Incidental venous thromboembolism in cancer patients

It is well known that patients with cancer are at high risk of venous thromboembolism (VTE), especially when initiating chemotherapy [1-3]. VTE detected on imaging performed for other reasons than VTE suspicion (e.g. diagnosing cancer or monitoring of tumor response to cancer therapy) is termed ‘incidental VTE’. There is an important distinction between ‘incidental’ and ‘asymptomatic’ VTE, as the former coincides with symptoms in up to 75% of cases [4]. With the improvements in resolution of computed tomography (CT)-scanning and its increased use in daily clinical practice, the incidence of incidental VTE in cancer patients has increased over the past decade [5-8]. It is estimated that approximately 50% of all pulmonary embolic events in cancer patients are now incidentally detected on routine imaging scans [9]. Based on a few cohort studies that observed a similar risk of recurrent VTE in cancer patients with incidental VTE and symptomatic VTE, international guidelines suggest a similar treatment duration and strategy in both groups of patients [10-12].

The Hokusai VTE Cancer study was a multicenter, open-label trial, which randomized 1,046 cancer patients to either dalteparin or edoxaban for the treatment of acute VTE[13]. All study outcomes were adjudicated by an independent committee unaware of treatment allocation. It was the first randomized trial in this setting that also enrolled patients with incidental VTE. Therefore, this study provided novel high-quality evidence on clinical outcomes in patients with incidental VTE. Here, we summarize our previously reported subgroup analysis of the patients with incidental VTE in the Hokusai VTE Cancer study [14].

Of the 1,046 cancer patients enrolled in this trial, 340 (32%) had a reported incidental VTE, which was confirmed in 331 patients (97%) by a radiologist who was also blinded to treatment allocation. Most of these patients had a solid tumor (n=315; 95%) and incidental pulmonary embolism (PE) with or without deep vein thrombosis (DVT) as the index event (n=290; 88%). During the 12-month study period, 26 of 331 patients (7.9%) developed recurrent VTE despite initiation of anticoagulant treatment, of whom 16 (4.8%) had recurrent PE with or without DVT and 10 (3.0%) had recurrent DVT only. Of the 10 recurrent DVT events, six (60%) were symptomatic and four (40%) were incidentally detected. Of the 16 patients with recurrent PE, seven (44%) were symptomatic, five (31%) were incidentally detected and four (25%) were deaths for which PE could not be ruled out. On-treatment major bleeding occurred in 6% of patients. Taken together, the substantial risk of recurrent VTE despite initiation of anticoagulant treatment supports current guidelines recommending that patients with incidental VTE should be treated similarly as those with symptomatic VTE.

In the group of 679 cancer patients with symptomatic VTE, 74 (11%) patients had recurrent VTE during the 12-month study period. The risk of recurrent VTE was thus higher in the group patients with symptomatic VTE than in those with incidental VTE (11% vs 7.9%), although this difference did not reach statistical significance (hazard ratio [HR]: 0.68; 95% CI: 0.43–1.06), also not when adjusting for age, sex, anticoagulant treatment, Eastern Cooperative Oncology Group performance status, cancer type, cancer stage and prior VTE (adjusted HR: 0.68; 95% CI: 0.42–1.11). Notably, the Hokusai VTE Cancer study was not powered to detected differences between patients with symptomatic and incidental VTE. Given the similar crude and unadjusted HRs, the findings suggest that symptomatic VTE may be associated with a higher risk of recurrence. There was no evidence that the risk–benefit ratio with edoxaban was different between patients symptomatic VTE and those with incidental VTE (P_interaction=0.97).

In summary, findings from the Hokusai VTE Cancer study show that the risk of recurrence is substantial in cancer patients with incidental VTE, despite anticoagulant treatment. The recently published SELECT-D trial and Caravaggio studies, which evaluated rivaroxaban and apixaban, respectively, for cancer-associated VTE, also enrolled cancer patients with incidental VTE [15,16]. A combined individual patient data analysis of this subgroup could help better substantiate the risk of complications in patients with incidental VTE and identify risk factors for recurrence and bleeding.

References

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