VTE management

VTE management guidelines

Professor Stavros Konstantinides, Medical Director of the Center for Thrombosis and Hemostasis at Johannes Gutenberg University Mainz in Germany, provides an overview of key updated guideline recommendations in 2019–2021 and their impact on clinical practice.

Clinical practice guidelines for management of VTE include:

• 2019 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines¹
• 2020 American Society of Hematology (ASH) guidelines²
• 2020 National Institute for Health and Care Excellence (NICE) guidelines³
• 2021 European Society for Vascular Surgery (ESVS) guidelines⁴
• 2021 update of the American College of Chest Physicians (CHEST) clinical practice guidelines⁵

The ASH, NICE and CHEST guidelines provide general recommendations for VTE including pulmonary embolism (PE) and deep vein thrombosis (DVT)^2,3,5; the ESC/ERS guidelines focus on PE¹; and the ESVS guidelines focus on DVT and provide additional recommendations for another type of VTE, superficial vein thrombosis (SVT)⁴.

The guidelines emphasise the need for patient-centric care at different stages, including initial management, primary treatment and secondary prevention of VTE, and treatment of recurrent VTE^1–4. They include recommendations on the type of treatment, dose and duration, and sequence of treatment for each stage^1–5.

Guidelines now consider direct-acting oral anticoagulants (DOACs) as the preferred option for oral treatment of intermediate-to-low risk PE (over vitamin K antagonists [VKAs]), and for treatment of provoked or unprovoked proximal DVT (over VKAs or low-molecular-weight heparin [LMWH] followed by VKAs, respectively)^1–4

The ESC/ERS, ASH and NICE guidelines provide conditional recommendations for primary treatment of uncomplicated DVT and low-risk PE at home^1–3,5.

Recommendations are also provided for management of VTE based on patient features including pregnancy, the presence of cancer, renal impairment, cardiopulmonary disease and haemodynamic instability^1,3.

In addition, thromboprophylaxis is recommended for patients with cancer who are hospitalised, as well as those who are ambulatory, receiving chemotherapy and are at intermediate- to high-risk of VTE ^6–8.

For these patients who are at higher risk of VTE, anticoagulants recommended for thromboprophylaxis include DOACs, LMHW, fondaparinux and unfractionated heparin (UFH)^6–8

An overview of VTE management

Management of VTE includes thromboprophylaxis for primary prevention of VTE in high-risk patients, and diagnostic assessment, treatment and follow-up of patients with VTE^1,4,6–8.

Prevention of VTE in high-risk patients

VTE thromboprophylaxis is recommended for patients who are at higher risk of VTE, including patients with cancer who are hospitalised, receiving systemic chemotherapy, undergoing major cancer surgery, and ambulatory cancer patients at intermediate or high risk of VTE (Khorana score ≥2)^6–8.

Learn about thromboprophylaxis in patients with cancer

Management of patients with VTE

For patients diagnosed with VTE, management generally includes²:

• Risk assessment to understand their risk of thrombosis/VTE recurrence, and their risk of bleeding
• Treatment of VTE across the initial and primary phases (short-term)
• Extended treatment for secondary prevention of VTE (optional)

Phases of VTE treatment are summarised in Figure 1.

Figure 1. Phases of venous thromboembolism treatment and timeframes for decision-making (Adapted²). DVT, deep vein thrombosis; PE, pulmonary embolism.

Which patients are suitable for VTE treatment at home?

Home treatment may be preferred by patients with VTE, considering both convenience and cost⁵.

According to guideline recommendations, the following patients with VTE may be considered for outpatient management from home:

• Patients with uncomplicated DVT²
• Patients with PE who are at low risk for complications^1,2,5, which may be based on the widely validated Pulmonary Embolism Severity Index (PESI) or simplified PESI (sPESI)²

Alternatively, if these patients have presented to hospital, they may be considered for early discharge and continuation of treatment at home, provided they are at low risk of early death or serious complications and have no serious comorbidity or aggravating conditions¹. When determining suitability for outpatient care, consider if the patient has access to proper outpatient care and anticoagulation treatment, and their anticipated adherence to treatment^1,5.

For patients with low-risk PE, either the Hestia rule or PESI/sPESI (with consideration of feasibility for early discharge/home treatment) may be used to triage patients for early discharge and home treatment¹.

