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Understanding the risk of VTE recurrence: Who needs extended anticoagulation?

Many patients with VTE need protection from recurrent events

Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a serious and common cardiovascular disease associated with chronic complications and death. VTE can be treated with anticoagulant therapy, but approximately 40% of patients may suffer a recurrent VTE within 10 years of treatment cessation.

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Risk of VTE recurrence within 10 years of treatment cessation

In patients without cancer, the use of non-vitamin K antagonist (VKA) oral anticoagulants (NOACs), such as rivaroxaban, dabigatran, apixaban and edoxaban, has been suggested over VKAs for the treatment of VTE. Current guidelines recommend anticoagulation therapy for at least 3 months in all patients with VTE, but anticoagulation beyond this time is dependent on an individual patient’s risk of recurrence. How is the risk of recurrence determined?


The underlying aetiology of the index VTE has an impact on the risk of VTE recurrence and treatment duration

Whereas approximately half of venous thromboembolic events are unprovoked (i.e. idiopathic), the other half are provoked by risk factors. Provoking risk factors can be stratified by determining whether the risk factor is persistent or transient, and whether it is minor or major.

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Effect of index VTE classification on 1-year risk of recurrent VTE in patients not receiving extended anticoagulation. Examples for the different risk factor categories are also shown.

Whether a VTE was unprovoked or provoked by risk factors has important implications on the risk of recurrence and the recommended duration of anticoagulant treatment. The risk of recurrence in patients with VTE provoked by major transient risk factors (e.g. major surgery) has been estimated to be only around ~1% within 1 year, and ~3% within 5 years, after stopping anticoagulation. As such, treatment can be limited to 3 months in these patients. In contrast, in patients with unprovoked VTE, the risk of recurrent VTE after discontinuation of therapy is approximately 10% after 1 year, and 30% after 5 years. Therefore, extended treatment beyond the initial 3 months is recommended in patients with unprovoked VTE and low bleeding risk.


The risk of VTE recurrence in patients with VTE provoked by persistent or minor transient risk factors is less certain, but has recently been reported to be similar to that of patients with unprovoked VTE. However, treatment guidance for these particular patients is sparse.


Randomized controlled trials provide evidence for the efficacy of extended treatment with NOACs in patients with VTE

Extended treatment with NOACs has been investigated versus placebo in the EINSTEIN EXT (rivaroxaban), AMPLIFY-EXT (apixaban), and RE-SONATE (dabigatran) trials, and versus warfarin in the RE-MEDY trial (dabigatran) and a post-hoc analysis of the Hokusai-VTE trial (edoxaban).


The placebo-controlled trials showed that extended treatment with NOACs can reduce the risk of VTE recurrence, without increasing the risk of major bleeding. In the active-comparator controlled trials, NOACs were found to be non-inferior compared with warfarin in preventing VTE recurrence.


More recently, the EINSTEIN CHOICE trial assessed whether at a standard dose of rivaroxaban 20 mg once daily (od) or a reduced dose of rivaroxaban 10 mg od were effective at lowering the risk of recurrent VTE in patients where there was uncertainty about the need for extended anticoagulation. Extended treatment with both rivaroxaban doses resulted in a significant reduction of the risk of recurrent VTE versus aspirin, with similar rates of major bleeding. Based on these data, rivaroxaban 10 mg od was approved in Europe for patients indicated for extended treatment who have been on anticoagulant therapy for at least 6 months, unless they are at high risk of VTE recurrence, such as patients with complicated co-morbidities, or those who developed recurrent PE or DVT while receiving extended prevention with the lower dose.

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Primary efficacy (A) and safety outcomes (B) of the EINSTEIN CHOICE trial

The EINSTEIN trials also provided important data on the effect of different risk factors on the risk of VTE recurrence. By pooling data from EINSTEIN EXT and EINSTEIN CHOICE, it can be seen that patients with VTE provoked by minor persistent or transient risk factors and those with unprovoked VTE have a similar risk of recurrence and are likely to benefit from extended anticoagulation.

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Reduction in recurrent VTE in patients with unprovoked VTE and VTE provoked by transient or persistent risk factors with extended rivaroxaban treatment


The high risk of recurrent VTE in certain patients highlights the need to understand who would benefit from extended anticoagulation. Recent data have shown that patients with index VTE provoked by minor risk factors have a similar risk of recurrence to those with unprovoked VTE and may, therefore, benefit from extended anticoagulation. In patients with an indication for extended anticoagulation, rivaroxaban is the only NOAC that offers the option to tailor treatment and reduce the dose after 6 months, unless the patient is at high risk of VTE recurrence, such as those with complicated co-morbidities, or those who developed recurrent PE or DVT while on extended anticoagulation with the lower dose.

Real-world evidence reflects the efficacy and safety results of extended treatment with NOACs

A recent analysis of a US healthcare claims database suggested that the results of the EINSTEIN EXT and EINSTEIN CHOICE trials are maintained in routine clinical practice. The study, which included data from 7469 patients, demonstrated that patients who continued rivaroxaban therapy after the initial 3- or 6-month treatment period had a significantly lower risk of VTE recurrence compared with those who discontinued treatment, with a similar risk of major bleeding.

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Reduction in the risk of recurrent VTE at 1 year in patients who continued rivaroxaban treatment for >3 or ≥6 months versus those who discontinued therapy, based on data from the US healthcare claims database analysis

“Patient case: When to choose extended VTE treatment?”

Think about how you would treat the following patient:

  • John is a 41-year-old man who was diagnosed with a proximal DVT 2 years ago
    • He has thrombophilia (Factor V Leiden) and a familial history of VTE
    • John also takes frequent long-haul flights for work
  • At the time of his index DVT he received anticoagulation therapy with a VKA for 1 year
  • Then, 6 months ago, he experienced a recurrent distal DVT and received treatment with a NOAC
  • John has returned for a follow-up appointment. Which of the following antithrombotic treatment regimens would you advise for John from this point onwards?
    • Stop anticoagulation therapy
    • Switch back to VKA treatment
    • Switch to treatment with aspirin 100 mg od
    • Switch to treatment with low molecular weight heparin
    • Continue treatment with a standard NOAC treatment dose
    • Switch to a reduced dose NOAC

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