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Biomarker-directed thromboprophylaxis in the outpatient setting significantly reduced the frequency of thromboembolism in high-risk patients with gastrointestinal (GI) or lung cancers, a randomized trial showed.

Patients at high risk for thrombotic events by fibrinogen and D-dimer assessment had an 8% incidence of thromboembolism with prophylactic enoxaparin versus 23% among patients randomized to placebo. Patients at low risk by biomarker assessment also had an 8% incidence of thromboembolism with observation.

The reduction in thromboembolic events in high-risk patients occurred with low mortality and without safety issues, and low-risk patients avoided unnecessary intervention, reported Marliese Alexander, PhD, of Peter MacCallum Cancer Centre in Melbourne, Australia, and coauthors in . The results added to those of previous randomized trials of thromboprophylaxis with apixaban (Eliquis) and rivaroxaban (Xarelto).

"The fibrinogen and D-dimer RAM [risk assessment model] identified individuals with lung and gastrointestinal cancers who would most benefit from thromboprophylaxis and those who could avoid intervention," the authors wrote in conclusion. "Future investigations in expanded tumor groups that incorporate clinician and consumer preference for choice of anticoagulant are warranted."

"Given established safety and efficacy data, we believe that the choice of an anticoagulant is less important than appropriate cohort selection and acknowledge that we are unlikely to see head-to-head trials of LMWH [low-molecular-weight heparin] vs oral agents," they stated. "[This trial] used LMWH as the gold standard at the time of trial commencement prior to availability of safety data of oral anticoagulants, for which potential drug interactions and bleeding risks have yet to be fully detailed in subgroup analyses. Despite the lack of comprehensive safety data, oral agents have several advantages, particularly related to individuals' preferences and adherence."

In addition to being consistent with previous studies, the trial added meaningfully to the existing evidence base, wrote the author of an . The findings also support existing guideline recommendations to offer thromboprophylaxis to high-risk patients in the outpatient setting.

"The biggest question in the field, then, is not which risk-based approach or which anticoagulant is the best for primary prevention," stated Alok A. Khorana, MD, of the Cleveland Clinic Taussig Cancer Institute. "Rather, it is this: What is stopping patients with cancer from being offered thromboprophylaxis in the first place? There are currently more RCT [randomized controlled trial] data to support outpatient thromboprophylaxis than inpatient prophylaxis in patients with cancer.... Yet, thromboprophylaxis is widely deployed in the inpatient setting but rarely considered in the outpatient setting."

"What is urgently needed is implementation science: systematically closing the gap between what we know and what we do," he added.

Cancer-associated thromboembolism remains a substantial problem for clinical management, burdening both patients and health systems, Alexander and coauthors noted in their introduction. Despite multiple positive trials, evidence-based guidelines, and extensive clinical experience, thromboprophylaxis for patients on anticancer drugs remains problematic, primarily because of the heterogeneity of risk profiles and concerns for bleeding.

In an effort to move the needle toward more rational use of thromboprophylaxis for cancer patients, investigators designed a randomized trial to evaluate RAM-directed outpatient treatment for GI and lung cancers, for which thromboprophylaxis RAMs have underperformed. The trial included 328 patients with GI or lung cancer, stratified into high- and low-risk groups on the basis of fibrinogen and D-dimer levels, using a RAM previously validated in lung and GI cancer.

Patients deemed at high risk on the basis of the RAM were randomized to enoxaparin or placebo, administered in an outpatient setting. Low-risk patients were observed. The primary endpoint was the incidence of objectively confirmed thromboembolism at 180 days, including deep-vein thrombosis, pulmonary embolism, and myocardial infarction.

The study population comprised 201 patients with GI cancer and 127 with lung cancer. Data analysis included 200 randomized high-risk patients and 128 low-risk patients. The results showed that the placebo group had about a threefold greater incidence of thromboembolism (HR 0.31, 95% CI 0.15-0.70, P=0.005). Additionally, high-risk patients assigned to placebo were more than three times as likely to have a thromboembolism as compared with low-risk patients who were observed (HR 3.33, 95% CI 1.58-6.99, P=0.002).

The rate of major bleeding was 1% in patients randomized to enoxaparin and 2% in the high-risk control group and the low-risk patients. Six-month mortality, a secondary endpoint, was twice as high in the high-risk placebo group, 26% vs 13% with enoxaparin (HR 0.48, 95% CI 0.24-0.93, P=0.03). High-risk patients assigned to placebo had almost a fivefold greater risk of 6-month mortality versus low-risk patients (HR 4.71, 95% CI 2.13-10.42, P<0.001).

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