For patients who will be treated for VTE at home, it is important to agree on a plan with the patient for monitoring and follow-up³. This should include information about symptoms and signs to look for, potential complications of thrombosis and treatment, and direct contact details for a healthcare professional and after-hours healthcare services³.

Other patients who may benefit from initial treatment at hospital include²:

• Patients who have limited or no support at home, cannot afford medications or have a history of poor compliance
• Patients with limb-threatening DVT
• Patients with low-risk PE with other conditions that require hospitalisation
• Patients with submassive (i.e. intermediate–high risk) or massive PE
• Patients at high risk of bleeding
• Patients who require intravenous analgesics

VTE risk assessment and prognostic stratification

For optimal management of venous thromboembolism (VTE), it is essential to understand a patient’s risk of thrombosis and risk of bleeding. Professor Konstantinides describes some key considerations when assessing a patient’s risk of thrombosis and bleeding.

In the infographic below, learn more about how a patient’s risk of thrombosis and bleeding can inform decisions about VTE treatment, including the type, sequence and duration of anticoagulant treatment.

Download infographic (PDF)

The balance between thrombotic and bleeding risk informs selection of treatment options for VTE and the duration of anticoagulation treatment. It also forms part of regular follow-up for patients on extended anticoagulation treatment, to determine whether continued anticoagulation treatment is still required^1–4.

A patient’s risk of VTE recurrence and bleeding while on anticoagulants can be informed by clinical judgement, through evaluation of relevant risk factors, and/or using risk assessment tools¹. For patients with pulmonary embolism (PE), prognostic risk stratification is an additional step that is recommended to guide management, including whether the patient may be considered for treatment at home.

Assessing risk of thrombosis

Generally, risk of thrombosis should be assessed:

• To determine if patients are suitable for primary VTE prophylaxis (thromboprophylaxis)^6–8. Thromboprophylaxis is recommended for patients at high risk of VTE, including patients with cancer who are hospitalised, receiving systemic chemotherapy, undergoing major cancer surgery, and ambulatory cancer patients at intermediate or high risk of VTE (Khorana score ≥2)^6–8
• In patients with VTE, to determine their risk of VTE recurrence²

Learn more about assessing risk of thrombosis in patients with cancer

How and when to assess risk of VTE recurrence?

After primary treatment of an initial VTE, the patient’s risk of VTE recurrence should be determined to inform the approach to management, including whether long-term anticoagulation will be required, and which treatment options are most appropriate^2,3.

Identifying and characterising risk factors associated with the VTE

Guidelines recommend considering whether the initial VTE was associated with an identifiable risk factor (i.e. provoked VTE) or occurred in the absence of an identifiable/provoking risk factor (i.e. unprovoked)^1,2,4.

If risk factors are identified, consider whether they are chronic (persistent) or transient (temporary), reversible, and whether they were present prior to the VTE event, as these can be associated with the rate of VTE recurrence and therefore influence duration of treatment^1,2.

After discontinuing anticoagulation treatment, recurrence rates were 2.5% per year for pulmonary embolism (PE) associated with transient risk factors and 4.5% per year for PE that occurred in the absence of transient risk factors¹

A summary of risk factors for VTE recurrence, classified according to risk of recurrence, is shown in Figure 2.

Figure 2. Risk factors for venous thromboembolism based on risk of recurrence over the long-term (Adapted¹). PE, pulmonary embolism; VTE, venous thromboembolism. *If anticoagulation is discontinued after 3 months¹.

An additional risk factor to consider is hereditary thrombophilia¹. This may be suspected in patients aged <50 years who present with VTE in the absence of an otherwise identifiable risk factor, and especially if there is a strong family history of VTE¹.

Risk prediction tools may assist decision-making

A number of risk prediction tools have been developed to assess risk of VTE recurrence, including validated models such as those for unprovoked VTE and for patients with cancer (Table 1)¹ and other patient populations (Table 2⁹). Although the clinical and therapeutic implications of these tools are less clear since the emergence of direct-acting oral anticoagulants (DOACs)¹, prognostic scores may be helpful when patients are undecided about continuing treatment, and if the balance between risks and benefits of indefinite anticoagulation is uncertain². However, the need for long-term anticoagulation should not be determined solely on the basis of risk prediction tools³.

