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....................................................................................................................................................................... antibodies and lupus anticoagulant)342 may be considered in patients in whom VTE occurs at a young age (e.g. aged <50 years) and in the absence of an otherwise identifiable risk factor, especially when this occurs against the background of a strong family history of VTE. In such cases, testing may help to tailor the regimen and dose of the anticoagulant agent over the long-term. On the other hand, no evidence of a clinical benefit of extended anticoagulant treatment is currently available for carriers of heterozygous factor V Leiden or prothrombin 20210A mutation.

A number of risk prediction models have been developed for the assessment of the risk of recurrence in an individual patient (Supplementary Data Table 13).343,344 The clinical value and, in particular, the possible therapeutic implications of these models in the NOAC era are unclear.

8.2 Anticoagulant-related bleeding risk

Incidence estimates from cohort studies conducted more than 15 years ago reported an 3% annual incidence of major bleeding in patients treated with VKAs.345 Meta-analyses of phase III studies focusing on the first 3 - 12 months of anticoagulant treatment showed an 40% reduction in the risk for major bleeding with NOACs compared with VKAs.346 The risk of major bleeding is higher in the first month of anticoagulant treatment, and then declines and remains stable over time. Based on currently available evidence, risk factors include: (i) advanced age (particularly >75 years); (ii) previous bleeding (if not associated with a reversible or treatable cause) or anaemia; (iii) active cancer; (iv) previous stroke, either haemorrhagic or ischaemic; (v) chronic renal or hepatic disease; (vi) concomitant antiplatelet therapy or non-steroidal anti-inflammatory drugs (to be avoided, if possible); (vii) other serious acute or chronic illness; and (viii) poor anticoagulation control. Existing bleeding risk scores and their current validation status are reviewed in Supplementary DataTable 14. The patient’s bleeding risk should be assessed, either by implicit judgement after evaluating individual risk factors or by the use of a bleeding risk score, at the time of initiation of anticoagulant treatment. It should be reassessed periodically (e.g. once a year in patients at low risk, and every 3 or 6 months in patients at high risk for bleeding). Bleeding risk assessment should be used to identify and treat modifiable bleeding risk factors, and it may influence decision-making on the duration and regimen/dose of anticoagulant treatment after acute PE.

8.3 Regimens and treatment durations

with non-vitamin K antagonist oral anticoagulants, and with other non-vitamin K antagonist antithrombotic drugs All patients with PE should be treated with anticoagulants for >_3 months.347 Beyond this period, the balance between the risk of VTE recurrence and that of bleeding, which has been used to select candidates for extended anticoagulation after a first VTE event in the VKA era, is currently being revisited based on the lower bleeding rates with NOACs. However, despite the improved safety of these drugs compared with VKAs, treatment with NOACs is not without risk. Phase III clinical trials on the extended treatment of VTE have shown that the rate of major bleeding may be 1%, and that of clinically relevant non-major (CRNM) bleeding as high as 6%. Bleeding rates may be higher in everyday clinical practice.348,349

The NOAC trials that focused on extended VTE treatment are summarized in Supplementary Data Table 15. In all studies, patients with PE made up approximately one-third of the entire study population, while the remaining two-thirds were patients with proximal DVT but no clinically overt PE. Patients needed to have completed the initial and long-term anticoagulation phase to be included in the extended studies. Dabigatran was compared with warfarin or placebo in two different studies (Supplementary Data Table 15).350 In these studies, dabigatran was non-inferior to warfarin for the prevention of confirmed recurrent symptomatic VTE or VTE-related death, and more effective than placebo for the prevention of symptomatic recurrent VTE or unexplained death.350 The rate of major bleeding was 0.9% with dabigatran compared to 1.8% with warfarin (HR 0.52, 95% CI 0.271.02).350 Rivaroxaban was compared with placebo or aspirin in two different studies in patients who had completed 612 months of anticoagulation treatment for a first VTE event (Supplementary Data Table 15). Treatment with rivaroxaban [20 mg once a day (o.d.)] reduced recurrent VTE by 80%, with a 6.0% incidence of major or CRNM bleeding as compared to 1.2% with placebo.351 Rivaroxaban given at a dose of 20 or 10 mg o.d. was compared with aspirin (100 mg o.d.) in 3365 patients.352 Both doses of rivaroxaban reduced symptomatic recurrent fatal or non-fatal VTE by 70% in comparison with aspirin. No significant differences in the rates of major or CRNM bleeding were shown between either dose of rivaroxaban and aspirin.352 Patients with VTE were randomized to receive two different doses of apixaban [2.5 or 5 mg twice a day (bis in die: b.i.d.)] or placebo after 612 months of initial anticoagulation (Supplementary Data Table 15).353 Both doses of apixaban reduced the incidence of symptomatic recurrent VTE or death from any cause compared with placebo, with no safety concerns.353 Patients at high bleeding risk—based on the investigator’s judgement, the patient’s medical history, and the results of laboratory examinations—were excluded from the extension studies mentioned above; this was also the case for studies on extended anticoagulation with VKAs.330,331 This fact should be taken into account during triage of a patient for extended anticoagulation with one of the above regimens. In a randomized, open-label study in high-risk patients with antiphospholipid syndrome (testing triple positive for lupus anticoagulant, anticardiolipin, and anti-b2-glycoprotein I), rivaroxaban was associated with an increased rate of thromboembolic and major bleeding events compared with warfarin (HR for the composite primary outcome 6.7; 95% CI 1.530.5).354 At present, NOACs are not an alternative to VKAs for patients with antiphospholipid syndrome. In two trials with a total of 1224 patients, extended therapy with aspirin (after termination of standard oral anticoagulation) was Downloaded from academic.oup.com/eurheartj/article/41/4/543/5556136 by guest on 07 October 2026