No Benefit From Tranexamic Acid Prophylaxis in Blood Cancers

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Despite being routinely used in clinical settings, prophylactic use of tranexamic acid, an antifibrinolytic agent administered with platelet transfusions, did not reduce bleeding among patients with blood cancers and severe thrombocytopenia, according to a new study.

The study compared tranexamic acid to placebo and found no significant differences in terms of the number of bleeding events, the number of red blood cell transfusions, or the number of platelet transfusions that were required.

However, the rate of occlusions in the central venous line was significantly higher for patients in the tranexamic acid group, although there was no difference between groups for other types of thrombotic events.

The findings were presented at the annual meeting of the American Society of Hematology (ASH), which was held online.

The study was highlighted as potentially practice changing at a press preview webinair by ASH Secretary Robert Brodsky, MD.

“They found absolutely no difference in bleeding or need for transfusion,” said Brodsky. “What they did find was more catheter-associated blood clots in the tranexamic acid group. This is a practice changer in that it probably should not be given prophylactically to patients with thrombocytopenia.”

Senior author Terry B. Gernsheimer, MD, of the University of Washington School of Medicine, Seattle, Washington, noted that tranexamic acid has been found to be effective in the treatment of bleeding related to childbirth, surgery, and inherited blood disorders.

It is also used for patients with blood cancers and severe thrombocytopenia. There is little evidence to support this use, which is why the researchers decided to investigate.

“Clearly patients with low platelet counts and blood cancers have a different kind of bleeding than the bleeding experienced by patients who have suffered some kind of trauma or surgery,” Gernsheirmer said in a statement.

“Their bleeding likely is due to endothelial damage ― damage to the lining of blood vessels ― that tranexamic acid would not treat,” she added.

“To prevent bleeding in these patients, we may need to look at ways to speed the healing of the endothelium that occurs with chemotherapy, radiation, and graft-vs-host disease in patients receiving a transplant,” Gernsheimer comemented.

Temper Enthusiasm

“Overall, I think these results will temper enthusiasm for using tranexamic acid in this setting,” said Mitul Gandhi, MD, a medical oncologist with Virginia Cancer Specialists, who was approached for comment.

These data do not support the routine use of prophylactic tranexamic acid in chemotherapy-induced thrombocytopenia for patients with platelet counts lower than 30,000/μL, he added.

“The primary objective was not met, and there was an observed increased rate of catheter-associated thrombosis,” he said. “Continued use of judicious transfusion support and correction of a concomitant coagulopathy remains the main clinical approach to these patients.”

Gandhi commented that tranexamic acid “remains a potentially useful adjunct agent in certain cases of recalcitrant bleeding related to thrombocytopenia or coagulopathy.

“While there is no uniform scenario, it is typically reserved on a case-by-case basis after addressing vascular defects, utilization of platelet, fresh frozen plasma, cryoprecipitate transfusions, vitamin K repletion, and of course excluding any antiplatelet or anticoagulant therapy,” he told Medscape Medical News. “For persistent bleeding in spite of all corrective measures or hemorrhage into noncompressible vascular beds, such as with intracranial bleeds, antifibrinolytic therapy may assist in mitigating further blood loss.”

However, this has to be balanced with the potential increased risk for thrombosis after correction of the hemostatic insult.

At present, tranexamic acid “only has an FDA indication for uterine bleeding, but it is frequently used in trauma settings and obstetrical emergencies,” said Douglas Tremblay, MD, an internist at the Icahn School of Medicine at Mount Sinai, New York City, who was also approached for comment.

“There is evidence from prior studies that were done 20 or 30 years ago that it may help in this setting, so it is used in some institutions, although we don’t give it prophylactically for patients with a hematologic malignancy.”

Although this was a negative study, Tremblay pointed out that one thing that may come out of it is that there may be subgroups who can benefit from the prophylactic use of tranexamic acid. “There is very wide inclusion criteria for the study — any type of hematologic malignancy in patients undergoing chemotherapy or stem cell transplant,” he told Medscape Medical News. “Even among chemotherapy and transplant patients, there are different risks for bleeding.”

For example, patients undergoing induction chemotherapy for acute myeloid leukemia are at an increased risk of bleeding in comparison with patients with other hematologic malignancies, and those undergoing allogeneic transplant are at an increased risk of bleeding in comparison with patients undergoing autologous transplant. “So while its unclear if a subgroup may benefit from this strategy, lumped together, it doesn’t appear it is of any benefit and potentially harmful, in terms of line occlusions,” he said. “While that may seem to be a nuisance, it can delay chemotherapy or supportive infusions, and that can be a big deal.”

No Evidence of Benefit

Gernsheimer and colleagues conducted the American Trial Using Tranexamic Acid in Thrombocytopenia (A-TREAT), which evaluated the effects of prophylactic tranexamic acid as an adjunct to routine transfusion therapy on bleeding and transfusion requirements.

A total of 330 patients were randomly assigned to receive either tranexamic acid 1000 mg IV or 1300 mg or placebo. Randomization was stratified by site and therapy: chemotherapy, allogeneic transplant, or autologous transplant. It was anticipated that all patients had hypoproliferative thrombocytopenia (expected platelet count, 10,000/µL for at least 5 days).

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 primary endpoint of the study was the proportion of patients with bleeding of World Health Organization (WHO) grade 2 or above over 30 days after beginning therapy. Secondary endpoints included the number of transfusions and the number of days alive without WHO grade 2+ bleeding during the first 30 days post activation of study drug.

The time to first WHO 2+ bleeding was “remarkably similar” between the tranexamic acid groups and the placebo group, said Gernsheimer.

In the cohort as a whole, 48.8% in the placebo group experienced a grade 2+ bleed, vs 45.4% in the tranexamic group (odds ratio [OR], 0.86).

Similar results were observed across subgroups: allogeneic transplant, 57.3% vs 58.8% (OR = 0.94); autologous transplant, 19.9% vs 24.7% ( OR = 0.71); or chemotherapy, 48% vs 52.1% (OR = 0.84).

There were no significant differences 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).

“A post hoc analysis of WHO 3+ bleeding showed these events to be rare and without any improvement with tranexamic acid,” she said.

A higher percentage of patients in the tranexamic acid group experienced thrombotic events (19.5% vs 11%). “But importantly, in both groups, it was primarily due to central line occlusions without an associated thrombus,” said Gernsheimer. “This was statistically significant.”

Fewer noncatheter-related thrombotic events occurred in the tranexamic acid group (3.7% vs 5.5%), but the difference was not statistically significant.

There was also no significant difference between groups 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%). No deaths associated with thrombosis had occurred in either group at 120 days.

The study was supported by the University of Washington and the National Heart, Lung, and Blood Institute. Gernsheimer has relationships with Rigel Corporation, Principia, Sanofi, Vertex, Dova Pharmaceuticals, Cellphire, Novartis, and Amgen. Tremblay and Gandhi have disclosed no relevant financial relationships.

American Society of Hematology (ASH) 2020 Annual Meeting: Abstract 2. Presented December 5, 2020

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