Table 1. Validated risk prediction tools to assess risk of VTE recurrence (Adapted¹). BMI, body mass index; DVT, deep vein thrombosis; PE, pulmonary embolism; TNM, tumour node metastasis; VKA, vitamin K antagonist; VTE, venous thromboembolism. ^*More details on scoring system, risk categories and validation are available in the ESC/ERS 2019 guidelines¹. ^†Refers to risk of VTE recurrence during anticoagulation only¹.

Table 2. Individual risk assessment models in different patient profiles (Adapted⁹). ART, assisted reproductive technology; BMI, body mass index; COMPASS-CAT, comparison of methods for thromboembolic risk assessment with clinical perceptions and awareness in real life patients-cancer associated thrombosis; ESA, erythropoietin-stimulating agents; Hb, haemoglobin; IMPROVE,  International Medical Prevention Registry on Venous Thromboembolism; IVF, in vitro fertilisation; OHSS, ovarian hyperstimulation syndrome; RAM, risk assessment model; RCOG, Royal College of Obstetricians and Gynaecologists; VTE, venous thromboembolism; WBC, white blood cell; WHO, World Health Organization.

Assessing risk of bleeding

While highly effective at preventing recurrent VTE, anticoagulation treatment is associated with an increased risk of bleeding^2,4.

The risk of bleeding on anticoagulants is usually higher in the first 3 months of treatment, followed by a gradual reduction in bleeding risk over time⁴

When should risk of bleeding be assessed?

For patients who are on anticoagulants, risk of bleeding should be assessed at multiple stages of treatment, including:

• At the time of initiating anticoagulation treatment¹
• Periodically during anticoagulation treatment (i.e. once a year for patients at low risk of bleeding, and every 3–6 months for those at high risk of bleeding)¹
• When considering whether to extend anticoagulation beyond the primary treatment period (i.e. initial 3–6 months) for secondary prevention¹
• As part of regular follow-up for patients who are on extended, long-term anticoagulation (at least once per year)³

Results of the bleeding risk assessment can inform decisions about the anticoagulation treatment regimen after VTE and provide an opportunity to identify and treat modifiable bleeding risk factors^1,4.

How to assess bleeding risk

A patient’s risk of bleeding can be assessed either by implicit clinical judgement, based on evaluation of bleeding risk factors, or via a bleeding risk score¹. Although several bleeding risk scores have been proposed, clinical consideration of risk factors should influence decisions on the duration of anticoagulation treatment⁴.

Risk factors for bleeding

Risk factors for bleeding include those that generally predispose the patient to bleeding complications, such as comorbid conditions and more specific risk factors for bleeding while on anticoagulation treatment^1,2. Consider the severity of the risk factor (such as the degree of thrombocytopenia or the location and extent of metastatic cancer), and the number of risk factors present².

General risk factors for bleeding complications and bleeding while on anticoagulants include^1,2,4:

• Older age (particularly >75 years)
• History of prior bleeding (if not associated with a reversible or treatable cause) or anaemia
• Active cancer
• Previous stroke (haemorrhagic or ischaemic)
• Chronic renal or hepatic disease
• Concomitant antiplatelet treatment or non-steroidal anti-inflammatory drugs (to be avoided, if possible)
• Other serious acute or chronic illness
• Poor anticoagulation control
• Hypertension
• Thrombocytopenia
• Alcohol abuse
• Frequent falls

On heparin, risk factors for bleeding include higher heparin dose and age >70 years. On low molecular weight heparin (LMWH), risk factors for bleeding include impaired renal function and increased age⁴. For patients with DVT, there is a lower risk of major bleeding with LMWH versus unfractionated heparin (UFH)⁴.

The risks of major bleeding, intracranial haemorrhage or fatal bleeding are statistically significantly lower with DOACs, compared with LMHW and vitamin K antagonists (VKAs)⁴. Indeed, the risk of major bleeding with DOACs is 30% lower than VKAs². However, the risk of gastrointestinal bleeding may be higher with dabigatran, rivaroxaban, edoxaban than with VKA treatment⁴.

Bleeding risk scores

Various bleeding risk scores have been developed to inform bleeding risk for patients receiving anticoagulants after VTE, including the following prediction models¹:

• OBRI: Outpatient Bleeding Risk Index
• RIETE: Registro informatizado de la Enfermedad Thromboembolica venosa
• HAS-BLED: Hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly (>65 years), drugs/alcohol concomitantly
• VTE-BLEED: Active cancer, male with uncontrolled hypertension at baseline, anaemia, history of bleeding, age >60 years, renal dysfunction

These tools consider risk factors such as age, history of stroke and bleeding, and comorbidities (such as cancer, renal dysfunction and uncontrolled hypertension)¹.

