Guidelines on Venous Thromboembolism Treatment Offer Key Resource

Venous thromboembolism (VTE) results from abnormal clot formation leading to venous thrombosis.

The primary forms of VTE are deep venous thrombosis (DVT) and pulmonary embolism (PE). A range of 300,000 to 600,000 cases of VTE occur annually, with 60,000 to 80,000 deaths attributed to DVT or PE.¹ Pharmacologic options for prevention and treatment of VTE include direct oral anticoagulants (DOACs); fondaparinux, an indirect synthetic inhibitor of activated factor Xa; low-molecular-weight heparins (LMWHs); unfractionated heparin; and vitamin K antagonists (VKAs).²

In late 2021, the American College of Chest Physicians published an update of its CHEST guidelines for the treatment of VTE, which includes 29 guidance statements.^3,4 This review provides a brief summary of those statements. For the management of acute isolated distal DVT, anticoagulation is suggested over serial imaging in patients with severe symptoms or risk factors for extension. Otherwise, serial imaging for 2 weeks is suggested over anticoagulation. After serial imaging, anticoagulation is not recommended if there is no thrombus extension present. If the thrombus extends but remains confined to the distal veins, anticoagulation is suggested, but if it extends to the proximal veins, then anticoagulation is strongly recommended.

In managing patients with a subsegmental PE and no proximal DVT in the legs, clinical surveillance is suggested over anticoagulation if there is a minimal risk of recurrent VTE, especially as findings of subsegmental PE are more likely to be false-positive.^5,6 If there is an elevated risk of recurrent VTE, then anticoagulation is suggested over clinical surveillance. Regarding acute PE, it is suggested that anticoagulant therapy for patients with an incidentally diagnosed asymptomatic acute PE not differ from comparable patients with symptomatic PE based on observational data suggesting a similar prognosis of asymptomatic versus symptomatic PE.⁷

For management of cerebral vein thrombosis (CVT), anticoagulation is strongly recommended for at least the treatment phase during the first 3 months, regardless of whether an intracranial hemorrhage occurs as a complication of CVT. Initial anticoagulant therapy should be given with dose-adjusted heparin or LMWH, and patients stabilized on heparin should be switched to oral anticoagulation.

When considering interventional (mechanical, pharmacomechanical, or thrombolytic) therapy, the increased risk of bleeding, including intracranial bleeding, must be considered.⁸ Anticoagulation alone is suggested over interventional therapy in managing acute DVT. As for interventional therapy in acute PE, the guidelines strongly recommend against systemic thrombolysis in most patients with acute PE not associated with hypotension. In selected patients with acute PE who deteriorate after receiving anticoagulant therapy, are not yet hypotensive, and have an acceptable bleeding risk, systemic thrombolysis is suggested. Systemic thrombolysis is also suggested if hypotension is present (eg, systolic blood pressure <90 mmHg) and there is no elevated risk of bleeding. An alternative mode of therapy, catheter-assisted thrombus removal, is suggested if hypotension is present along with a high bleeding risk, failed systemic thrombolysis, or shock that is likely to cause death before systemic thrombolysis can take effect. Otherwise, systemic thrombolysis is suggested over catheter-directed thrombolysis.

Regarding the use of an inferior vena cava (IVC) filter, it is only recommended in patients with acute proximal DVT who have a contraindication to anticoagulation. Otherwise, the guidelines recommend against the use of IVC filter in addition to anticoagulants in treating acute DVT.

It is also strongly recommended to treat patients with low-risk PE on an outpatient basis provided the adequacy of home circumstances and access to outpatient care. Specifically, patients must be clinically stable with good cardiopulmonary reserve, be compliant with treatment, feel well enough to be treated at home, and have no contraindications such as severe renal disease.

For patients who have an acute VTE, the strongly recommended treatment is apixaban, dabigatran, edoxaban, or rivaroxaban over a VKA during the treatment phase for the first 3 months. This choice is also based on payor considerations and patient-specific factors, such as bleeding risk, preference, and renal function. For patients with cancer with an acute VTE, a DOAC, such as apixaban, edoxaban, or rivaroxaban is strongly recommended over a LMWH for the initiation and treatment phases of therapy. LMWH has been associated with a decreased risk of VTE. However, it is considered a lifestyle burden and is costly for many patients.⁹ Cancer patients do present with a higher risk of major bleeding than those without cancer, but a DOAC has led to a decrease in VTE risk in many trials.⁹

Additionally, in patients with antiphospholipid syndrome (APS), patients should be treated with an adjusted dose of VKA over DOAC therapy during the treatment phase. For initiating VKA therapy, an overlap dose of anticoagulation should be included as well.¹⁰ Reasons why DOACs are not chosen include inhibition of only 1 coagulation factor versus several with VKA, low adherence to treatment, and their short half-lives, but further literature is needed to evaluate DOACs in patients with APS.¹⁰

Regarding superficial venous thrombosis (SVT), though it has historically been classified as benign, recent experience has demonstrated its seriousness. Hence, it is recommended that anticoagulation be continued for 45 days to lessen the risk of progression to DVT or PE. A dose of Fondaparinux 2.5 mg is recommended daily over other anticoagulation treatments. If the parenteral route is inappropriate, then a DOAC, such as rivaroxaban, can be used. In the open-label SUPRISE (NCT01499953) study, patients were randomly assigned to receive 10 mg oral rivaroxaban or subcutaneous fondaparinux.¹¹ This non-inferiority study found that rivaroxaban was non-inferior to fondaparinux for the treatment of SVT in terms of diagnosis of DVT or PE events.¹¹ The use of rivaroxaban simplifies treatment for many patients, because of its oral route of administration.

