The diagnosis of VTE is dependent on three elements: clinical pre-test probability, D-dimer testing, and imaging. Deep vein thrombosis and pulmonary embolism cannot be diagnosed by symptoms and signs only. Pre-test probability is calculated by one of various clinical prediction scores followed by D-dimer testing. The problem with D-dimer values is that the level rises with increasing age, and an age-adjusted value is suggested: age x 10ng/ml for patients older than 50 years. Compression venography of the proximal veins is a reliable test for the presence of proximal DVT.
Computed tomography pulmonary angiography to confirm the diagnosis of a pulmonary embolism has a good diagnostic accuracy and is relatively easy to perform and increasingly more widely available.
Treatment of venous thromboembolism
Aims of treatment
The concept is that the aim of treatment is prevention:
- Prevention of thrombus extension and embolisation
- Prevention of cardiopulmonary collapse
- Prevention of death
- Prevention of recurrent venous thromboembolism
- Prevention or reduction in the risk of long-term complications, especially bleeding.
- Anticoagulation is the first-line treatment therapy for most patients
- When a patient has a high probability to have VTE, it is advisable to initiate parenteral anticoagulation with LMWH subcutaneous 1mg’kg weight 12 hourly while awaiting test results
- The treatment of VTE has conceptually three phases of treatment:
Initial treatment for 5-10 days
- Hypoxaemia is a feature of severe PE and is due to a ventilation/perfusion mismatch. Supplemental oxygen is indicated when the oxygen saturation is below 90%2
- Low-molecular heparin (LMWH) such as Enoxaparin 1mg per kg body weight subcutaneous twice daily. Is preferred above that of unfractionated heparin. LMWH is associated with lower risk of recurrence and a lower risk of major bleeding than unfractionated heparin
- Direct-acting oral anticoagulants (DOACs) eg, rivaroxaban, dabigatran etc, are as effective in reducing recurrent VTE and associated with lower risk of bleeding. The DOACs are now the recommended anticoagulants for the treatment of VTE in most patients.
Rivaroxaban was tested as an initial treatment as a single oral drug compared to LMWH in objectively confirmed acute deep venous thrombosis cases in a dose of 15mg twice daily for three weeks followed by 20mg once daily for three, six and 12 months compared to subcutaneous enoxaparin 1mg/kg twice daily followed by vitamin-K-dependent antagonist in the EINSTEIN trial. Rivaroxaban was non-inferior with 36 events (recurrent VTE events) vs 51 events in LMWH plus Vitamin-K dependent antagonists with a p-value of < 0.001 for non-inferiority. Major bleeding was seen in 8.1% in both groups. Similar results were seen in the EINSTEIN-PE trial in patients with proven pulmonary embolism.
Dabigatran was evaluated in patients with VTE after the first 5-10 days in patients treated with LMWH. In this second period of treatment Dabigatran was compared to warfarin (Vitamin-K-dependant antagonist) and found to be non-inferior with less bleeding than warfarin.
The second phase of treatment for three-six months
Patients with a VTE should be treated for a minimum of three-six months to reduce the risk of a recurrent episode of VTE.
i. After the initial days on LMWH the choice would be a DOAC for three-six months.
ii. After the initial days on DOAC it is then continued for three-six months.
DOACs compared to initial LMWH followed by long-term warfarin, are noninferior with a lower risk of major bleeding as shown in this meta-analysis: 1.1% vs 1.8% risk ratio 0.62(95%CI: 0.45-0.85).
DOACs are generally avoided in patients who are also taking P-glycoprotein inhibitors or Cytochrome P450 inhibitors or inducers such as azole antimycotics (eg, ketoconazole), several proteases that are used to treat HIV (eg ritonavir), and antiepileptics (phenytoin and carbamazepine) because these drugs alter the plasma levels of DOACs.
Cancer patients have an increased risk of both a recurrent VTE and an increased bleeding risk and these patients are treated slightly differently.
In VTE associated with cancer, LMWH is preferred above warfarin. In a meta-analysis, the use of DOACs in cancer patients with VTE, is associated with 32% lower risk of recurrent VTE, but with a 36% higher risk of bleeding as compared to LMWH.
In patients with an unprovoked VTE, consider testing for anti-cardiolipin and Beta2-glycoprotein-1 antibodies and initiate a DOAC as therapy. If there is high antibody titre or positivity for both, switch to LMWH followed by warfarin.
Less data is available for DOACs in the following circumstances:
- eGFR less than 30ml/min
- Pregnant women, as DOACs cross placenta, should be avoided until tested.
The third phase is an extended duration of anticoagulation
After six months a decision must be made to discontinue or continue indefinitely after weighing up the consequences of long-term risk versus the risk of a major bleed due to the anticoagulant. Continuing anticoagulation beyond three-six months with a DOAC is associated with a reduction of 80% or more in recurrent VTE compared to placebo, with an increase of major bleeding of one-three times with a DOAC and four-five times with a vitamin-K dependent antagonist.
Consequently, DOACs are preferred over warfarin for indicated extended treatment of VTE.