The ASH 2020, ESC/ERS 2019 and ESVS 2021 guidelines do not state a preference for one bleeding risk score over another, whereas the NICE 2020 guidelines suggest the HAS-BLED score can be considered to assess risk for major bleeding in unprovoked proximal DVT or PE^1–4.

The VTE-BLEED risk score is now considered the most validated risk score in VTE settings, with good prediction for major bleeding events for those receiving oral anticoagulants, and reliability in identifying patients at risk of intracranial and fatal bleeding events⁹. However, this risk score is not yet formally recommended by current VTE management guidelines^1,2.

Prognostic risk stratification for PE

For patients with PE, a risk-based approach is recommended for management¹.

If haemodynamic instability is present, the patient is considered to have high-risk PE and requires emergency treatment with immediate referral for reperfusion treatment¹.

In the absence of haemodynamic instability, patients with PE should be stratified according to prognostic risk¹. This includes consideration of:

• Clinical, imaging and laboratory parameters, to stratify patients into low- or intermediate-risk categories, informing the severity of PE and risk of PE-related early death¹
• Clinical prediction rules that integrate aggravating conditions and comorbidities into the risk assessment, preferably the PESI or sPESI, which help to assess the patient’s overall mortality risk and early outcomes¹

These results inform subsequent management, including any requirement for hospitalisation, whether further tests are required (i.e. troponin tests), and whether the patient is eligible for early discharge and treatment at home (Figure 3)¹.

Figure 3. Prognostic risk stratification and risk-adjusted management of patients with PE (Adapted¹). CTPA, computed tomography pulmonary angiography; PE, pulmonary embolism; PESI, pulmonary embolism severity index; RV, right ventricular; sPESI, simplified pulmonary embolism severity index; TTE, transthoracic echocardiogram. *Haemodynamic instability, combined with confirmation of PE on CTPA and/or evidence of RV dysfunction on TTE, is sufficient to classify a patient into the high-risk PE category. In this case, neither calculation of the PESI nor measurement of troponins or other cardiac biomarkers is necessary¹. ^†Early discharge and home treatment may be considered if (a) there are no other reasons for hospitalisation, (b) there is family and social support and (c) there is easy access to medical care¹.

Initial and primary VTE treatment

Professor Konstantinides provides an overview of treatment options for venous thromboembolism (VTE), and key factors to consider when selecting the most appropriate anticoagulant for each patient.

Treatment options for venous thromboembolism (VTE) include pharmacological anticoagulation treatments such as vitamin K antagonists (VKAs), low-molecular-weight heparin (LMWH), direct-acting oral anticoagulants (DOACs) and thrombolytic therapies.

Careful consideration of patient characteristics and comorbidities is essential, as management of VTE can be complicated by the presence of other conditions such as renal impairment, active cancer and antiphospholipid syndrome^1–3. Management of VTE can also be influenced by use of concomitant medications, and patient characteristics such as age and extremes in body weight^1–3.

In patients with cancer, challenges for VTE management include an elevated risk of recurrence and major bleeding, alongside cancer-associated treatments, procedures and related side effects^6–8.

Learn about the challenges of managing VTE in patients with cancer

Interim anticoagulation while awaiting diagnosis

For patients with suspected deep vein thrombosis (DVT) or pulmonary embolism (PE), interim anticoagulation should be commenced while awaiting results of diagnostic tests^1,3, particularly for those with an intermediate or high probability of PE¹.

Learn more about the diagnosis of PE

Options for interim anticoagulation include LMWH, fondaparinux or unfractionated heparin (UFH), DOACs or VKA (such as warfarin)¹. It can be helpful to choose an interim anticoagulant that can be continued once diagnosis of DVT or PE is confirmed³. Usually, LMWH or fondaparinux are preferred over UFH (unless the patient has renal impairment or haemodynamic instability)¹.

Initial and primary treatment of VTE

Following diagnosis of VTE, anticoagulation treatment should start at the initial treatment phase and be continued through the primary treatment phase, unless contraindicated².

