Compared with full-dose anticoagulation, modified-dose anticoagulation was associated with lower rates of major hemorrhage in patients with cancer, venous thromboembolism (VTE), and thrombocytopenia, according to a recent study published in Blood Advances. Additionally, researchers led by Brian J. Carney, MD, of Beth Israel Deaconess Medical Center in Boston, reported that patients in the study did not experience recurrent VTE after the initiation of modified-dose anticoagulation.
“Anticoagulation management in patients with cancer who develop VTE in the setting of thrombocytopenia is challenging given the high risk of hemorrhage balanced against the risk of recurrent thrombosis,” Dr. Carney wrote. Previous studies have suggested modified-dose anticoagulation is a viable alternative to full-dose anticoagulation with platelet transfusion support.
The prospective TROVE study enrolled a total of 121 adult patients at six U.S. hospitals through the Venous thromboEmbolism Network US (VENUS) from March 2018 to August 2020. Patients had histologically confirmed active malignancy, defined as cancer diagnosis or treatment with cancer-directed therapy within six months of study enrollment, as well as radiologically confirmed VTE and concurrent thrombocytopenia with platelet count of <100×109/L within 72 hours of VTE diagnosis. Enrollment was required to occur within seven days of VTE diagnosis.
At the discretion of the treating clinician, patients received the following:
- full-dose anticoagulation with platelet transfusion support (n=75, 62%)
- modified-dose anticoagulation (e.g., unfractionated heparin with decreased activated partial thromboplastin time or anti-Xa targets, enoxaparin dose less than 1.5 mg/kg/24 hours, 2.5 mg apixaban twice daily, or 10 mg rivaroxaban daily [n=33, 27%])
- no anticoagulation (n=13, 11%)
At baseline, 80% of the 45 patients with pulmonary emboli received full-dose anticoagulation. Out of 101 patients with deep vein thrombosis (DVT), 59% received full-dose anticoagulation, 38% received modified-dose anticoagulation, and 12% did not receive anticoagulation. A majority of the 48 cases of index upper extremity DVT (79%) were catheter-associated.
Across the anticoagulation groups, the most common anticoagulant used was low-molecular-weight heparin. Among the 16 patients who were initially treated with a direct oral anticoagulant, 13 received apixaban and three received rivaroxaban.
At 30 and 60 days after enrollment, laboratory studies, anticoagulation status and compliance, hemorrhage, and recurrent VTE events were assessed. Adherence to the documented anticoagulation and platelet transfusion plans were classified as “excellent,” “poor,” or “mixed,” by the site investigator at each study visit. Hemorrhage events included major hemorrhage and clinically relevant non-major bleeding classified according to International Society on Thrombosis and Haemostasis criteria. Recurrent VTE was confirmed using imaging studies or documentation.
Researchers found no difference in adherence between the full-dose and modified-dose anticoagulation cohorts, with site investigators classifying 94.8% and 89.1% of follow-up visits as “excellent” in patients initiated on full-dose and modified-dose anticoagulation, respectively (p=0.21).
Median platelet counts were 65×109/L, 37×109/L, and 16×109/L in the full-dose, modified-dose, and no anticoagulation cohorts, respectively. At 30 days follow-up, platelet count nadir remained significantly lower in patients who initially received modified-dose anticoagulation (26×109/L; p=0.02) and patients who did not receive anticoagulation (8×109/L; p<0.001), compared with those who initially received full-dose anticoagulation (42×109/L).
A total of 23 hemorrhagic events occurred during the study. At 60 days, the cumulative incidence of total hemorrhage was 24% in the full-dose anticoagulation group (95% CI 13.9-34.1%) compared with 15.9% in the modified-dose arm (95% CI 2.8-28.9%). No hemorrhagic events occurred in patients who did not receive anticoagulation. The cumulative incidence of major hemorrhage at 60 days was 12.8% in the full-dose cohort (95% CI 4.9-20.8%), compared with 6.6% in the modified-dose group (95% CI 2.4-15.7%). One of 11 major hemorrhagic events occurred while the patient was receiving modified-dose anticoagulation, and four out of five patients initially treated with modified-dose anticoagulation who experienced a hemorrhage were receiving full-dose anticoagulation at the time of the event.
Out of five recurrent VTE events during the study, four occurred in patients who initially received full-dose anticoagulation and one occurred in a patient who did not receive anticoagulation. In patients who initially received full-dose anticoagulation, the cumulative incidence of recurrent VTE at 60 days was 5.6% (95% CI 0.2-11%). In patients who initially received modified-dose anticoagulation, it was 0%.
During the 60-day follow-up period, 22 patients died. At 60 days, the survival rate was 81.5% in the full-dose anticoagulation group and 80.1% in the modified-dose anticoagulation cohort.
“As anticoagulation management was not randomized in this study, not unexpectedly, there were baseline imbalances including more patients with pulmonary emboli receiving full-dose anticoagulation,” the authors noted. Additionally, 94% of patients in the modified-dose arm were diagnosed with a hematologic malignancy, compared with 57% in the full-dose cohort. As such, the severity of thrombocytopenia was more pronounced in the modified-dose group, which represented a population at higher risk of hemorrhage than the full-dose cohort. “Despite this imbalance, there were no major hemorrhages observed in those patients who received modified-dose anticoagulation, providing additional reassurance regarding the safety of this approach during periods of thrombocytopenia,” the authors wrote.
Study authors report no relevant conflicts of interest.
Carney BJ, Wang TF, Ren S, et al. Anticoagulation in cancer-associated thromboembolism with thrombocytopenia: a prospective, multi-center cohort study [published online ahead of print, 2021 Oct 18]. Blood Adv. doi: 10.1182/bloodadvances.2021005966.