Exposure-Response Relationship of Tranexamic Acid in Cardiac Surgery.
Research article published in Anesthesiology (2021)
Abstract
BACKGROUND: It is unclear whether high-dose regimens of tranexamic acid in cardiac surgery (total dose, 80 to 100 mg/kg) confer a clinical advantage over low-dose regimens (total dose, approximately 20 mg/kg), particularly as tranexamic acid-associated seizure may be dose-related. The authors' aim was to characterize the exposure-response relationship of this drug. METHODS: Databases were searched for randomized controlled trials of intravenous tranexamic acid in adult patients undergoing cardiopulmonary bypass surgery. Observational studies were added for seizure assessment. Tranexamic acid concentrations were predicted in each arm of each study using a population pharmacokinetic model. The exposure-response relationship was evaluated by performing a model-based meta-analysis using nonlinear mixed-effect models. RESULTS: Sixty-four randomized controlled trials and 18 observational studies (49,817 patients) were included. Seventy-three different regimens of tranexamic acid were identified, with the total dose administered ranging from 5.5 mg/kg to 20 g. The maximum effect of tranexamic acid for postoperative blood loss reduction was 40% (95% credible interval, 34 to 47%), and the EC50 was 5.6 mg/l (95% credible interval, 0.7 to 11 mg/l). Exposure values with low-dose regimens approached the 80% effective concentration, whereas with high-dose regimens, they exceeded the 90% effective concentration. The predicted cumulative blood loss up to 48 h postsurgery differed by 58 ml between the two regimens, and the absolute difference in erythrocyte transfusion rate was 2%. Compared to no tranexamic acid, low-dose and high-dose regimens increased the risk of seizure by 1.2-fold and 2-fold, respectively. However, the absolute risk increase was only clinically meaningful in the context of prolonged open-chamber surgery. CONCLUSIONS: In cardiopulmonary bypass surgery, low-dose tranexamic acid seems to be an appropriate regimen for reducing bleeding outcomes. This meta-analysis has to be interpreted with caution because the results are observational and dependent on the lack of bias of the predicted tranexamic acid exposures and the quality of the included studies.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Zusammenfassung
It is unclear whether high-dose regimens of tranexamic acid in cardiac surgery (total dose, 80 to 100 mg/kg) confer a clinical advantage over low-dose regimens (total dose, approximately 20 mg/kg), particularly as tranexamic acid-associated seizure may be dose-related. The authors' aim was to characterize the exposure-response relationship of this drug.
Warum dies für die Hirudotherapie relevant ist
Diese modellbasierte Metaanalyse fasste 64 randomisierte kontrollierte Studien und 18 Beobachtungsstudien (49.817 Patienten) unter Verwendung eines populationspharmakokinetischen Modells zusammen, um die Expositions-Wirkungs-Beziehung des Antifibrinolytikums tranexamic acid in der Herzchirurgie zu charakterisieren, und fand eine maximale postoperative Blutverlustreduktion von etwa 40%, wobei niedrig dosierte Regime bereits nahezu den Maximaleffekt erreichten (der vorhergesagte kumulative Blutverlust unterschied sich zwischen Niedrig- und Hochdosis-Regimen um nur 58 ml, bei einer absoluten Differenz von 2% in der Erythrozytentransfusionsrate), während eine Hochdosis das Krampfanfallrisiko gegenüber einem 1,2-fachen Anstieg bei Niedrigdosis etwa verdoppelte, was für niedrig dosierte Regime spricht. Für die hirudotherapy ist dies als Kontrastfall auf der Achse Blutung-versus-Fibrinolyse relevant: tranexamic acid unterdrückt die Fibrinolyse, um Blutungen zu verringern — der entgegengesetzte Pol zu Molekülen des Blutegelsekretoms (wie destabilase und hirudin), die Antikoagulation und Gerinnselauflösung fördern, was veranschaulicht, wie fein Dosis und Exposition das hämostatische Gleichgewicht steuern, das auch die Blutegeltherapie beeinflusst. Vorbehalt: Die Autoren warnen ausdrücklich, dass die Ergebnisse modellabgeleitet und teils beobachtend sind, mit vorhergesagten (nicht gemessenen) Wirkstoffexpositionen, und die Studie betrifft ein synthetisches Antifibrinolytikum in der Chirurgie, ohne jeglichen Inhalt zu Blutegeln oder hirudotherapy.
Zitation
Exposure-Response Relationship of Tranexamic Acid in Cardiac Surgery.
Zufferey PJ et al. · Anesthesiology, 2021
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