Review article
The risk of recurrent thromboembolic disorders in patients with unprovoked venous thromboembolism: New scenarios and opportunities

https://doi.org/10.1016/j.ejim.2013.09.005Get rights and content

Highlights

  • We reviewed the baseline factors that increase the risk of recurrent VTE.

  • We reviewed the post-baseline factors that predict the risk of recurrent VTE.

  • We reviewed evidence favouring the use of risk stratification models.

  • We discussed the optimal duration of anticoagulation in patients with unprovoked VTE.

  • We reviewed the opportunities offered by aspirin and by the new antithrombotic compounds.

Abstract

The risk of recurrent thromboembolic disorders in the 10-year period following an episode of unprovoked venous thromboembolism (VTE) ranges between 30 and 50%, the rate being higher in patients with primary deep venous thrombosis (DVT) than in those with primary pulmonary embolism (PE). The clinical presentation with primary PE increases by more than three times the risk of a new PE episode over that with isolated DVT. Baseline parameters that increase this risk are the proximal location of DVT, obesity, old age and male sex, whereas the role of thrombophilia is controversial. An increasing role is played by post-baseline parameters such as the ultrasound assessment of residual vein thrombosis and the determination of D-dimer. While the latest international guidelines suggest indefinite anticoagulation for most patients with the first episode of unprovoked VTE, new scenarios are being offered by the identification of risk stratification models and by strategies that have the potential to help identify patients in whom anticoagulation can be safely discontinued, such as those that incorporate the assessment of D-dimer and residual vein thrombosis. New opportunities are being offered by low-dose aspirin, which has recently been reported to decrease by more than 30% the risk of recurrent events without increasing the bleeding risk; and especially by a few emerging anti-Xa and anti-IIa oral compounds, which are likely to induce fewer haemorrhagic complications than vitamin K antagonists while preserving at least the same effectiveness, do not require laboratory monitoring, and can be used immediately after the thrombotic episode.

Introduction

After discontinuing anticoagulation, a substantial proportion of patients with unprovoked deep venous thrombosis (DVT) and/or pulmonary embolism (PE) will develop recurrent venous thromboembolic (VTE) events. According to the findings from prospective cohort studies conducted at our Institution [1], [2] and elsewhere [2], [3], [4], [5], [6], [7], recurrent events are expected to develop in up to 50% of all such patients. This figure will not change after prolonging anticoagulation up to 6, 12 or 24 months [8], [9], [10], [11], [12], [13]. Interestingly enough, while the risk is negligibly low after major surgery or trauma, it remains substantial in individuals whose thrombotic episode is triggered by “minor” transient risk factors, such as minor injury, knee arthroscopy, hormonal treatment, pregnancy or puerperium, and long trips [5]. Indeed, current strategies addressing the optimal duration of anticoagulation after a VTE episode tend to aggregate patients with unprovoked episodes and those whose events are associated with minor risk factors for venous thrombosis.

Section snippets

Inherited thrombophilia and family history of VTE

While inherited thrombophilia does not increase the risk of recurrent thromboembolism while on warfarin [14], whether and to which extent carriers of inherited thrombophilia exhibit a higher risk of recurrent VTE after discontinuing anticoagulation are controversial. It is generally accepted, although not conclusively demonstrated, that carriers of AT, protein C and S defects [15], carriers of hyperhomocysteinemia [16] and carriers of increased levels of factor VIII or IX [17], [18], [19], have

Residual vein thrombosis

In a few cohort studies, the ultrasound persistence of residual thrombosis after an episode of proximal DVT was found to be an independent risk factor for recurrent thromboembolism [42], [43]. A recent meta-analysis of available investigations suggest that, whichever the method used for measuring the thrombotic mass, residual vein thrombosis is a powerful and independent risk of recurrent VTE in patients with proximal vein thrombosis [44]. Interesting enough, residual vein thrombosis predicts

Risk stratification models

A novel approach for assessing risk of recurrent VTE consists of linking clinical patient characteristics with laboratory testing. Several such scoring models which can be used to assess the risk of recurrent VTE have been developed, but they await prospective validation before they can be applied in daily routine care [51], [52], [53], [54]. In a Canadian model, women with idiopathic VTE and none or 1 of several parameters (age older than 65, obesity, D-dimer positivity at time of

Optimal duration of anticoagulation in patients with unprovoked VTE

Patients presenting with a first episode of unprovoked VTE should be offered at least 3 months of vitamin K antagonists, targeting an INR between 2.0 and 3.0 [55]. The decision as to go on or discontinue anticoagulation after the first conventional three months this period should be individually tailored and balanced against the haemorrhagic risk. While an indefinite anticoagulation can be considered in selected patients at very low bleeding risk, especially in those presenting with primary PE

Low-dose aspirin

In a multicenter, double-blind study, more than 400 patients with unprovoked VTE who had completed 6 to 18 months of oral anticoagulant treatment were randomly assigned to aspirin, 100 mg daily, or placebo for at least two years [67]. VTE recurred in 28 of the 205 patients who received aspirin and in 43 of the 197 patients who received placebo (6.6% vs. 11.2% per year; HR, 0.58; 95% CI, 0.36 to 0.93). One patient in each treatment group had a major bleeding episode.

The ASPIRE trial, which

Learning points

  • Patients with the first episode of unprovoked VTE have a risk of recurrences over years that approach 50% of all such patients. The latest international guidelines suggest an indefinite anticoagulation in all those who are reputed to be at low bleeding risk.

  • A number of models that help stratify the risk of recurrent events have recently been published; however, they need validation from prospective studies.

  • Algorithms that incorporate the ultrasound assessment of residual vein thrombosis and the

Conflict of interests

The authors state that they have no conflicts of interest.

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