|Year : 2021 | Volume
| Issue : 1 | Page : 5-10
Consensus document on anticoagulant management of deep vein thrombosis: A review
VS Bedi1, Tarun Grover2, R Sekhar3, N Sekar4
1 Department of Peripheral Vascular and Endovascular Surgery, Sir Ganga Ram Hospital, New Delhi, India
2 Department of Peripheral Vascular and Endovascular Sciences, Medanta Hospital Delhi NCR, Gurugram, Maharashtra, India
3 Department of Vascular and Endovascular Surgery, Kokilaben Dhirubhai Ambani Hospital, Mumbai, Maharashtra, India
4 Department of Vascular and Endovascular Surgery, Kauvery Hospital, Chennai, Tamil Nadu, India
|Date of Submission||10-May-2020|
|Date of Acceptance||08-Oct-2020|
|Date of Web Publication||20-Feb-2021|
V S Bedi
Department of Peripheral Vascular and Endovascular Surgery, Sir Ganga Ram Hospital, New Delhi
Source of Support: None, Conflict of Interest: None
Deep-vein thrombosis (DVT) is encountered commonly in clinical practice. Recently, the European Society of Cardiology released guidelines on the diagnosis and management of venous thromboembolism. In this article, the authors reviewed the important aspects of DVT and advised on the clinical diagnosis and management of the same. Further, assessment of bleeding risk, risk of recurrences of DVT, and management of DVT in special situations is reviewed briefly. This will help physicians effectively diagnose and manage DVT in routine practice. Some of the essential clinical pearls include the following. Clinical risk prediction scores such as modified Wells score and Padua prediction score are effective tools used for screening DVT. Along with D-dimer assessment, venous ultrasound is helpful in confirming the DVT in “likely DVT” patients. Anticoagulation should be offered to all the patients diagnosed with DVT. Newer direct oral anticoagulants (DOACs) should be preferred. Among four commonly used DOACs, dabigatran and edoxaban use should be preceded by parenteral anticoagulants for at least 10 days without any drug overlap, whereas rivaroxaban and apixaban should be used as single-drug approach. Treatment duration should be 3–6 months and extended treatment should be based on the assessment of risk of bleeding and recurrences. Special situations such as DVT in upper extremity and in the elderly should be managed as recommended otherwise. For DVT pregnancy, low-molecular-weight heparin should be the anticoagulant of choice.
Keywords: Anticoagulants, D-dimer, deep-vein thrombosis, direct oral anticoagulants, venous ultrasonography
|How to cite this article:|
Bedi V S, Grover T, Sekhar R, Sekar N. Consensus document on anticoagulant management of deep vein thrombosis: A review. Indian J Vasc Endovasc Surg 2021;8:5-10
|How to cite this URL:|
Bedi V S, Grover T, Sekhar R, Sekar N. Consensus document on anticoagulant management of deep vein thrombosis: A review. Indian J Vasc Endovasc Surg [serial online] 2021 [cited 2021 Mar 1];8:5-10. Available from: https://www.indjvascsurg.org/text.asp?2021/8/1/5/309697
| Introduction|| |
It is estimated that the annual incidence rate of deep-vein thrombosis (DVT) is 67/100,000 general population. The incidence rate is higher for men (114/100,000) than women (105/100,000). The elderly are more frequently affected. Patients who had underwent recent surgery or hospitalization are at greatest risk of DVT. Development of pulmonary embolism (PE), thrombus extension in acute setting and DVT recurrences, postthrombotic syndrome, pulmonary hypertension, and mortality in long term necessitate early diagnosis and treatment of DVT.,, Anticoagulant treatment remains central to the management of DVT. The European Society of Cardiology (ESC) guidelines suggest three phases of DVT treatment. Parenteral therapy and Vitamin K antagonists (VKAs) or high-dose direct oral anticoagulants (DOACs) is the usual treatment modality for initial and long-term treatment. Risk/benefit analysis should be performed before consideration of treatment in extended phase (beyond 3–6 months). In addition, endovascular thrombus removal techniques such as catheter-directed thrombolysis (CDT) contribute to increased venous valvular function and potential reduction in the risk of long-term complications such as postthrombotic syndrome (PTS). Percutaneous mechanical thrombectomy (PMT) with CDT is considered safe and effective in patients with venous thrombo-embolism. In this review, we have discussed the current evidence with anticoagulants in the management of DVT.
| Diagnostic Approach to Deep-Vein Thrombosis|| |
Clinical prediction score in outpatient and inpatient settings, ultrasound imaging, and D-dimer testing are crucial in ascertaining the diagnosis of DVT.
