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............................................................................................................................................................................. dosing of UFH is adjusted based on the activated partial thromboplastin time (Supplementary Data Table 7).266

6.2.2 Non-vitamin K antagonist oral anticoagulants NOACs are small molecules that directly inhibit one activated coagulation factor, which is thrombin for dabigatran and factor Xa for apixaban, edoxaban, and rivaroxaban. The characteristics of NOACs used in the treatment of acute PE are summarized in Supplementary Data Table 6. Owing to their predictable bioavailability and pharmacokinetics, NOACs can be given at fixed doses without routine laboratory monitoring. Compared with vitamin K antagonists (VKAs), there are fewer interactions when NOACs are given concomitantly with other drugs.259 In the phase III VTE trials, the dosages of dabigatran, rivaroxaban, and apixaban were not reduced in patients with mildmoderate renal dysfunction (CrCl between 3060 mL/min), whereas edoxaban was given at a 30 mg dose in these patients. Patients with CrCl <25 mL/min were excluded from the trials testing apixaban, whereas patients with CrCl <30 mL/min were excluded from those investigating rivaroxaban, edoxaban, and dabigatran (Supplementary Data Table 8). Phase III trials on the treatment of acute VTE (Supplementary Data Table 8), as well as those on extended treatment beyond the first 6 months (see section 8), demonstrated the non-inferiority of NOACs compared with the combination of LMWH with VKA for the prevention of symptomatic or lethal VTE recurrence, along with significantly reduced rates of major bleeding.267 The different drug regimens tested in these trials are displayed in Supplementary Data Table 8. In a meta-analysis, the incidence rate of the primary efficacy outcome was 2.0% for NOAC-treated patients and 2.2% for VKA-treated patients [relative risk (RR) 0.88, 95% CI 0.741.05].268 Major bleeding occurred in 1.1% of NOAC-treated patients and 1.7% of VKAtreated patients for an RR of 0.60 (95% CI 0.410.88). Compared with VKA-treated patients, critical site major bleeding occurred less frequently in NOAC-treated patients (RR 0.38, 95% CI 0.23 0.62); in particular, there was a significant reduction in intracranial bleeding (RR 0.37, 95% CI 0.210.68) and in fatal bleeding (RR 0.36, 95% CI 0.150.87) with NOACs compared with VKAs.268 Suggestions for the anticoagulation management of PE in specific clinical situations, for which conclusive evidence is lacking, are presented in Supplementary Data Table 9. Practical guidance for clinicians regarding the handling of NOACs and the management of emergency situations related to their use are regularly updated by the European Heart Rhythm Association.259

6.2.3 Vitamin K antagonists VKAs have been the gold standard in oral anticoagulation for more than 50 years. When VKAs are used, anticoagulation with UFH, LMWH, or fondaparinux should be continued in parallel with the oral anticoagulant for >_5 days and until the international normalized ratio (INR) value has been 2.03.0 for 2 consecutive days. Warfarin may be started at a dose of 10 mg in younger (e.g. aged <60 years) otherwise healthy patients and at a dose <_5 mg in older patients.269 The daily dose is adjusted according to the INR over the next 57 days, aiming for an INR level of 2.03.0. Pharmacogenetic testing may increase the precision of warfarin dosing.270,271 When used in addition to clinical parameters, pharmacogenetic testing improves anticoagulation control and may be associated with a reduced risk of bleeding, but does not reduce the risk of thromboembolic events or mortality.272

The implementation of a structured anticoagulant service (most commonly, anticoagulant clinics) appears to be associated with increased time in the therapeutic range and improved clinical outcome, compared with control of anticoagulation by the general practitioner.273,274 Finally, in patients who are selected and appropriately trained, self-monitoring of VKA is associated with fewer thromboembolic events and increased time in the therapeutic range compared with usual care.275

6.3 Reperfusion treatment

6.3.1 Systemic thrombolysis Thrombolytic therapy leads to faster improvements in pulmonary obstruction, PAP, and PVR in patients with PE, compared with UFH alone; these improvements are accompanied by a reduction in RV dilation on echocardiography.276279 The greatest benefit is observed when treatment is initiated within 48 h of symptom onset, but thrombolysis can still be useful in patients who have had symptoms for 614 days.280 Unsuccessful thrombolysis, as judged by persistent clinical instability and unchanged RV dysfunction on echocardiography after 36 h, has been reported in 8% of high-risk PE patients.281 A meta-analysis of thrombolysis trials that included (but were not confined to) patients with high-risk PE, defined mainly as the presence of cardiogenic shock, indicated a significant reduction in the combined outcome of mortality and recurrent PE (Supplementary Data Table 10). This was achieved with a 9.9% rate of severe bleeding and a 1.7% rate of intracranial haemorrhage.282 In normotensive patients with intermediate-risk PE, defined as the presence of RV dysfunction and elevated troponin levels, the impact of thrombolytic treatment was investigated in the Pulmonary Embolism Thrombolysis (PEITHO) trial.179 Thrombolytic therapy was associated with a significant reduction in the risk of haemodynamic decompensation or collapse, but this was paralleled by an increased risk of severe extracranial and intracranial bleeding.179 In the PEITHO trial, 30 day death rates were low in both treatment groups, although meta-analyses have suggested a reduction in PErelated and overall mortality of as much as 5060% following thrombolytic treatment in the intermediate-risk category (Supplementary Data Table 10).282,283 The approved regimens and doses of thrombolytic agents for PE, as well as the contraindications to this type of treatment, are shown in Table 10. Accelerated i.v. administration of recombinant tissuetype plasminogen activator (rtPA; 100 mg over 2 h) is preferable to prolonged infusions of first-generation thrombolytic agents (streptokinase and urokinase). Preliminary reports on the efficacy and safety of reduced-dose rtPA284,285 need confirmation by solid evidence before any recommendations can be made in this regard. UFH may be administered during continuous infusion of alteplase, but should be discontinued during infusion of streptokinase or urokinase.65 Reteplase,286 desmoteplase,287 or tenecteplase179,278,279 have also been investigated; at present, none of these agents are approved for use in acute PE. It remains unclear whether early thrombolysis for (intermediateor high-risk) acute PE has an impact on clinical symptoms, functional Downloaded from academic.oup.com/eurheartj/article/41/4/543/5556136 by guest on 07 October 2026