For patients with acute VTE with no contraindications, a 3-month treatment phase is strongly recommended. At 3 months, all patients should be properly assessed for an extension of therapy. For patients who have a provoked VTE, an extended phase of treatment is recommended against, but in patients with an unprovoked VTE, the use of a DOAC is strongly recommended. For patients who do undergo extended-phase therapy, it is weakly recommended to use a low-dose DOAC and there is not much literature supported.¹² Specifically, the guidelines prefer apixaban 2.5 mg twice daily or rivaroxaban 10 mg daily. Additionally, in the case of choosing between aspirin and an anticoagulant for extended-phase therapy, a low-dose anticoagulant is strongly recommended over aspirin, as the latter has been much less effective in secondary VTE prevention.¹³ However, if a patient chooses to completely stop anticoagulation, then aspirin is weakly recommended over completely discontinuing therapy. With patients with DVT in the leg, compression stockings are also not recommended to prevent any post-thrombotic syndrome.¹⁴

Overall, the updated CHEST guidelines are a valuable resource, as they are backed by many randomized controlled trials that would lead health care professionals in the right direction in treating VTEs. Health care professionals should look into the weak, moderate, and strong recommendations and assess for the most relevant ones to provide individualized patient care.

References

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2. Lyman GH, Carrier M, Ay C, et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Blood Adv. 2021;5(4):927-974. doi:10.1182/bloodadvances.2020003442

3. Stevens SM, Woller SC, Kreuziger LB, et al. Antithrombotic therapy for VTE disease: second update of the CHEST guideline and expert panel report. Chest. 2021;160(6):e545-e608. doi:10.1016/j.chest.2021.07.055

4. Stevens SM, Woller SC, Kreuziger LB, et al. Antithrombotic therapy for VTE disease: second update of the CHEST guideline and expert panel report (executive summary). Chest. 2021;160(6):2247-2259. doi:10.1016/j.chest.2021.07.056

5. Carrier M, Righini M, Le Gal G. Symptomatic subsegmental pulmonary embolism: what is the next step? J Thromb Haemost. 2012;10(8):1486-1490. doi:10.1111/j.1538-7836.2012.04804.x

6. Stein PD, Fowler SE, Goodman LR, et al. Multidetector computed tomography for acute pulmonary embolism. N Engl J Med. 2006;354(22):2317-2327. doi:10.1056/NEJMoa052367

7. van der Hulle T, den Exter PL, Planquette B, et al. Risk of recurrent venous thromboembolism and major hemorrhage in cancer-associated incidental pulmonary embolism among treated and untreated patients: a pooled analysis of 926 patients. J Thromb Haemost. 2016;14(1):105-113. doi:10.1111/jth.13172

8. Kearon C, Gu CS, Julian JA, et al. Pharmacomechanical catheter-directed thrombolysis in acute femoral-popliteal deep vein thrombosis: analysis from a stratified randomized trial. Thromb Haemost. 2019;119(4):633-644. doi:10.1055/s-0039-1677795

9. Wang TF, Li A, Garcia D. Managing thrombosis in cancer patients. Res Pract Thromb Haemost. 2018;2(3):429-438. doi:10.1002/rth2.12102

10. Zuily S, Cohen H, Isenberg D, et al. Use of direct oral anticoagulants in patients with thrombotic antiphospholipid syndrome: guidance from the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost. 2020;18(9):2126-2137. doi:10.1111/jth.14935

11. Beyer-Westendorf J, Schellong SM, Gerlach H, et al. Prevention of thromboembolic complications in patients with superficial-vein thrombosis given rivaroxaban or fondaparinux: the open-label, randomised, non-inferiority SURPRISE phase 3b trial. Lancet Haematol. 2017;4(3):e105-e113. doi:10.1016/S2352-3026(17)30014-5

12. Streiff MB, Agnelli G, Connors JM, et al. Guidance for the treatment of deep vein thrombosis and pulmonary embolism. J Thromb Thrombolysis. 2016;41:32-67. doi:10.1007/s11239-015-1317-0

13. Becattini C, Agnelli G, Schenone A, et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012;366(21):1959-1967. doi:10.1056/NEJMoa1114238

14. Kahn SR, Shapiro S, Wells PS, et al. Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet. 2014;383(9920):880-888. doi:10.1016/S0140-6736(13)61902-9