Clinical prediction rules
Using these rules, patients can be categorized into low, moderate, or high probability of DVT. Based on ten evaluations included in the modified Wells score, patients are categorized into low risk (score 0 to 2), moderate risk (score 1–2), and high risk (score ≥3). Alternatively, DVT can be categorized as unlikely (score <2) and DVT likely (score >2). The Padua prediction score categorizes DVT as low risk for venous thromboembolism (VTE) (score <4) and high risk for VTE (score ≥4). Indian experts suggest modified Wells score in outpatient setting and the Padua score in hospitalized patients. Further, they suggest the use of Caprini score to determine the risk of DVT in patients undergoing general and abdomino-pelvic surgery. Caprini prediction score for surgical patients categorizes patients into four different risk groups “low risk” (0–1 points), “moderate risk” (2 points), “high risk” (3–4 points), and “highest risk” (≥5 points). With the advantage of easy calculation, this score is widely adopted and applied to hospitalized patients. The ESC guidelines recommend the use of modified Wells score (two levels – likely and unlikely) in stratifying patients suspected with DVT in the lower limbs. Here, we advise that modified Wells score should be used in DVT assessment of OPD patients, whereas Padua prediction score should be used in hospitalized patients.
The elevated levels of D-dimer may reflect nonspecific activation of the coagulation and fibrinolytic systems. For the exclusion of suspected VTE, D-dimer test is an excellent noninvasive test by virtue of its high negative predictive value.
Enzyme-linked immunofluorescent immunoassays (ELFAs) and microplate enzyme-linked immunosorbent assay (ELISA) are highly sensitive but moderately specific, whereas the latex qualitative and whole-blood D-dimer assays have higher specificities. Compared to the conventional cutoff level of 500 μg/L, Schouten et al. proposed cutoff levels of (age in years × 10 μg/L) in patients aged >50 years, or 750 μg/L in patients aged ≥60 years. There was a considerable increase in the number of patients who can safely be excluded with the use of the proposed cutoff levels than the conventional cutoff levels. A meta-analysis also confirmed this finding. The D-dimer test is recommended by guidelines to be included in the diagnostic considerations of all patients suspected with DVT, especially in those with “unlikely” DVT., The authors advise that D-dimer should be included in diagnostic assessment of all patients suspected with DVT.
Venous ultrasonography (VUS) incorporating compression ultrasonography with or without Doppler flow assessment is widely used. The ESC recommends VUS as first-line imaging for DVT. A mete-analysis by Kearon et al. observed that VUS is most accurate for a first symptomatic proximal DVT but not in asymptomatic postoperative patients. The accuracy of VUS was lower for symptomatic isolated distal (calf) than for proximal DVT and therefore, its clinical utility in distal vein DVT remains uncertain. Here, we advise that venous ultrasound of all patients in DVT-likely group should be carried to determine the site and extent of DVT.
Venous computed tomography
The sensitivity and specificity of computed tomography (CT) are similar to that of VUS in patients with suspected PE to determine suspected DVT but in patients with suspected DVT alone, its utility remains unclear. Possibly due to this reason, venous CT has been recommended in select patients only. Furthermore, it helps in the evaluation of etiologies such as intra-abdominal malignancies, especially in elderly patients with unprovoked DVT. The extent of PE can be delineated clearly using pulmonary CT angiography. It can also guide the decision-making whether the patients require an inferior vena cava filter or not.
Here, we advise that venous CT should be carried out in selected patients especially when VUS is indeterminate. Pulmonary CT angiography can be considered especially in high-risk patients, patients with extensive ileo-femoral DVT, and symptomatic VTE patients.