It is important to involve the patient in the decision-making process regarding short-term and long-term anticoagulation, and consider their preferences, to optimise and maintain treatment adherence^1,3.

Considerations for initial management and choice of anticoagulant

Guidelines now consider DOACs as the preferred option for oral treatment of intermediate-to-low risk PE (over VKAs), and for treatment of provoked or unprovoked proximal DVT (over VKAs or LMWH followed by VKAs, respectively)^1–4

An overview of the general approach to initial management of PE and proximal DVT is provided in Figure 4.

Figure 4. General guidance for initial management of PE and proximal DVT^1–4. DOAC, direct-acting oral anticoagulant; LMWH, low-molecular-weight heparin; UFH, unfractionated heparin; VKA, vitamin K antagonist. *DOAC is preferred (if patient is eligible), unless severe renal impairment, during pregnancy and lactation, or if patient has antiphospholipid syndrome¹. ^†Consider pharmacological systemic thrombolytic therapy³, or surgical pulmonary embolectomy if thrombolysis is contraindicated or has failed, in which case percutaneous catheter-directed treatment can be considered¹. ^‡After evaluating thrombotic and bleeding risks, with periodic reassessment⁴. ^§Reduced dose of the DOACs apixaban (2.5 mg twice a day) or rivaroxaban (10 mg once a day) should be considered⁴.

PE with haemodynamic instability

For PE with haemodynamic instability, emergency treatment usually involves primary reperfusion treatment (i.e. with systemic thrombolysis) and haemodynamic stabilisation, after which the patient can be switched from parenteral to oral anticoagulation (Figure 4)¹.

DVT and PE without haemodynamic instability

For DVT or PE without haemodynamic instability, treatment with a DOAC is generally preferred over VKA². Regarding choice of DOAC:

• ASH 2020 guidelines do not state a preference for one DOAC over another², as this choice can be influenced by any requirements for lead-in parenteral anticoagulation, dosing preferences, out-of-pocket costs, renal function, concomitant medications (for example if the concomitant drug is metabolised through the CYP3A4 enzyme or P-glycoprotein) and whether the patient has cancer²
• NICE 2020 guidelines suggest a preference for apixaban or rivaroxaban for patients with confirmed proximal DVT or PE³. Alternative options include LMWH followed by dabigatran or edoxaban, or LMWH and VKA followed by VKA alone³.
• CHEST 2021 guidelines recommend apixaban, dabigatran, edoxaban or rivaroxaban over VKA for primary treatment of VTE (DVT of the leg or PE)⁵. Based on limited direct comparative evidence, there may be a lower risk of bleeding with apixaban, compared with other DOACs⁵.

Note, DOACs are not recommended in patients with severe renal impairment, during pregnancy and lactation, and in patients with antiphospholipid antibody syndrome¹.

Mechanical interventions may also be considered in certain cases, such as when anticoagulation treatment is contraindicated, for acute PE with active bleeding, and if a PE has occurred while on anticoagulation treatment^1,3. Elastic compression stockings may be used to manage leg symptoms of DVT³.

Sequence of treatment

The following points should be considered for pretreatment and dosing for specific types of anticoagulation treatments²:

• When planning VKA treatment, initiation must be overlapped with UFH or LMWH for a minimum of 5 days. A therapeutic international normalised ratio (INR) should be achieved for 24 hours, at which time the heparin can be discontinued.
• When planning treatment with dabigatran or edoxaban, pretreatment with UFH or LMWH is required for up to 5–10 days before switching to the DOAC
• When planning treatment with rivaroxaban or apixaban, no pretreatment is required. However, administration of a higher dose is recommended for the first 3 weeks of treatment with rivaroxaban and for the first week of treatment with apixaban.

These points are particularly important for patients being considered for treatment at home, rather than in the hospital².

Duration of initial and primary treatment

Generally, 3–6 months is the minimal recommended length of time to treat an initial VTE^1,2,5, taking into account contraindications, comorbidities and the person’s preferences^2,3

A longer primary treatment phase (i.e. 6–12 months) may be considered if planning to stop anticoagulation after primary treatment, or if the VTE was provoked by a persistent risk factor that is expected to improve over time².

For proximal DVT, the recommended duration of treatment is determined according to whether the event was considered as provoked or unprovoked⁴, as outlined in Figure 4.

