Recurrent Thrombosis and Bleeding in Patients with Cancer-Associated Venous Thromboembolism Receiving Anticoagulation: Are These Modifiable Risk Factors for Mortality?

Patients with cancer-associated venous thromboembolism (VTE) have a higher risk of recurrent VTE than those without cancer and require long-term anticoagulation,[1] but these patients are also at a higher risk of anticoagulant-related bleeding because of the frequent presence of disease- or treatment-related predispositions for bleeding ([Fig. 1]).[2] [3] Arterial thromboembolic events are also common in cancer, partly associated with some anticancer therapies and types of cancer, as well as ethnicity.[4] [5] There is a widely held perception that recurrent thrombosis is more serious than bleeding in patients with cancer-associated VTE receiving anticoagulation. In a recent meta-analysis, recurrent VTE had a higher case fatality rate than major bleeding (14.8 vs. 8.9%),[6] supporting guideline recommendation for indefinite anticoagulant therapy for cancer-associated VTE in the absence of contraindication.[7] [8]

Fig. 1 Risk factors for VTE and bleeding in patients with cancer-associated VTE treated with anticoagulation. This figure illustrates the risk factors for VTE and bleeding and how these adverse outcomes are related to mortality. In patients with cancer-associated VTE receiving anticoagulation, data from McBane and colleagues indicate that both VTE recurrence and major bleeding predict mortality and are associated with a >50% and >80% increase in mortality, respectively. However, it is presently unclear whether interventions that address these risk factors (intervention at level A) or whether more effective or safer anticoagulant approaches (intervention at level B, e.g., such as factor XI inhibitors) would improve outcomes in patients with cancer-related VTE, in whom mortality may be mostly driven by the underlying cancer. Factors identified in the study of McBane and colleagues are labeled with asterisks (*). CRNMB, clinically relevant nonmajor bleeding; VTE, venous thromboembolism.

Less well known are the indirect (and longer term) effects of recurrent VTE or bleeding on mortality in this population. Notwithstanding the short-term consequences on mortality (fatal pulmonary embolism or fatal bleeding), both recurrent VTE and major bleeding could worsen prognosis through various indirect mechanisms, including the interruption of essential anticancer treatment.[9] [10] [11] So, a better understanding of the complex relations among VTE recurrence, bleeding, and mortality could improve risk stratification and spur the development of novel approaches that have the potential to improve outcomes.

In this issue of Thrombosis and Haemostasis, McBane and colleagues[12] took a different approach to many of the earlier studies by focusing on the impact of recurrent VTE and bleeding on overall mortality rather than case fatality alone,[13] and report the findings of a prospective cohort study of 1,812 consecutive patients diagnosed with cancer-associated VTE and treated with anticoagulant therapy between 2013 and 2021. Consistent with guideline recommendations, most patients were treated with either a direct oral anticoagulant (DOAC; 62%) or low-molecular-weight heparin (32%) and the remaining patients were treated with alternative anticoagulants, including warfarin. Their study has at least three clinically relevant findings. First, patients with cancer-associated thrombosis have dismal survival; indeed by 1 year >30% of the cohort had died and >80% had died by 5 years, confirming the findings of other studies in this population. Second, they found a similar frequency of thrombosis recurrence, major bleeding, and clinically relevant nonmajor bleeding (CRNMB), each approximately 5%. Third, recurrent VTE (hazard ratio [HR]: 1.52; 95% confidence interval [CI]: 1.16–2.00; p = 0.0028), major bleeding (HR: 1.82; 95% CI: 1.41–2.31; p = 0.006) as well as CRNMB (HR: 1.38; 95% CI: 1.05–1.81; p = 0.018) were all significantly associated with higher mortality. Interestingly, major bleeding appeared to have a greater impact on mortality than recurrent VTE. In addition, McBane and colleagues explored predictors of recurrent VTE and bleeding. Deep vein thrombosis as the incident thrombotic manifestation was associated with VTE recurrence but not with other factors (such as cancer type, stage, chemotherapy, Ottawa risk category). Lower body weight, high Ottawa scores, and apixaban use were associated with fewer major bleeding, but they could not show that anticoagulant choice improved mortality.

The strengths of the study include the large sample size, the focus on overall mortality, and attempts to derive risk predictors. Limitations include (1) the potential for underestimating the frequency of recurrent VTE/bleeding because of the competing risk of cancer-related mortality; (2) unclear duration of follow-up; (3) the presence of confounders when exploring the relation between events and mortality, and (4) the lack of granularity regarding the type of VTE recurrence or the site of bleeding and their associations with mortality. Nonetheless, the study offers important insights that improve our understanding of the impact of recurrent VTE and bleeding on mortality and their relative importance.

Perhaps, the most important insight provided by McBane and colleagues is the strong association between bleeding and mortality and their data are among the firsts to highlight that anticoagulant-related bleeding is at least as important as recurrent VTE in predicting mortality in patients with cancer-associated VTE. Consistent with these findings are data in other populations that associate antithrombotic-related bleeding with higher mortality, and that its prevention may improve survival. In patients with symptomatic atherosclerosis receiving antithrombotic therapy, bleeding was associated with at least twofold higher rates of thromboembolism and mortality,[14] and in pivotal trials of DOACs in patients with atrial fibrillation, the mortality benefit was linked to reductions in bleeding and ischemic events.[15] Through various mechanisms, including discontinuation of anticoagulation, reactive hypercoagulability, and transfusion-related adverse effects, major bleeding could contribute to thrombotic events and deaths. Although McBane and colleagues showed that bleeding and recurrent VTE identify patients at higher risk of death, it remains unclear from the published data whether these associations are modifiable and to what extent preventing bleeding or recurrent VTE would improve survival in a population with cancer.

More work remains to be done to identify modifiable risk factors for bleeding and VTE recurrence in this population, and to identify subgroups who may benefit from interventions. This is particularly important given observations of the increasing prevalence of cancer-associated VTE events.[16]

Publication History

Accepted Manuscript online:
19 January 2023

Article published online:
22 February 2023

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