Tranexamic acid fails to reduce bleeding for thrombocytopenic patients with blood cancers
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The addition of tranexamic acid prophylaxis to platelet transfusion did not reduce bleeding among patients with blood cancers and severe thrombocytopenia, according to study results presented at the virtual ASH Annual Meeting and Exposition.
“At present, it is not clear that any other pharmacologic therapy could either substitute for, or augment, the effect of platelets in these patients,” study author Nigel S. Key, MD, vice chief for research in the division of hematology, director of the UNC Blood Research Center, and director of the UNC Hemophilia and Thrombosis Center at The University of North Carolina at Chapel Hill, told Healio. “However, it should be noted that our study does not rule out the possibility that tranexamic acid might be efficacious as an interventional — rather than prophylactic — strategy for significant bleeding events, such as intracranial or intrapulmonary hemorrhage in these patients.”
Up to 70% of patients treated for hematologic malignancies experience WHO grade 2 or higher bleeding despite prophylactic platelet transfusion therapy. These events can range from nosebleeds to potentially life-threatening events that require blood transfusions.
“Bleeding is a significant cause of morbidity and mortality [among] these patients,” said Key, a HemOnc Today Editorial Board Member. “Severe thrombocytopenia is a major — but not the sole — cause of bleeding, and replacement of platelet numbers by transfusion accounts for approximately one-third of the platelet units transfused in the United States annually. Thus, from both a clinical outcomes as well as an economic perspective, better treatments for severe thrombocytopenic bleeding in patients with blood cancers are badly needed.”
Tranexamic acid is an antifibrinolytic agent shown to reduce bleeding in a range of clinical scenarios, Key said. These include major trauma, postpartum hemorrhage or major orthopedic surgery.
Results of small studies suggested the agent may offer benefit as adjunctive therapy for thrombocytopenia-associated bleeding.
“Mechanistically, we postulated that reduced concentrations of platelet-derived inhibitors of fibrinolysis — such as [plasminogen activator inhibitor-1] — could contribute to thrombocytopenic bleeding and, thus, be amenable to antifibrinolytic therapy,” Key said.
Key and colleagues conducted the randomized, double-blind A-TREAT trial to assess whether the addition of prophylactic tranexamic acid to routine transfusion therapy affected bleeding and transfusion requirements for patients with hematologic malignancies.
Researchers enrolled 330 patients between June 15, 2016, and Feb. 4 of this year. All patients were undergoing chemotherapy or hematopoietic stem cell transplantation at one of three U.S. academic medical centers and were anticipated to have hypoproliferative thrombocytopenia (expected platelet count, 10,000/µL for at least 5 days).
Exclusion criteria included history of thromboembolism or thrombotic cardiac event, current receipt of anticoagulant therapy or high risk for thrombosis, diagnosis of acute promyelocytic leukemia, elevated platelet transfusion threshold or severe uremia/dialysis.
Researchers assigned 165 patients to tranexamic acid dosed at 1,000 mg via IV or 1,300 mg orally. The other 165 patients received IV saline or oral placebo.
Patients received treatment every 8 hours, starting when platelet counts were below 30,000/µL. Treatment continued for 30 days or platelet count recovery (> 30,000/µL), diagnosis of thrombosis or veno-occlusive disease, recurrent line occlusion, visible hematuria, or physician or patient request.
The tranexamic acid and placebo groups were balanced with regard to age (mean, 54.1 years vs. 54.3 years), sex (male, 55.8% vs. 60.6%), and treatment type (allogeneic transplant, 38.2% vs. 39.4%; autologous transplant, 21.8% each; chemotherapy/immunotherapy, 40% vs. 38.8%).
Trained research staff performed daily bleeding assessments for inpatients. Chart reviews were performed to account for laboratory data, medication use, transfusions or other procedures, and adverse events.
Outpatients performed daily bleeding self-assessments.
The proportion of patients with WHO grade 2 or higher bleeding over 30 days after study drug activation served as the primary endpoint. Secondary endpoints included number of transfusions and number of days alive without WHO grade 2 or higher bleeding during the first 30 days after study drug activation.
Safety endpoints included thrombosis, veno-occlusive disease and mortality.
Sixty percent of patients stopped treatment due to platelet recovery, 9% finished the 30-day treatment course, and 16% chose to stop treatment early. Patients spent a mean 12 days on their assigned study drug.
Results showed tranexamic acid prophylaxis did not significantly reduce grade 2 or higher bleeding (45.4% vs. 48%; OR = 0.86; 95% CI, 0.52-1.38). This trend persisted regardless of whether patients underwent allogeneic transplant (57.3% vs. 58.8%; OR = 0.94; 95% CI, 0.45-1.95), autologous transplant (19.9% vs. 24.7%; OR = 0.71; 95% CI, 0.21-2.37) or chemotherapy/immunotherapy (48% vs. 52.1%; OR = 0.84; 95% CI, 0.4-1.78).
Researchers also reported no significant difference in mean number of transfusions (difference, 0.1; 95% CI, –1.9 to 2) or days alive without grade 2 or higher bleeding (difference, 0.1; 95% CI, –1.4 to 1.5).
Results showed no differences in exploratory outcomes, including mean difference in transfusions per thrombocytopenic day (–0.02; 95% CI, –0.09 to 0.04) or mean difference in red blood cell transfusions per thrombocytopenic day (0.03; 95% CI, –0.05 to 0.11).
The average number of days with thrombocytopenia or bleeding appeared comparable between those who received tranexamic acid prophylaxis and those who did not (9.2 days [standard deviation = 6.7] vs. 9.1 days [standard deviation, 6.2]).
Researchers observed no difference in time to grade 2 or higher bleeding or death (HR = 0.96; 95% CI, 0.43-2.16) or mean difference in highest grade of bleeding (–0.1; 95% CI, –0.2 to 0.1) with tranexamic acid prophylaxis.
The results suggest patients who have undergone surgery or experienced trauma experience a different type of bleeding than patients with hematologic malignancies who have severe thrombocytopenia, according to the researchers. The latter group likely experiences bleeding due to endothelial damage, which tranexamic acid may not affect, they added.
“It is worth noting that, in trauma and in postpartum hemorrhage, tranexamic acid was only effective when administered within the first 3 hours,” Key told Healio. “This suggests that, in these conditions, there was a time-limited ‘fibrinolytic burst’ that may not occur in the most common types of thrombocytopenic bleeding. This hypothesis will need further mechanistic studies to confirm.”
A higher percentage of patients assigned tranexamic acid experienced thrombotic events (19.5% vs. 11%). However, the majority of these events in both groups were central line occlusions only (16.5% vs. 6.7%). Fewer noncatheter-related thrombotic events occurred in the tranexamic acid group (3.7% vs. 5.5%), but the difference was not statistically significant.
“Line occlusion was more common [among] patients receiving tranexamic acid, suggesting a local prothrombotic effect within the catheter,” Key said. “Notably, however, there was no increase in upper extremity venous thrombosis, or any other form of thrombosis, suggesting that this was more of a ‘nuisance’ complication.”
Researchers reported no significant difference in veno-occlusive disease after 30 days (1.8% vs. 1.2%) or all-cause mortality at 30 days (2.4% vs. 3%) or 100 days (11.5% vs. 11.5%) between the experimental and placebo groups. No patients in either group had died due to thrombosis at 120 days.
A similar trial conducted in the United Kingdom and Australia is nearing completion, Key said.
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Gernsheimer TB, et al. Abstract 2. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
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