VTE management in specific populations

Some considerations for managing VTE in specific patient populations are summarised below.

• Stable cardiovascular disease: If taking aspirin for cardiovascular risk modification, consider suspending aspirin while receiving anticoagulation treatment (unless recent acute coronary event or coronary intervention)²
• Renal impairment: Options depend on creatinine clearance (CrCl):
  • If CrCl 15–50 ml/min: apixaban, rivaroxaban, LMWH followed by edoxaban or dabigatran; or LMWH or UFH and a VKA then VKA alone
  • If CrCl <15ml/min: LMWH or UFH ± VKA then VKA alone^1,3
• Antiphospholipid syndrome: offer LMWH and VKA then VKA alone³
• Active cancer (if receiving antimitotic treatment, diagnosed in the past 6 months, recurrent, metastatic or inoperable): a DOAC is preferred. Other options include LMWH ± VKA then VKA alone^1,3
• Extremes of body weight (i.e. <50 kg or >120 kg): consider using an anticoagulant with monitoring of therapeutic levels, taking into account relevant cautions and requirements for dose adjustment and monitoring³
• PE during pregnancy: LMWH throughout pregnancy and >6 weeks postpartum¹

Treatment failure

If anticoagulation treatment fails, it is recommended to check adherence to the anticoagulation treatment, address other sources of hypercoagulability and, if required, increase the dose of anticoagulant or change to an anticoagulant with a different mechanism of action³. After taking these steps, inferior vena cava filters may also be considered, ensuring a strategy is in place to remove the filter at the earliest opportunity³.

Secondary prevention and recurrent VTE

Beyond the primary phase, venous thromboembolism (VTE) treatment may involve secondary prevention and treatment of recurrent VTE.

Professor Konstantinides discusses key considerations when determining the duration of treatment for a patient with VTE, and when choosing an anticoagulant for secondary prevention.

Secondary prevention

After completing primary treatment of VTE, a decision is required on whether to discontinue anticoagulation treatment or continue with long-term anticoagulation as secondary prevention of VTE recurrence². In making this decision, healthcare professionals must weigh up the patient’s risk for recurrent VTE against their risk of bleeding^1,2, involve the patient and take into account their preference and values^3,5.

For pulmonary embolism (PE), extended anticoagulation may be indicated if the index event occurred in the presence of a minor transient or reversible risk factor, or a persisting risk factor², or no identifiable risk factor¹.

When considering extended anticoagulation for a patient with deep vein thrombosis (DVT), residual vein obstruction on ultrasound, and/or D-dimer level may assist in the decision-making process⁴.

Guideline suggestions and recommendations on when to discontinue or continue anticoagulation for secondary prevention are outlined in Table 3.

Table 3. Guideline suggestions for when anticoagulation may be discontinued after primary prevention or continued for secondary prevention^1–3,5. DVT, deep vein thrombosis; IBD, inflammatory bowel disease; PE, pulmonary embolism; VKA, vitamin K antagonist; VTE, venous thromboembolism.

Which anticoagulant to choose?

If extending anticoagulation to long-term treatment, continued treatment with the current anticoagulant can be offered if is well tolerated³. However, the current treatment may be switched if it is not well tolerated or if the clinical situation or person’s preferences have changed³.

In addition, if the current treatment is a direct-acting oral anticoagulant (DOAC) other than apixaban, consider switching to apixaban³. If continuing treatment with a DOAC, a standard dose or lower dose regimen may be considered^2,5. The lower dose regimens include rivaroxaban 10 mg daily or apixaban 2.5 mg twice daily^2,5.  These lower dose DOAC regimens should also be considered for patients with PE in the absence of cancer, after 6 months of therapeutic anticoagulation¹.

Long-term anticoagulation

Annual follow-up and review are recommended for all patients on long-term anticoagulation treatment^1–3

All patients on anticoagulants for secondary prevention of recurrent VTE, including those on extended and indefinite treatment, should have an annual follow-up to review bleeding risk, risk of recurrent VTE, as well as treatment preferences, treatment adherence, drug tolerance, hepatic and renal function, and general health^1–3.

Treatment of recurrent VTE

For patients with recurrent VTE, indefinite anticoagulation treatment is suggested if²:

• The recurrent VTE is unprovoked, or
• The VTE is considered to be provoked in a patient who has a history of either unprovoked VTE or VTE provoked by a persistent risk factor

If the recurrent and previous VTE were provoked by transient risk factors, anticoagulation may be stopped after primary treatment².