Other tests are reserved for selected unresolved patients. CT venography may be considered in younger especially male patients who develop acute ileo-femoral DVT, who have malignancy or limb swelling or lymphedema, and who have bilateral limb swelling.
| Treatment of Deep-Vein Thrombosis|| |
The 2017 ESC guidelines recommend three therapy phases [Table 1]. Initial therapy for the first 5-21 days and long-term therapy for the first 3-6 months. The first two phases are compulsory for all DVT patients. Continuing therapy in extended phase, that is, beyond the first 3–6 months needs to be decided by taking into account the benefit/risk of the ongoing anticoagulation.
Intravenous (IV) unfractionated heparin (UFH) may be preferred as the initial treatment in patients with severe renal failure, or patients at high risk of bleeding. However, it has disadvantages such as inter-individual dose variability, need of laboratory monitoring, and risk of heparin-induced thrombocytopenia. Given these problems with UFH, low-molecular-weight heparin (LMWH) can be considered the initial parenteral treatment modality. A mete-analysis by Gould et al. involving 37 studies reported that compared to UFH, LMWH reduced mortality rates over 3–6 months (odds ratio, 0.71; 95% confidence interval, 0.53–0.94; P = 0.02) with slightly lower risk of major bleeding complications (absolute risk reduction, 0.61%; 95% confidence interval, 20.04%–1.26%; P = 0.07). In preventing thrombo-embolic recurrences, both agents had equivalent effectiveness (odds ratio, 0.85; 95% confidence interval, 0.63–1.14; P > 0.2).
In a randomized trial involving 2205 patients with acute symptomatic DVT, fondaparinux was found equally effective to enoxaparin in preventing DVT recurrences over 3-month follow-up with no significant differences in major bleeding and mortality. Another study involving 2213 patients with acute symptomatic PE reported that once-daily, subcutaneous fondaparinux is similar in effectiveness and safety to adjusted-dose, IV UFH. The conclusion was based on a finding that fondaparinux compared to UFH had lower rates of recurrent thromboembolic events (3.8% vs. 5%, respectively). Major bleeding rates were comparable in two groups (1.3% vs. 1.1%, respectively).
Here, we advise that parenteral anticoagulant with LMWH should be considered in treatment algorithm if Vitamin K antagonists, dabigatran, and edoxaban are the oral agents being used for DVT. Fondaparinux can be an alternative choice to LMWH.
Vitamin K antagonist
Warfarin is the oldest and most widely oral anticoagulant which acts by inhibiting Vitamin K epoxide reductase (VKORC). This reduces hepatic production of coagulation factors such as II, VII, IX, and X. Its role in DVT and prevention of recurrences is well established. However, because of its multiple limitations, newer anticoagulants were developed. The limitations of warfarin are summarized in [Table 2].
Direct oral anticoagulants
[Table 3] describes the pharmacology of the four DOACs.,,,,, Among various DOACs, dabigatran and edoxaban have been evaluated after initial treatment (nearly 7–9 days) with a parenteral agent, whereas apixaban and rivaroxaban have been evaluated by the single-drug approach. A network meta-analysis by Cohen et al. found no significant differences in DOACs with regard to the risk of “VTE and VTE-related death.” Major bleeding or clinically relevant nonmajor bleeding was significant lower with apixaban compared to rivaroxaban (relative risk 0.47), dabigatran (relative risk 0.69), and edoxaban (0.54). A meta-analysis of randomized trials involving 27,023 patients reported equal rates of VTE recurrence after treatment with DOACs or conventional therapy (2.0% vs. 2.2%, relative risk 0.90). Major bleeding, fatal bleeding, intracranial bleeding, and clinically relevant nonmajor bleeding were found to be significantly lower in DOAC-treated patients. Here, we advise that DOACs should be considered as first-line agents in the treatment of DVT. If safety is a major concern, apixaban can be considered over other DOACs.
