Introduction
Randomized trials of venous thromboembolism (VTE) treatment in cancer have primarily focused on the initial 6-month period and the risk/benefit of additional anticoagulant therapy beyond this time point has not been fully evaluated. Current guidelines recommend continuing full dose anticoagulation after 6 months in patients who have ongoing active cancer and/or those undergoing anti-neoplastic treatment. This recommendation, however, is based on little evidence. Here, we describe clinical outcomes of patients who have completed at least 6 months of anticoagulation. Our aim was to compare VTE recurrence, bleeding rate, and overall survival in patients who continued vs. discontinued anticoagulation after the initial 6-month treatment period.
Methods
We evaluated a prospective cohort of patients referred to the Cleveland Clinic cancer-associated thrombosis clinic from 8/2014-12/2018. We evaluated clinical characteristics, VTE recurrence, bleeding (major or clinically relevant non-major bleeding (CRNMB) as defined by ISTH criteria), and overall survival in patients who continued vs. discontinued anticoagulation after 6 months. Low-risk for recurrent VTE was defined as not having active cancer and not receiving systemic therapy. Statistical methods included t-tests, chi-squared tests, Cox model, and log rank test where appropriate. Multivariable analysis was performed to analyze outcomes of interest.
Results
The study population was comprised 284 (73.2%) patients who were followed 6 months after the initial VTE event. Of these, 93 (32.7%) did not continue anticoagulation beyond 6 months, and 191 (67.3%) continued anticoagulation treatment (table 1). Anticoagulation was discontinued for the following reasons: low risk (n=33, 35.5%), bleeding (n=12, 12.9%), clinical decision (n=4, 4.3%) and other including financial reasons (n=43, 46.2%; table 2). In patients who continued anticoagulation, 86/191 (45%) had stage IV disease and the most frequent cancers were hematologic malignancies (58/191, 30.4%) and gastrointestinal cancers (37/191, 19.4%). Low molecular weight heparin was the most commonly prescribed anticoagulant (110/191; 57.6%) followed by direct oral anticoagulants (68/191, 35.6%).
There was no difference in the rate of recurrent VTE in patients who remained on treatment beyond six months (23/191; 12%) vs. those who stopped treatment at six months (11/93; 11.8%; p= 0.81; figure 1).
In patients who continued anticoagulation 6-12 months after the initial treatment period, 13/191 (6.8%) had a bleeding event (major bleeding n=4, CRNMB n=9). There was 1 major bleed and no CRNMB in the group that stopped anticoagulation. After multivariable analysis, recurrent VTE was associated with worse overall survival [hazard ratio (HR) 1.88; 95% Confidence Interval (CI) 1.06-3.35, p=0.03].
Discussion
This prospective analysis found no difference in the rate of recurrent VTE and more bleeding in patients who continued anticoagulation, although recurrent VTE rates were high in both cohorts. Furthermore, a recurrent VTE event was associated with worse overall survival. Emerging data with DOACs may alter recurrence rates and the ability to continue treatment beyond 6 months. Although limited by a small study population, this study adds to available data regarding outcomes beyond six months of treatment. Future studies should focus on exploring the outcomes of extending anticoagulation and better identifying patients at risk for recurrent VTE.
McCrae:Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Sanofi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Khorana:Janssen: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy.
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