For patients with recurrent DVT while compliant with treatment, consider switching to a different anticoagulant, increasing the dose of low-molecular-weight heparin (LMWH) or DOAC to therapeutic dose (if applicable) or switching to vitamin K antagonist (VKA) with a higher international normalized ratio (INR) target⁴.

For patients on VKA who experience breakthrough DVT and/or PE, LMHW is suggested over DOAC treatment². It is also suggested to investigate potential underlying causes (unless there is poor INR control, where a DOAC may be a reasonable option)².

Learn about VTE symptoms, risk factors and diagnosis

Learn about cancer-associated VTE

Real-world evidence for VTE management

The use of direct-acting oral anticoagulants (DOACs) for the treatment of venous thromboembolism (VTE) significantly increased with the release of clinical guidelines recommending their use¹¹. Treatment of VTE with DOACs is shown to improve overall clinical outcomes in general populations^12,13 and high-risk populations, including the elderly (>65 years)¹⁴, octogenarians¹⁵, and cancer patients¹⁵.

The infographic below summarises key real-world evidence which can inform an individualised approach for managing VTE with DOACs.

When compared to warfarin for the secondary prevention of VTE in patients with VTE and active malignancy, DOACs are more efficacious and have a reduced risk of bleeding¹⁶.

The Monotherapy Anticoagulation to expedite Home Treatment of VTE (MATH-VTE) implementation trial demonstrated that monotherapy oral anticoagulation is adequately effective and safe for treating patients with DVT and pulmonary embolism (PE) in the emergency care setting who are classified as low risk, either by the modified Hestia criteria or the simplified PE Severity Index, plus clinical judgement¹⁷. These findings support the idea that outpatient therapy with a DOAC for low-risk patients with DVT and PE should be regarded as a fair and responsible standard of care¹⁷.

Evidence for VTE prophylaxis

In outpatient VTE treatment and prevention in the United States, the risks of major bleeding, clinically relevant non-major (CRNM) bleeding, and recurrent VTE were significantly lower in patients receiving apixaban than in those receiving warfarin¹⁸.

In a large longitudinal study (N = 225,559), apixaban was associated with a lower risk of haemorrhagic complications and improved efficacy in preventing recurrent VTE compared with rivaroxaban¹⁹. While both rivaroxaban and apixaban had a low risk of intracranial haemorrhage (ICH), non-ICH haemorrhage was much more common in patients receiving rivaroxaban¹⁹. Overall, the risk of emergent readmission for haemorrhage was higher in rivaroxaban-treated patients than in apixaban-treated patients¹⁹. Older age, female sex, a prior prescription of antiplatelet therapy and complicated hypertension are all risk factors for emergent haemorrhage in apixaban-treated patients¹⁹.

In another small study, apixaban (N= 154) had a better safety profile versus enoxaparin (N = 161) when used for extended-duration VTE prophylaxis²⁰.

In hospitalised medically ill patients, thromboprophylaxis with enoxaparin was associated with significantly lower in-hospital VTE events, death and major bleeding, as well as lower hospital costs when compared to unfractionated heparin (UFH)²¹. Table 4 summarises the prophylaxis treatment in intensive care unit.

Table 4. Prophylaxis in trauma intensive care unit (Adapted²²). BMI, body mass index; LMWH, low-molecular-weight heparin; TBI, traumatic brain injury; UFH, unfractionated heparin; VTE, venous thromboembolism.

Evidence for acute VTE treatment

 A large population-based study in France (N = 58,137) found that treatment-naïve adults with VTE who received apixaban had lower risks of hospitalisation-related bleeding, intracranial bleeding, gastrointestinal bleeding, other bleeding, all-cause death, and first recurrent VTE than patients who received VKAs. In addition, adults with VTE who received rivaroxaban had lower risks of intracranial bleeding and all-cause death than patients who received VKAs²³.

In a propensity-matched analysis, patients who were new users of apixaban had lower risk of nonmajor bleeds than warfarin²⁴. Both newly prescribed apixaban and rivaroxaban also had lower risk of PE than warfarin²⁴. There was no statistically significant difference in hospitalisations or length of stay between warfarin and either DOAC²⁴. Despite a significant increase in VTE-related costs compared with apixaban, warfarin use, however, was associated with a significant decrease in total cost of care²⁴.