|Table 3: Comparative pharmacological properties of direct oral anticoagulants|
Click here to view
Other treatment options
Thrombolysis and thrombectomy
Removal of clot early in the course of DVT can help prevent postthrombotic syndrome (PTS) development. Catheter-directed thrombolysis (CDT) is found to be more efficient compared to systemic thrombolysis. In the CAVENT trial in patients with first-time acute DVT (iliac, common femoral, and/or upper femoral vein), the use of CDT in addition to anticoagulation was associated with 26% reduction of PTS compared to anticoagulation alone over 2 years. With the availability of newer minimally invasive endovascular modalities, mechanical thrombectomy is being performed with increasing frequency. Urgent procedure may be performed for salvation of limb from severe edema caused by venous obstruction. Emergent procedure may be necessary in IVC thrombosis especially in those with a risk of renal failure or Budd–Chiari syndrome due to renal or hepatic vein involvement, respectively. Elective procedure may be performed in symptomatic acute ileo-femoral DVT to prevent PTS. However, in patients with proximal DVT with acute venous thrombosis, no significant difference in occurrence of PTS in patients treated with pharmacomechanical-thrombolysis and the control group (47% and 48% respectively) was observed.
As per the expert opinion, at present, there is a major shift toward CDT for patients with proximal DVT, and CDT should be the treatment of choice for all patients with proximal DVT if there is no contraindication to CDT because of its significant benefits.
A major concern about caval filters is the development of thrombosis in inferior vena cava (IVC). Here, we advise that IVC filter should be used only when there are absolute contraindications or there is failure of oral or parenteral anticoagulants. Anticoagulants should be initiated immediately if the contraindications are resolved and filter should be removed.
Here, we advise that compression should be used in conjunction with other treatments for severe symptoms on presentation.
Home-based or in-hospital management
Here, we advise that patients with DVT can be effectively managed at home. Domiciliary or home-based treatment is especially good for infra-inguinal DVT and for patients who are asymptomatic for VTE.
Approach to treatment
For the proximal DVT, treatment for at least 3 months is recommended. Patients with distal DVT who are at high risk of recurrence should be anticoagulated as proximal DVT. In patients with distal DVT with low risk of recurrence, low-dose anticoagulation or ultrasound surveillance can be undertaken. If warfarin is used, concomitant initiation of parenteral coagulation along with warfarin is necessary for at least 5 days or till international normalized ratio (INR) is >2. Here, we advise that use of dabigatran or edoxaban should be preceded (at least 10 days) by parenteral anticoagulants with no drug overlap. If warfarin is being used, parenteral anticoagulants should be started simultaneously. Treatment should be continued for at least 3–6 months. The decision for extended treatment should be based on the risk of bleeding and likelihood of recurrences.
Bleeding risk assessment
In acute VTE cases, Hypertension, Abnormal renal/liver function, Stroke, Bleeding, Labile INR, Elderly, Drugs or alcohol use (HAS-BLED) score of ≥3 is associated with increased risk of major bleeding. Here, we advise that HAS-BLED risk score should be used to assess the risk of bleeding.
Assessment of recurrence of deep-vein thrombosis
Factors associated with recurrence include proximal DVT, old age, male gender, obesity, persistence of residual vein thrombosis, high D-dimer values, and early PTS development. The ESC guidelines advised Vienna prediction model, DASH score, and HERDOO-2 score for this purpose. A meta-analysis from the MARVELOUS Collaborators reported increasing cumulative incidence for recurrent VTE from 10% at 1 year, 16% at 2 years, 25% at 5 years, and 36% at 10 years. The mortality rate was 4% in recurrent VTE events. Here, we advise that assessment of risk of recurrence should be carried out using any of these validated scores.
| Deep-Vein Thrombosis in Special Situations|| |
Deep-vein thrombosis in upper extremity
Here we advise that the anticoagulation of VTE in upper limbs is similar to that recommended for lower limbs.
Deep-vein thrombosis in pregnancy
VUS is the main imaging test. Here, we advise that LMWH is the choice of anticoagulation in pregnancy. It should be given till 6 weeks postpartum or at least for a total period of 3 months. Lower doses can be considered in women with high bleeding risk, lower risk of recurrence, or high risk of osteoporosis.
