Pharmacokinetics of Direct Oral Anticoagulants in Emergency Situations: Results of the Prospective Observational RADOA-Registry

Abstract

Background Direct oral anticoagulants (DOAC) are increasingly used worldwide. Little is known so far about their pharmacokinetics in emergency situations. Methods A prospective, observational registry was performed to determine the clinical course in consecutive patients with major bleeding or urgent surgery treated with DOACs. In back-up blood samples from routine care DOAC drug concentrations were measured using UPLC-MS/MS. Anticoagulant intensity at first presentation and drug half-life (t1/2), tested in repeat samples, were evaluated. Results 140 patients were prospectively included. Pharmacokinetic data were available in 94% (132/140) of patients. 67% (89/132) experienced life-threatening bleeding and 33% (43/132) needed an urgent surgery. For pharmacokinetic analysis a total of 605 blood samples was available. Median concentration on admission was 205 ng/mL for rivaroxaban and 108 ng/mL for apixaban. All treatment groups showed a high variation of drug concentrations at baseline. In rivaroxaban treated patients t½ was 17.3 hours (95% CI: 15.4 – 19.7) without significant difference in both groups (major bleeding: t½ 16.7 hours, 95% CI: 14.7 - 19.3; urgent surgery: t½ 19.7 hours, 95% CI 15.2 - 27.9; p=0.292). In apixaban treated patients t½ was 25.0 hours (95% CI: 22.9 – 27.6) with a longer t½ after urgent surgery (t1/2: 30.8 hours; 95% CI: 26.9 – 36.4) compared to severe bleeding (t1/2: 20.8 hours; 95% CI: 18.8 – 23.2; p<0.001). Conclusions Emergency patients under DOAC treatment show a high variation of anticoagulant concentrations at baseline. Compared with rivaroxaban, apixaban showed a lower median concentration on admission and a longer t½.

Direct Oral Anticoagulants: Laboratory Challenges and Antidotes

“…Repeated testing demonstrated half-lives of 17.3 hours for rivaroxaban and 25.0 hours for apixaban emergencies. 45 Therefore, dedicated DOAC quantifications (dTT for dabigatran and anti-Xa measurements calibrated for the respective DXI) should be made available 24/7 and implemented into SOPs wherever possible. 29 46 If no such tests are available or if turnaround times are too long, alternatives could include POC devices to detect DOAC activity.…”

Management of major bleeding for anticoagulated patients in the Emergency Department: an European experts consensus statement

“…The half-life of a DOAC is considerably shorter (8-12 h) so patients with a last DOAC intake >12 h before admission often demonstrate subtherapeutic levels; however, the reported short half-lives of DOACs are derived from healthy volunteer studies, while data from the German RADOA (Reversal Agent use in patients treated with Direct Oral Anticoagulants or vitamine K antagonists) registry have demonstrated a prolongation of DOAC half-lives in emergency patients of up to 20 h [35]. In contrast to VKA all coagulation factors are fully carboxylated and functional in a DOAC patient with only factor II or factor X being inhibited.…”

Grundlagen zur Anwendung von Andexanet

“…Besonders hohe DOAK-Plasmaspiegel können aus einer Akkumulation bei eingeschränkter Nierenfunktion resultieren, wodurch sich auch die Abklingdauer der DOAK-Wirkung deutlich verlängern kann 40…”