Rivaroxaban became the first DOAC to be approved for use in extended treatment of VTE as discussed in an editorial in 2013.
In the Einstein-extension trial Rivaroxaban reduced the risk of a recurrent VTE by 82% (HR 018 95% CI: 0.09-0.39) with only four cases of a major bleed.
Aspirin is not recommended for extended treatment of VTE given its lower efficacy and similar safety profile than DOACs.
Major bleeding events occur at 1-2% per year on an anticoagulant and such bleeding has a larger risk of death than a recurrent VTE episode. Therefore, evaluating a bleeding risk takes preference in the decision to continue an anticoagulant. The risk factors that may predict the long-term risk of bleeding is:
- Age older than 65 years
- Antiplatelet therapy
- Chronic renal impairment with creatinine clearance of less than 50ml/min
- History of bleeding.
The presence of two or more of these risk factors is associated with an increased risk of bleeding of more than 2-3% every year. VTE associated provoked by a major transient factor, or an unprovoked isolated distal deep venous thrombosis have a low risk of recurrence and anticoagulation can be stopped after three months.
Patients with antiphospholipid syndrome, active cancer or a second episode of unprovoked VTE it is recommended to continue anticoagulation indefinitely.
Catheter-directed thrombolysis as the initial treatment of an acute DVT is not recommended unless the patients have a threatened limb due to the thrombus. Systemic thrombolysis as initial therapy for VTE is not recommended for patients that are haemodynamically stable even if there is right ventricular dysfunction and elevated cardiac biomarkers because the benefit in these circumstances is opposed by a high risk of intracranial bleeding and non-intracranial major bleeding. Systemic thrombolysis is recommended for high-risk PE with a rating of Class 1 (Indicated) with an evidence level of C. (consensus opinion or data only from an observational study or a registry).
Systemic thrombolysis (rescue thrombolysis) is also indicated in those patients who deteriorate haemodynamically while on full anticoagulation: Class 1 level B (single large RCT).
Vena Cava filters
This should only be used in patients in whom anticoagulation is contra-indicated.
Thromboprophylaxis in patients at risk for VTE is imperative in reducing the global burden and is warranted in those patients where the risk of major thromboembolism is higher than the risk of bleeding. Such patients are seen in major orthopaedic surgery and cancer surgery.
Some important concepts from the European Guidelines
- If you suspect a PE, start with anticoagulant therapy while awaiting confirmation of the diagnosis
- Prefer a DOAC over the traditional LMWH plus Vitamin-K-Dependant antagonist (Warfarin) if the patient does not have a contra-indication
- There is a life-long risk of recurrent VTE risk except in those patients who had a major transient risk factor. Therefore, it is necessary to evaluate the patient after the first three-six months of therapy to determine whether such a patient is eligible for extended treatment with an anti-coagulant
- Ongoing studies aims to improve the diagnostic work-out
- There are also ongoing studies with different DOACs comparing safety for the initial treatment to determine the initial preferred choice of drug.
The search for safer anticoagulant continues.
- Khan F, Tritschler T, Khan SR, Rodger MA. Venous thromboembolism. Lancet 2021;398: 64-77.
- 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). European Heart J 2020; 41: 543-603.
- Heit JA. Epidemiology of venous thromboembolism. Nat Rev Cardiol 2015; 12(8): 464-474.
- Goldhaber SZ. Risk factors for venous thromboembolism. J of the American College of Cardiology. 2010; 56(1): 1-7.
- Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13: 34-45.
- EINSTEIN investigators. Oral rivaroxaban for symptomatic venous thromboembolism. New Engl J Med 2010; 363: 2499-24510.
- Gomez-Outes A, Terleira-Fernandes AI, Lecumberri R et.al. Direct oral anticoagulants in the treatment of acute venous thromboembolism; a systematic review and meta-analysis. Thromb Res 2014; 134(4): 774-782.
- Tritschler T, Kraaijpoel N, Le Gal G et.al. JAMA Review. Venous thromboembolism: Advances in diagnosis and treatment, JAMA 2018; 320(15): 1583-1594.
- Mulder FI, Bosch FTM, Young AM et.al. Direct oral anticoagulants for cancer-associated venous thromboembolism: a systematic review and meta-analysis. Blood 2020; 136: 1433-1441.
- Cohen H, Hunt BJ, Efthymiou M et.al. Rivaroxaban vs. warfarin to treat patients with thrombotic antiphospholipid syndrome with or without systemic lupus erythematosus (RAPS): a randomised controlled open-label phase 2/3 non-inferiority trial Lancet Haematol 2016; 3: e426-436.
- Wang KL, van Es n, Cameron C et.al. Extended treatment of venous thromboembolism: a systematic review and network meta-analysis. Heart 2019; 105: 545-552.
- Kearon C, Khan SR. Longterm treatment of venous thromboembolism. Blood 2020; 135: 317-325.
Connors JM Extended treatment of venous thromboembolism. New Engl J Med 2013; 368: 767-769.
- Schulman S, Kearon C, Kakkar AE et.al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. New Engl J Med 2009; 361: 2342-52.