Deep-vein thrombosis in the elderly
The risk of recurrence increases with age (~15%–20% increase per decade). Nearly 50% of patients may not receive adequate thrombo-prophylactic treatment. Here, we advise that DVT in the elderly should be diagnosed early and adequately treated with the use of anticoagulants.
| Conclusion|| |
Early identification is the key for effective treatment of DVT. Anticoagulation has remained a standard treatment. DOACs are preferred drugs for the management of DVT over long term. All patients should be adequately assessed for the risk of recurrences. Continuation of treatment for over 3–6 months needs clinical decisions to be based on the risk–benefit ratio in individual patients.
The authors would like to thank Dr. Vijay Katekhaye from QuestMedpharma for providing support in manuscript writing.
We gratefully acknowledge the contribution of experts across India who gave their expert opinion in advisory board meeting: V. S. Bedi, Tarun Grover, N. Sekar, Roy Varghese, Rajesh, R. Sekhar, Sanjay Godbole, Kapil Rathi, Simit D Vora, Hemil Patel, and Srujal Shah.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Silverstein MD, Heit JA, Mohr DN, Petterson TM, O'Fallon WM, Melton LJ 3rd
. Trends in the incidence of deep vein thrombosis and pulmonary embolism: A 25-year population-based study. Arch Intern Med 1998;158:585-93.
Heit JA. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol 2008;28:370-2.
Mazzolai L, Aboyans V, Ageno W, Agnelli G, Alatri A, Bauersachs R, et al
. Diagnosis and management of acute deep vein thrombosis: A joint consensus document from the European society of cardiology working groups of aorta and peripheral vascular diseases and pulmonary circulation and right ventricular function. Eur Heart J 2017;39:4208-18.
Kesieme E, Kesieme C, Jebbin N, Irekpita E, Dongo A. Deep vein thrombosis: A clinical review. J Blood Med 2011;2:59-69.
Leizorovicz A. Long-term consequences of deep vein thrombosis. Haemostasis 1998;28(Suppl. 3):1-7.
Fleck D, Albadawi H, Shamoun F, Knuttinen G, Naidu S, Oklu R. Catheter-directed thrombolysis of deep vein thrombosis: Literature review and practice considerations. Cardiovasc Diagn Ther 2017;7(Suppl 3):S228-37.
Liu B, Liu M, Yan L, Yan J, Wu J, Jiao X, et al
. Percutaneous mechanical thrombectomy combined with catheter-directed thrombolysis in the treatment of acute pulmonary embolism and lower extremity deep venous thrombosis: A novel one-stop endovascular strategy. J Int Med Res 2018;46:836-51.
Wells PS, Anderson DR, Bormanis J, Guy F, Mitchell M, Gray L, et al
. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 1997;350:1795-8.
Barbar S, Noventa F, Rossetto V, Ferrari A, Brandolin B, Perlati M, et al
. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: The Padua Prediction Score. J Thromb Haemost 2010;8:2450-7.
Parakh R, Krishna PR, Amin P, Bedi VS, Desai S, Dumra HS, et al
. Consensus on Management of Deep Vein Thrombosis with Emphasis on NOACs (Non-Vitamin K Antagonist Oral Anticoagulants): Recommendations from Inter-Disciplinary Group of Indian Experts. J Assoc Physicians India2016;64 (9 Suppl):7-26.
Caprini JA. Thrombosis risk assessment as a guide to quality patient care. Dis Mon; 51:70-8.
Grant PJ, Greene MT, Chopra V, Bernstein SJ, Hofer TP, Flanders SA. Assessing the Caprini score for risk assessment of venous thromboembolism in hospitalized medical patients. Am J Med 2016;129:528-35.
Di Nisio M, Squizzato A, Rutjes AW, Büller HR, Zwinderman AH, Bossuyt PM. Diagnostic accuracy of D-dimer test for exclusion of venous thromboembolism: A systematic review. J Thromb Haemost 2007;5:296-304.
