Assessing Recurrence Risk Following Acute Venous Thromboembolism

Use of Algorithms

Daniela Poli; Gualtiero Palareti

Disclosures

Curr Opin Pulm Med. 2013;19(5):407-412. 

In This Article

Clinical Risk Factors Associated With Recurrent Venous Thromboembolism

Several risk factors are associated with recurrence; however, their weight in determining recurrent VTE is different and still not completely defined. We examined the different risk factors.

Type of Venous Thromboembolism Event

Patients with isolated distal deep vein thrombosis (DVT), especially if provoked by a major transient risk factor, have a very low risk of recurrence; therefore, a short course of anticoagulant therapy is recommended (6–12 weeks).[5,12]

Duration of Anticoagulant Therapy

In a recent meta-analysis of individual patient data from randomized trials, during the 2 years after stopping anticoagulant therapy, treatment of 3 months compared with longer treatment was associated with similar risk of recurrence.[12] Therefore, although anticoagulants are very effective in preventing recurrence while patients are receiving therapy, when anticoagulants are stopped patients with unprovoked VTE have a high risk of recurrence independently from the duration of therapy.

Male Sex

The risk of recurrent VTE is higher in men, with a relative risk vs. women of about 1.6.[13,14] In patients with a first unprovoked VTE, men have a 2.2-fold higher risk of recurrence than do women, which remains 1.8-fold higher in men after adjustment for previous hormone-associated events. Instead, in patients with a first provoked VTE, the risk of recurrence does not differ between men and women.[14] Indefinite anticoagulation should be considered strongly in men with unprovoked events.

Thrombophilia, Lupus Anticoagulant, and Antiphospholipid Antibodies

Hereditary thrombophilia, such as factor V Leiden mutation, prothrombin gene mutation, antithrombin deficiency, protein C deficiency, protein S deficiency, high levels of factor VIII and XI, or hyperhomocysteinemia, are detected in more than 50% of patients with a first unprovoked VTE. However, these abnormalities are associated with a slight increase of the risk of recurrent VTE. In addition, studies addressing the duration of treatment based on thrombophilia markers failed to identify the high-risk patients.[15] Therefore, some authors do not recommend thrombophilia tests in patients after a first VTE event[16] and the duration of treatment is rarely influenced by these data.

Instead, acquired thrombophilia because of antiphospholipid syndrome is of great relevance. The diagnosis of the antiphospholipid syndrome should be made when patients with a thrombotic event show the presence of lupus anticoagulant, and anticardiolipin antibodies and antiα2 glycoprotein-I antibodies in two repeated tests performed 8–12 weeks apart.[17] Patients with a first episode of VTE have a two-fold higher risk of recurrent VTE than those with negative tests; therefore, a long-term treatment is warranted for these patients.[18]

Cancer

Thrombotic events are the second leading cause of death in cancer patients (after cancer itself) and are associated with worsened short-term and long-term survival.[19] The risk of recurrent VTE after stopping therapy in patients with cancer is still uncertain, estimated at an annualized rate of about 15%, although it varies according to the presence of metastasis or whether undergoing chemotherapy, or in rapidly progressing cancer. The standard of care for the treatment of acute VTE in patients with active cancer is treatment with low molecular weight heparins (LMWH) for at least 6 months, on the basis of available data that demonstrate this nearly halves recurrent acute VTE.[20] The optimal duration of anticoagulation in cancer patients with VTE is not known, but extended anticoagulation beyond the standard 6 months should be considered, especially for those with active cancer and those receiving anticancer treatments.[5] When cancer is not considered active or chemotherapy is stopped, oral anticoagulation could be stopped.

