Rivaroxaban reversal with prothrombin complex concentrate or tranexamic acid in healthy volunteers

Abstract

Essentials• Specific reversal agents for managing severe factor Xa inhibitor-associated bleeding are lacking.• We assessed 4-factor-prothrombin complex concentrate (4F-PCC) and tranexamic acid (TXA).• 4F-PCC, but not TXA, reduced the prothrombin time and increased endogenous thrombin potential.• These agents may be viable options for reversal of therapeutic doses of rivaroxaban.Summary. Background: Oral activated factor X inhibitors such as rivaroxaban are widely used, but specific reversal agents are lacking. Although four-factor prothrombin complex concentrate (4F-PCC) and tranexamic acid (TXA) are sometimes used to manage serious bleeding, their efficacy is unknown. Prior studies in healthy subjects taking rivaroxaban revealed that 4F-PCC partially reverses the prolonged prothrombin time (PT), and fully restores the endogenous thrombin potential (ETP). The effect of TXA has not been evaluated. Methods: In this double-blind, parallel-group study, 147 healthy volunteers given rivaroxaban 20 mg twice daily for 3 days were randomized after their morning dose on day 4 to receive intravenous 4F-PCC (50 IU kg À1 ), TXA (1.0 g), or saline. Standardized punch biopsies were performed at baseline and after 4F-PCC, TXA or saline administration. Reversal was assessed by measuring bleeding duration and bleeding volume at biopsy sites, and by determining the PT and ETP. Results: As compared with saline, 4F-PCC partially reversed the PT and completely reversed the ETP, whereas TXA had no effect. Neither 4F-PCC nor TXA reduced bleeding duration or volume. All treatments were well tolerated, with no recorded adverse events. Conclusions: Although 4F-PCC reduced the PT and increased the ETP in volunteers given supratherapeutic doses of rivaroxaban, neither 4F-PCC nor TXA influenced punch biopsy bleeding.

Pharmacological reversal of the direct oral anticoagulants—A comprehensive review of the literature

“…4FPCC (50 IU/kg) reduced bleeding duration after punch biopsy in edoxaban‐treated human volunteer subjects . However, administration of 4FPCC or TXA to healthy volunteers on rivaroxaban had no effect on bleeding duration or bleeding volume following skin punch biopsy …”

“…A total of 8 animal studies, 13 in vitro human volunteer studies, and 8 in vivo human volunteer studies evaluated the use of PCC, aPCC, or rFVIIa to reverse the anticoagulant effect of direct factor Xa inhibitors (Tables ).…”

“…84,90 There was no correction of abnormal anti-Xa activity seen with in vivo administration of 3FPCC or 4FPCC. 84,88 The effect of PCC on thrombin generation indices was variable, but most studies reported at least partial correction of ETP 30,[61][62][63]66,75,76,80,81,[84][85][86][87][88][89][90] and increased peak thrombin generation in 10 of 11 studies. 30,61,62,75,76,78,[80][81][82]88 ETP overshoot was seen in six studies.…”

Update on diagnosis and anticoagulant therapy for venous thromboembolism

“…[56][57][58] Testing may be considered after careful counselling in younger patients with an unprovoked VTE and a strong family history, particularly if cessation of anticoagulation is being considered. 64 As such, other options should be considered including drug discontinuation, supportive care and use of other haemostatic agents. Andexanet alfa (andexanet) and ciraparantag are two agents in advanced clinical trials.…”

“…A recent study reported that four-factor prothrombin complex concentrate partially reverses the anticoagulant effect of rivaroxaban but has no significant effect on bleeding duration, and tranexamic acid does not have any measurable effects. 64 As such, other options should be considered including drug discontinuation, supportive care and use of other haemostatic agents. For further management strategies with regards to management of DOAC-related bleeding, we refer to the previously published IMJ article.…”