Update Management of Venous Thromboembolism

Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism, is a common cardiovascular disease associated with significant morbidity ranging from painful leg swelling, chest pain, shortness of breath, to the most debilitating manifestation of death. Long-term complications include recurrent VTE, post-pulmonary embolism syndrome, chronic thromboembolic pulmonary hypertension (CTEPH), and post-thrombotic syndrome (PTS). Management of VTE requires immediate anticoagulation therapy based on risk of bleeding. Direct oral anticoagulants (DOACs) have become an important option for patients as reflected in the most recent American College of Chest Physician treatment guidelines.1-3

The initial management of patients with a PE is based on the patient’s risk stratification into low, intermediate, or high risk for 30-day mortality. This risk stratification can be done by using pulmonary embolism severity index (PESI) or its simplified version (simplified PESI).1 Low-risk patients, who are hemodynamically stable, can be treated as outpatients if home circumstances are adequate. 2 While at the other extreme, patients with acute PE and hypotension or patients with DVT-associated phlegmasia of the lower leg should be considered for treatment with thrombolytic agents3

Oral anticoagulants
Anticoagulants are the mainstay treatment of VTE and are given in three phases of acute, long-term (in the first 3 months), and extended treatment.3 For many years initial treatment was started with a parenteral anticoagulant such as low-molecular-weight heparin (LMWH), overlapping with a vitamin K antagonist (VKA), such as warfarin. The combination was continued for at least 5 days until the therapeutic level of international normalized ratio of 2 to 3 is achieved. Although conventional therapy with VKAs is effective and safe, it has some limitations including delayed onset, needs for parental daily injections, and also interactions with dietary vitamin K and numerous drugs. Over the past 5 years, four types of DOACs have been approved for acute and long-term treatment of VTE.

Thrombolytic and interventional treatment for acute venous thromboembolism
Anticoagulant therapy alone is recommended over thrombolysis for most patients with an acute DVT with an exception for those with extensive iliofemoral or proximal DVT at high risk of limb ischemia.3,4Thrombolytic therapy (systemic or catheter-directed) increases clot lysis and reduces the incidence of PTS compared to anticoagulation alone.4 Massive proximal DVT or iliofemoral thrombosis associated with limb-threatening ischemia or severe symptomatic swelling may be treated with thrombolysis. Thrombolysis can be considered only after objective diagnosis of the DVT and in a patient with low bleeding risk.

Systemic thrombolysis is a widely accepted treatment for PE in patients with persistent hypotension (e.g., systolic blood pressure ≺ 90 mmHg for 15 min) and not at high risk of bleeding.4 The use of thrombolytic therapy in intermediate-risk patients with acute PE associated with right ventricle (RV) dysfunction is controversial. The RV dysfunction is confirmed by echocardiogram or computed tomography and a positive troponin I/T. The potential indication for thrombolysis in this group is based on evidence that patients with severe RV dysfunction have worse prognosis than those without RV dysfunction.5

In a trial comparing the combination of LMWH plus an intravenous bolus of tenecteplase versus LMWH alone in intermediate-risk PE patients, those treated with tenecteplase had fewer adverse outcomes and better functional capacity at 90 days.5 Catheter Directed Thrombolysis (CDT) may be used in patients with acute PE at increased risk of bleeding as a lower dose of a thrombolytic agent is infused directly into the pulmonary artery via a catheter. 7 CDT is also effective in lowering pulmonary arterial pressure and improving RV function.

Outpatient treatment of venous thromboembolism
Home therapy is commonly employed for patients with an acute DVT in clinical practice with a few exceptions. Several randomized controlled trials and meta-analyses, which have compared home therapy with LMWH versus inpatient therapy with intravenous unfractionated heparin, suggest that outpatient therapy is safe and feasible in most patients with acute DVT. The decision for outpatient management should take into account the patient’s clinical condition, bleeding risk, preference, and availability of home support. Low-risk patients without RV dysfunction are potential candidates for a short in-hospital stay or entirely outpatient management.5

Vitamin K antagonists versus direct oral anticoagulants
Four DOACs including dabigatran, rivaroxaban, apixaban, and edoxaban were compared with conventional therapy in the RE-COVER I and II, EINSTEIN-DVT and PE, AMPLIFY, and Hokusai-VTE trials, respectively. The primary efficacy outcome was recurrent VTE or VTE-related mortality in all trials. The primary safety outcome was either major bleeding or a composite of major and clinically relevant non-major bleeding (CRNMB). All of the trials excluded patients with severe renal dysfunction, those with active bleeding or at high risk of bleeding, and patients already on therapeutic anticoagulation.

A recent pooled analysis of these 6 trials reported that DOACs have similar efficacy as VKA in the treatment of acute VTE and significantly lower risk of major bleeding than VKA. Compared with recipients of VKA therapy, intracranial bleeding, fatal bleeding, and CRNMB were significantly reduced in the DOACs group.8 Given the better safety profile of DOACs with less major bleeding, similar efficacy in prevention of recurrent VTE, and the convenience of administration of DOACs, the recent ACCP guidelines suggested DOACs over VKA for the acute and long-term treatment of VTE in patients without cancer.7

Management of VTE in patients with cancer
The major society guidelines including the ACCP, American Society of Clinical Oncology, and the National Comprehensive Cancer Network recommend the use of LMWH for treatment of VTE in cancer patients.4,7 Randomized trials have compared therapy with LMWH versus warfarin in cancer patients.9 There was a reduction in the rates of recurrent VTE using LMWH with no effect on mortality or bleeding.

  1. Donzé J, Le Gal G, Fine MJ, Roy PM, Sanchez O, Verschuren F, et al. Prospective validation of the Pulmonary Embolism Severity Index. A clinical prognostic model for pulmonary embolism. Thromb Haemost. 2008;100:943–8.
  2. Zondag W, Kooiman J, Klok FA, Dekkers OM, Huisman MV. Outpatient versus inpatient treatment in patients with pulmonary embolism: a meta-analysis. Eur Respir J. 2013; 42: 134–44.
  3. Chatterjee S, Chakraborty A, Weinberg I, Kadakia M, Wilensky RL, Sardar P, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014; 311: 2414–21.
  4. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel Report. Chest. 2016; 149: 315–52.
  5. Grifoni S, Olivotto I, Cecchini P, Pieralli F, Camaiti A, Santoro G, et al. Short-term clinical outcome of patients with acute pulmonary embolism, normal blood pressure, and echocardiographic right ventricular dysfunction. Circulation. 2000; 101: 2817–22.
  6. Kline JA, Nordenholz KE, Courtney DM, Kabrhel C, Jones AE, Rondina MT, et al. Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double-blind, placebo-controlled randomized trial. J Thromb Haemost. 2014; 12: 459–68.
  7. McCabe JM, Huang PH, Riedl L, Eisenhauer AC, Sobieszczyk P. Usefulness and safety of ultrasound-assisted catheter-directed thrombolysis for submassive pulmonary emboli. Am J Cardiol. 2015; 115: 821–4.
  8. van Es N, Coppens M, Schulman S, Middeldorp S, Büller HR. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood. 2014; 124: 1968–75.
  9. Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002; 162: 1729–35.

Written by: Alya Tanti N, S. Ked.

The writer is currently on her clerkship as a final year of co-assistant in West Nusa Tenggara Central Hospital, Universitas Mataram, West Nusa Tenggara. She has been actively writing on medical subject.

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Update Management of Venous Thromboembolism

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