Schouten HJ, Koek HD, Oudega R, Geersing GJ, Janssen KJ, van Delden JJ, et al
. Validation of two age dependent D-dimer cut-off values for exclusion of deep vein thrombosis in suspected elderly patients in primary care: Retrospective, cross sectional, diagnostic analysis. BMJ 2012;344:e2985.
Schouten HJ, Geersing GJ, Koek HL, Zuithoff NP, Janssen KJ, Douma RA, et al
. Diagnostic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with suspected venous thromboembolism: Systematic review and meta-analysis. BMJ 2013;;346:f2492.
Kearon C, Julian JA, Math M, Newman TE, Ginsberg JS. Noninvasive diagnosis of deep venous thrombosis. Ann Intern Med 1998;128:663-77.
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. Clinical Radiol 2008;63:299-304.
Alduk AM, O'Sullivan GE. CT venography: Technique and indication. Endovasc Today 2018;17:60-2.
Gould MK, Dembitzer AD, Doyle RL, Hastie TJ, Garber AM. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis: A meta-analysis of randomized, controlled trials. Ann Intern Med 1999;130:800-9.
Büller HR, Davidson BL, Decousus H, Gallus A, Gent M, Piovella F, et al
. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: A randomized trial. Ann Intern Med 2004;140:867-73.
Matisse Investigators. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 2003;349:1695-702.
Gross PL, Weitz JI. New anticoagulants for treatment of venous thromboembolism. Arterioscler Thromb Vasc Biol 2008;28:380-6.
Cohen AT, Hamilton M, Mitchell SA, Phatak H, Liu X, Bird A, et al
. Comparison of the Novel Oral Anticoagulants Apixaban, Dabigatran, Edoxaban, and Rivaroxaban in the Initial and Long-Term Treatment and Prevention of Venous Thromboembolism: Systematic Review and Network Meta-Analysis. PLoS One 2015;10:E0144856.
van Es N, Coppens M, Schulman S, Middeldorp S, Buller HR. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: Evidence from phase 3 trials. Blood 2014;124:1968-75.
Enden T, Haig Y, Klow NE, Slagsvold CE, Sandvik L, Ghanima W, et al
. Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): A randomised controlled trial. Lancet 2012;379:31-8.
Kohi MP, Kohlbrenner R, Kolli KP, Lehrman E, Taylor AG, Fidelman N. Catheter directed interventions for acute deep vein thrombosis. Cardiovasc Diagn Ther 2016;;6:599-611.
Vedantham S, Goldhaber SZ, Julian JA, Kahn SR, Jaff MR, Cohen DJ, et al
. Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis. N Engl J Med 2017;377:2240-52.
Andreoli JM, Thornburg BG, Hickey RM. Inferior vena cava filter-related thrombus/deep vein thrombosis: Data and management. Semin Intervent Radiol 2016;33:101-4.
DeYoung E, Minocha J. Inferior vena cava filters: guidelines, best practice, and expanding indications. Semin Intervent Radiol 2016;33:65-70.
Othieno R, Okpo E, Forster R. Home versus in-patient treatment for deep vein thrombosis. Cochrane Database Syst Rev 2018;1:CD003076.
Kooiman J, van Hagen N, Iglesias del Sol A, Planken EV, Lip GY, van der Meer FJ, et al
. The HAS-BLED score identifies patients with acute venous thromboembolism at high risk of major bleeding complications during the first six months of anticoagulant treatment. PLoS One 2015;10:E0122520.
Khan F, Rahman A, Carrier M, Kearon C, Weitz JI, Schulman S, et al
. Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: Systematic review and meta-analysis. BMJ 2019;366:l4363.
Silverstein RL, Bauer KA, Cushman M, Esmon CT, Ershler WB, Tracy RP. Venous thrombosis in the elderly: More questions than answers. Blood 2007;1:110:3097-101.
Piazza G, Seddighzadeh A, Goldhaber SZ. Deep-vein thrombosis in the elderly. Clin Appl Thromb Hemost 2008;14:393-8.
[Table 1], [Table 2], [Table 3]