D-dimer

D-dimer is the final product of the plasmin-mediated degradation of cross-linked fibrin. Its blood concentration depends on clotting activation with fibrin generation, stabilization by factor XIIIa, and subsequent degradation by the endogenous fibrinolytic system. D-dimer concentration is increased in all conditions associated with enhanced fibrin formation. D-dimer has high sensitivity and negative predictive value in the diagnostic workup of VTE for the exclusion of the disease, reducing the need for imaging tests.[21] D-dimer has been also studied as a predictor of recurrent VTE when measured after a standard course of 3–6 months of anticoagulation in patients with a first VTE. Following the observation that D-dimer plasma levels tend to increase in some patients with previous VTE after oral anticoagulation withdrawal,[22] subsequent prospective studies showed that D-dimer levels have a strong predictive value for the occurrence of recurrent VTE episodes.[23–28] These studies suggested that D-dimer measurement after anticoagulation withdrawal could help to identify patients at low risk of recurrent VTE, in whom anticoagulation therapy may be discontinued, whereas an abnormal D-dimer level may identify patients with a persistent prothrombotic tendency who warrant long-term anticoagulation and who carry a 9% annual absolute risk for recurrent VTE.[29] Repeated D-dimer testing in the first 3 months after anticoagulation withdrawal confirms the low risk of recurrence of patients with persistent negative D-dimer tests.[30] The prognostic utility of D-dimer was independent by age, timing of postanticoagulation D-dimer testing, the D-dimer cut-point used to define a positive test, and associated comorbidity.[31,32] However, it is known that D-dimer levels are higher in the elderly, and age-specific D-dimer cutpoints may increase its specificity.[33] Available data indicate that repeated D-dimer testing, especially in the first 3 months after anticoagulation withdrawal for a first episode of unprovoked VTE, could identify a subgroup of patients with a low risk of recurrence, which may not warrant prolonged anticoagulation. To address this issue, a multicenter prospective management study DULCIS (D-Dimer and Ultrasonography in Combination Italian Study; http://clinicaltrials.gov; NCT00954395) is used, in which D-dimer is tested in the first 3 months after vitamin K antagonist (VKA) withdrawal together with residual vein obstruction (RVO). Individuals with repeated normal D-dimer during the first 3 months after anticoagulation withdrawal and without significant RVO do not resume treatment, whereas individuals in whom D-dimer becomes abnormal during that time interval resume treatment. The results of the study should be available by the end of 2013.

Residual Vein Obstruction

The measurement of RVO on ultrasonography was found associated with a higher risk of recurrent VTE[34,35] and this observation was confirmed in three randomized trials.[36–38] RVO was interpreted as a marker for a hypercoagulable state, because of associated impaired venous flow, stasis, and activation of the coagulation cascade to explain the higher risk. However, this finding was not confirmed by other authors;[28,39] furthermore, there are no widely accepted criteria for the definition of thrombus regression, the assessment of RVO is not currently standardized, and a poor interobserver agreement has previously been described.[40] A recent meta-analysis of the available studies found that RVO was associated with a modestly increased risk of recurrent VTE in patients with DVT.[41] In particular, the persistence of a RVO does not seem to be an independent predictor of recurrent VTE in patients with unprovoked DVT following discontinuation of anticoagulation.

Bleeding Risk Score

Current guidelines recommending administer anticoagulant treatment for the secondary prevention of a first episode of unprovoked VTE for at least 3 months and to extend this treatment indefinitely in patients who have a low-to-moderate bleeding risk;[5] this requirement underlines the importance of an adequate risk-to-benefit ratio assessment of a long anticoagulant treatment in these patients. However, to date, the evaluation of the bleeding risk in VTE patients is not clearly defined. Several scores have been proposed to stratify VTE patients in relation to their bleeding risk, but none has been adequately validated.[5,42–47] In addition, some of these scores have been studied in atrial fibrillation patients only.[46,47] Recently, two studies[7,8] addressed the predictive accuracy of available scores in elderly patients, a group of fragile patients in whom the assessment of the risk-to-benefit ratio of a long-term anticoagulant treatment is of particular clinical importance. Both studies found that in elderly patients with VTE, the currently used criteria to estimate the anticoagulation-associated bleeding risk are not able to discriminate between the patients who are at high risk of a short-term major bleeding event and those who are not.

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