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...................................................................................................................................................................... 8.5 Management of pulmonary embolism in patients with cancer Five RCTs compared LMWH vs. conventional VTE treatment (heparin followed by VKA) in the treatment of VTE in cancer-associated thrombosis.360364 In 2003, a significant reduction in VTE recurrence was reported with LMWH compared with conventional (VKA) treatment without an increase in bleeding complications.362 In a more recent trial, long-term administration of tinzaparin failed to achieve a statistically significant reduction in overall VTE recurrence over conventional treatment (HR 0.65, 95% CI 0.411.03); however, the overall rate of recurrent VTE in the control arm was lower than that previously observed, probably as a result of the recruitment of patients with a lower cancer-specific thrombotic risk.360 Overall, LMWHs were found to decrease the risk of recurrent VTE by 40% with a risk of major bleeding complications similar to that of VKAs.365

Accordingly, LMWHs have become the standard of care. However, these agents are associated with a relevant cost and burden for patients. In addition, the absolute rate of recurrent VTE while on LMWH remains high (79%) compared with that observed in noncancer patients with VTE on conventional treatment (1.53%).365 NOACs could make the treatment of VTE easier and more convenient in patients with cancer, due to their oral administration in fixed-dose regimens and their lower cost compared with LMWH. However, only 39% of patients included in phase III studies with NOACs for the treatment of VTE had concomitant cancer.260,261,312,314,351 A randomized, open-label trial compared edoxaban with LMWH in the secondary prevention of VTE in 1050 patients with cancer-associated thrombosis (mostly symptomatic or asymptomatic PE).366 Edoxaban (60 mg o.d., reduced to 30 mg in subjects with moderate renal impairment, low body weight, or concomitant need for strong inhibitors of glycoprotein-P) was started after 5 days of LMWH and treatment was given for >_6 months. Edoxaban was non-inferior to dalteparin in the prevention of VTE recurrence or major bleeding over 12 months after randomization (HR 0.97, 95% CI 0.701.36). Major bleeding occurred in 6.9% of the patients in the edoxaban arm and 4.0% in the dalteparin arm (difference in risk 2.9 percentage points, 95% CI 0.15.6). This difference appears to have been mainly accounted for by the high rate of bleeding in patients with gastrointestinal cancer allocated to the edoxaban group.366 Similar results were reported by a randomized, open-label pilot trial comparing rivaroxaban with dalteparin in 406 patients with VTE and cancer, 58% of whom had metastases.367 A significant decrease in the risk of recurrent VTE was observed with rivaroxaban (HR 0.43, 95% CI 0.190.99). The 6 month cumulative rate of major bleeding, which was mostly gastrointestinal, was 6% (95% CI 311%) for rivaroxaban and 4% (95% CI 28%) for dalteparin (HR 1.83, 95% CI 0.684.96). Corresponding rates of CRNM bleeds were 13% (95% CI 919%) and 4% (95% CI 29%), respectively (HR 3.76, 95% CI 1.638.69).367 Based on the currently available evidence, as described above, patients with acute PE and cancer, particularly those with gastrointestinal cancer, should be encouraged to continue LMWH for >_ 36 months. This also applies to patients in whom oral treatment is unfeasible due to problems of intake or absorption, and to those with severe renal impairment. In all other cases, especially in patients with an anticipated low risk of bleeding and without gastrointestinal tumours, the choice between LMWH and edoxaban or rivaroxaban is left to the discretion of the physician, and the patient’s preference.

Owing to the high risk for recurrence, patients with cancer should receive indefinite anticoagulation after a first episode of VTE. Although existing evidence is limited, it is conceivable that once cancer is cured the risk for recurrence decreases and anticoagulation can be stopped. However, the definition of cured cancer is not always clear. The risk of recurrence of PE in cancer was assessed in a cohort study of 543 patients and was validated in an independent set of 819 patients.368 The proposed score to predict the risk of recurrence included breast cancer (minus 1 point), Tumour Node Metastasis stage I or II (minus 1 point), and female sex, lung cancer, and previous VTE (plus 1 point each). Patients with a score <_0 were at low risk (<_4.5%) and those with a score >_1 were at high (>_19%) risk of VTE recurrence over the first 6 months.368 After the first 36 months, extended anticoagulation may consist of continuation of LMWH or transition to an oral anticoagulant. Two cohort studies have assessed the safety of extended treatment with LMWH (<_12 months) in cancer-associated thrombosis.369,370 In both studies, the incidence of bleeding complications was higher in the first months and then reached a plateau that remained unchanged after the sixth month. In the absence of conclusive evidence, the decision to continue with LMWH or to change to VKA or a NOAC should be made on a case-by-case basis after consideration of the success of anticancer therapy, the estimated risk of recurrence of VTE, the bleeding risk, and the preference of the patient. Periodic reassessment of the risk-to-benefit ratio of continued anticoagulant treatment is mandatory. As mentioned in section 5, venous filters are principally indicated when anticoagulation is impossible due to active haemorrhage or an excessive bleeding risk. However, the risk of VTE recurrence in the absence of anticoagulation is particularly high in patients with cancer, and the insertion of a filter should not delay the initiation of anticoagulation as soon as it is safe to do so. There is no evidence to support the use of venous filters as an adjunct to anticoagulation treatment in patients with cancer. A number of studies have reported that a proportion of patients presenting with PE in the absence of identifiable risk factors develop cancer within the first year after diagnosis.371 Consequently, the optimal strategy to achieve early diagnosis of these occult cancers was investigated. Two large randomized trials failed to show that comprehensive CT of the abdomen or 18F deoxy-fluoro-glucose positron emission tomography were able to detect more cancers than limited screening in patients with an unprovoked VTE.372,373 Therefore, based on current evidence, the search for occult cancer after an episode of VTE may be restricted to careful history taking, physical examination, basic laboratory tests, and a chest X-ray (if no CTPA was performed to diagnose PE).372,374,375 In patients with cancer, incidental PE should be managed in the same manner as symptomatic PE, whether it involves segmental or more proximal branches, multiple subsegmental vessels, or a single subsegmental vessel in association with detectable DVT.376,377 Downloaded from academic.oup.com/eurheartj/article/41/4/543/5556136 by guest on 07 October 2026