic work-up, particularly if there is a delay in testing. In patients who are diagnosed with acute proximal DVT, the clinician should initiate anticoagulation with either a parental anticoagulant or apixaban or rivaroxaban immediately unless contraindicated. If a vitamin k antagonist (VKA) is chosen for the long-term phase of therapy, it should be started on the same day as the parental anticoagulant. Robust evidence on the treatment of an isolated calf vein thrombosis is lacking. Immediate initiation of anticoagulation is preferred in patients whose symptoms (particularly if severe) are probably related to calf vein thrombosis or if the patient has a high risk for thrombus propagation (i.e., active cancer, large thrombus burden, location of
姝 2015 American College of Physicians ITC10 In the Clinic Downloaded From: http://annals.org/ by a Scott Memorial Library User on 05/13/2015
thrombus close to the popliteal junction, or history of DVT), particularly if the bleeding risk is low (39). Weekly surveillance ultrasonography for two weeks is preferred in other patients (31).
Which anticoagulants should clinicians use? Figure 2 summarizes the treatment options for each phase of anticoagulation therapy. Several of the NOACs have been studied for the treatment of VTE and have been shown to be effective and safe (48). Table 6 outlines the anticoagulant regimens that can be used for DVT. Subcutaneous heparin (either with monitored or unmonitored activated partial thromboplastin time [aPTT]) is an alternative to intravenous heparin in patients with renal insufficiency, those with poor intravenous access, or pregnant patients beyond 36 weeks of gestation. A meta-analysis comparing the efficacy and safety of various anticoagulation options showed that the combination of UFH and VKAs was associated with a higher risk for recurrent VTE than the combination of low-molecular-weight heparin (LMWH) and VKAs. All of the NOACs were found to be as effective as standard therapy. Rivaroxaban and apixaban were associated with a lower
Annals of Internal Medicine
5 May 2015
Table 6. Drug Treatment for DVT Drug, Dosage
Mechanism of Action
Side Effects
LMWH Dalteparin, 200 IU/kg SC once daily Enoxaparin, 1 mg/kg SC every 12 h or 1.5 mg/kg every 24 h Tinzaparin, 175 IU/kg SC once daily IV or SC UFH to keep aPTT ≥1.5 times control value
Direct anti-factor Xa effect; also inhibits thrombin via antithrombin activation
Bleeding, thrombocytopenia, hypersensitivity, osteoporosis, HIT
Enhances antithrombin activity, thereby inhibiting thrombin activation (and to a lesser extent factor Xa activity) Inhibits factor Xa
Bleeding, thrombocytopenia, hypersensitivity, osteoporosis, elevation of liver enzymes, hyperkalemia, HIT
Fondaparinux 100 kg, 10 mg SC daily Coumarin derivatives Overlap UFH, LMWH, or fondaparinux for at least 5 d and until INR 2–3 for 24 h Apixaban Acute phase*: 10 mg twice daily × 7 d followed by 5 mg twice daily Extended phase†: 2.5 mg twice daily Rivaroxaban Acute phase*: 15 mg twice daily for 21 d followed by 20 mg daily Extended phase‡: 20 mg daily IV direct thrombin inhibitors Lepirudin, 0.1 mg/kg/h Bivalirudin, 0.75mg/kg IV loading; then 1.75 mg/kg/h Argatroban, 2 μg/kg/min Consider dose reduction in critically ill Oral direct thrombin inhibitor Dabigatran etexilate Acute phase: 150 mg twice daily after at least 5 d of parenteral anticoagulation Extended phase: 150 mg twice daily
Inhibits generation of vitamin k–dependent coagulation factors II, VII, IX, and X Direct anti-Xa effect
Bleeding, purpura, anemia
Hypercoagulability during first few days of treatment, bleeding, hypersensitivity, teratogenicity, drug interactions, skin necrosis, osteoporosis Bleeding, hypersensitivity, interaction with p-GP or cytochrome p450 inducers/inhibitors
Direct anti-Xa effect
Bleeding, hypersensitivity, case reports of possible liver toxicity, interaction with p-GP or cytochrome p450 inducers/inhibitors
Directly inhibits thrombin activity
Bleeding, hypersensitivity, injection-site reactions
Bleeding, hypersensitivity, dyspepsia, possible increased risk for ACS compared with VKA, interaction with p-GP inducers/inhibitors
ACS = acute coronary syndrome; aPTT = activated partial thromboplastin time; DVT = deep venous thrombosis; HIT = heparininduced thrombocytopenia; INR = international normalized ratio; IV = intravenous; LMWH = low-molecular-weight heparin; p-GP = p-glycoprotein; SC = subcutaneous; UFH = unfractionated heparin; VKA = vitamin k antagonist. * Acute phase = first 5–10 d of treatment for acute DVT. † Extended phase = period after first 6 mo of treatment. ‡ Extended phase = period after first 21 d of treatment.
risk for major bleeding than either the UFH- or the LMWH-VKA combination in this analysis (49). In a separate meta-analysis, the NOACs were found to be as effective as the VKAs and were associated with a lower risk for bleeding complications (50).
All of the NOACs as well as the LMWHs undergo renal excretion. UFH and VKAs thus remain the anticoagulants of choice in patients with renal insufficiency. The elderly and patients with active cancer or underlying thrombophilia were underrepresented in the NOAC clinical trials. In a
pooled analysis, clinically relevant bleeding occurred more often in patients older than 85 years who were treated with dabigatran for VTE than in those who received warfarin. However, sex, creatinine clearance, ethnicity, and body mass index did not influence bleeding outcomes. In this analysis, there was no difference in efficacy between dabigatran and standard therapy in patients with cancer or those who presented with a symptomatic PE (51). In a pooled analysis of the rivaroxaban
trials, fragility (age >75 years, creatinine clearance