In a recent meta-analysis of real-world studies (N = 63,144), apixaban is associated with significantly lower bleeding risk (major, minor and any bleeding) than rivaroxaban (HR 0.61; 95% CI, 0.56–0.70; P = 0.008), but similar efficacy in the prevention of recurrent VTE²⁵. There was no significant difference of major bleeding between dabigatran and rivaroxaban and betweenapixaban and dabigatran (Figure 5)²⁵.

Figure 5. Comparison of apixaban and rivaroxaban clinical outcomes (Adapted²⁵). CI, confidence interval; HR, hazard ratio.

The real-world evidence for rivaroxaban treatment in acute VTE mostly supports the findings of phase 3 trials (Table 5²⁶). Rivaroxaban and standard anticoagulation methods have similar safety and efficacy profiles for VTE treatment in many parts of the world²⁷. For the long-term treatment of patients with with recurrent or unprovoked VTE¹², rivaroxaban has been seen to be safe and effective. Data from multiple UK hospitals revealed that rivaroxaban can be safe and effective option for acute VTE in obesity²⁸. Similarly, a real-world study in the US showed that rivaroxaban was associated with fewer VTE recurrences, similar rates of major bleeding and lower medical costs than warfarin in morbidly obese patients²⁹. Additionally, rivaroxaban was found to be more cost-effective than VKAs for the treatment of VTE^28-30.

Table 5. Summary of real-world data of VTE treatment with DOACs (Adapted²⁶). DOAC, direct-acting oral anticoagulant; HR, hazards ratio; ICD, International Classification of Diseases; ISTH, International Society on Thrombosis and Haemostasis; NOAC, new oral anticoagulants; PE, pulmonary embolism; pts., patients; VTE, venous thromboembolism.

In the European ETNA-VTE study, ongoing treatment with edoxaban reduced the risk of VTE recurrence to less than 0.4% in the first 3 months following the original episode and reduced the risk of serious bleeding complications to less than 1% in the general VTE population³¹.

Evidence for extended treatment for VTE

According to European guidelines, extension of anticoagulation beyond 90 days should be considered for all VTE patients except for patients with VTE associated with a major transient/reversible risk factor¹. American guidelines recommend extended treatment for patients with unprovoked VTE⁸.

DOACs can be one of the treatment options for long-term treatment for both cancer and non-cancer patients with VTE (Table 6)³². Compared with warfarin, apixaban is shown to have a better safety profile with fewer major bleeding events in a real world-setting. Extended anticoagulation with either apixaban or warfarin (beyond 6 months) is associated with decreased risk of recurrent VTE compared with no extended therapy³³. With continued use of either apixaban or warfarin, there was a lower risk of mortality³³. These findings remained consistent for many patient categories, including those with or without a history of malignancy, chronic kidney disease, hypercoagulable status, or obesity or type of VTE (provoked or unprovoked)³⁴.

Table 6. Choice of anticoagulants for long-term treatment (Adapted³²). APA, antiphospholipid antibodies; DOAC, direct-acting oral anticoagulant; LMWH, low-molecular-weight heparin; INR, international normalised ratio. *Approved dosing for long-term treatment of VTE according to renal impairment (CrCl in millilitres per minute generally estimated using the Cockcroft-Gault method).

New tools have been developed to estimate the absolute benefits and risks of prolonged anticoagulation for individual patients and to aid in shared decision-making (Figure 6).

Figure 6. Overview of VTE-PREDICT risk score (Adapted³⁵). BMI, body mass index; DOAC, direct-acting oral anticoagulant; DVT, deep vein thrombosis; Hb, haemoglobin; SBP, systolic blood pressure; VKA, vitamin K antagonist; VTE, venous thromboembolism.

When choosing the ideal anticoagulation duration following VTE, there should be a balance of shared decision-making (Figure 7)³⁶.

Figure 7. Overview of factors in determining anticoagulation therapy in VTE (Adapted³⁶).

VTE management is an important area of research and clinical practice, and there is a considerable amount of real-world evidence that supports various approaches to VTE management. Overall, real-world evidence supports the use of various approaches to VTE management, including anticoagulant therapy. However, the choice of management approach may depend on various factors, including the patient's individual risk factors and clinical presentation.