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Andexxa Effective in GI Bleeds
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SAN ANTONIO — Andexxa helped produce high rates of hemostasis in patients with major gastrointestinal bleeding, according to study results presented at the American College of Gastroenterology Annual Meeting.
“[Andexxa (andexanet alfa, Portola) is a recombinant modified human factor Xa molecule that was specifically designed to reverse the effects of factor Xa inhibitor anticoagulants,” Deborah Siegal, MD, MSc, of McMaster University, said in her presentation.
Researchers examined the drug in the ANNEXA-4 trial, a single-arm study comprising 352 patients with acute major bleeding while taking a FXa inhibitor. They included patients with major GI bleeding if they had signs of hemodynamic compromise or bleeding associated with a hemoglobin drop (drop 2 g/dL or baseline Hb 8 g/dL).
After enrollment, patients received one of two andexanet regimens that were based on the type, timing and dose of their most recent inhibitor intake.
The primary endpoints of the study were change in anti-FXa activity and achievement of hemostasis, which was judged by an independent committee 12 hours after treatment and placed into three categories — excellent if the red blood cell transfusion-corrected Hb at 12 hours was no greater than 10% lower than baseline, good if Hb was 10% to 20% lower, and poor/none if Hb was more than 20% lower.
At the time of dosing, the mean Hb was 4.9 ± 1.4 g/dL. Among patients taking Xarelto (rivaroxaban, Janssen), the baseline anti-FXa activity was 267 ± 168.5 ng/mL, and the percent reduction with andexanet was 94% (95% CI, 89%–96%). In patients who received Eliquis (apixaban, Bristol-Myers Squibb, Pfizer) the baseline anti-FXa activity was 244 ± 215.0 ng/mL, and the percent reduction with andexanet was 92% (95% CI, 88%–95%).
Siegal and colleagues found that 85% of patients achieved excellent or good hemostasis after treatment.
In their safety assessment, researchers found that 58 of 62 patients received red blood cell transfusions, three received platelet transfusions and two received coagulation factor product. In the safety population, the 30-day rate of thrombosis was 6% and 13% for death.
“A majority of patients did not restart oral anticoagulants within 30 days of bleeding,” Siegal said. “Which represents an area of critical need.” – by Alex Young
Reference:
Siegal D, et al. Abstract 53. Presented at: American College of Gastroenterology Annual Meeting; Oct. 25-30, 2019; San Antonio.
Disclosures: Siegal reports consulting for Aspen Pharmaceuticals, Bayer, Bristol-Myers Squibb, Leo Pharma, Novartis, Pfizer, Portola Pharmaceuticals and Servier Canada.
Perspective
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Sunguk Jang, MD
The study by Siegal and colleagues reports on the efficacy and safety of andexanet alfa, a relatively new drug that reverses the effect of factor Xa inhibitors in patients with major bleeding. The researchers attempted to assess if the use of this medication would result in a meaningful hemostasis of gastrointestinal bleeding (GIB).
In this single-arm, prospective study, the researchers concluded that andexanet alfa was effective, in hemostasis of significant GIB without a significant increase in the thrombotic events with its use. As the study concluded “high rate of effective hemostasis” with the drug, andexanet alfa would become a part of an arsenal in the reversal of direct oral anticoagulants (DOACs) such as rivaroxaban and apixaban for the patients with major GIB while receiving factor Xa inhibitors. As such, judicious use of this drug can be inferred from the study.
The significance of this study is that this new drug can significantly improve the outcome of the patients with major GIB while taking factor Xa inhibitors. There are, however, some salient points to be mentioned. First, this is a single-arm prospective study without a “control” group (ie, the group without pharmacologic intervention). Thus, the degree of perceived benefit cannot be fully assessed. A prospective, comparative (and randomized, if feasible) study would have provided a more robust conclusion. Second, the methodology needs further clarification. For example, the definition of hemodynamic compromise and the methods used to delineate bleeding source require further explanation, perhaps in the full manuscript that may follow this sub-analysis. The investigators used the post treatment hemoglobin level as the methods of differentiating “excellent,” “good,” and “poor” without providing the details of blood transfusion. It is difficult to gauge the effect of andexanet alfa if transfusion requirements are not reported at the same time.
In the end, this is an interesting preliminary study on the effect of a new drug, andexanet alfa. However, without clearer delineation of methodology and lack of a comparative group, it is difficult to truly appreciate the degree of its efficacy. In light of the potential financial implication of its use, a study with bigger patient volume and better design is a requisite before contemplating its use.
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