title: The effect of ultrafiltration with cardiopulmonary bypass on the removal of dabigatran from the circulation of adult pigs.
abstract: Dabigatran etexilate is a direct thrombin inhibitor approved for use in patients with non-valvular atrial fibrillation. There is no currently available pharmacological therapy to reverse this renally cleared anticoagulant. Dabigatran has a low level of plasma protein binding and has been considered dialyzable. We used a pig model with renal artery ligation to exclude intrinsic drug excretion to examine the efficacy of ultrafiltration (UF) during cardiopulmonary bypass (CPB) for dabigatran removal.
  
  
  
  Dabigatran was intravenously infused (20 mg) in Yorkshire pigs (male, n=7, 70±1 kg) following renal artery ligation. CPB with UF was initiated after heparinization and continued until a total volume of 6 liters of UF effluent was removed. Serial labs, including dabigatran concentration, activated coagulation times (ACT), hematocrit and creatinine were drawn at intervals before the start of CPB and then incrementally during UF (0, 2, 4 and 6 L removed). Hemodialysis (HD) was performed on one animal following UF.
  
  
  
  Dabigatran concentration (ng/mL) rose from undetectable levels at baseline to 296±70 (p<0.05) at the conclusion of infusion, but dropped significantly upon administration of heparin (178±40, p<0.05). A further decrement in dabigatran concentration was observed from the administration of heparin to the start of CPB (to 135±28, p<0.05). Once on CPB, dabigatran remained stable, with the end UF (eUF) dabigatran concentration being 133±34. Dabigatran concentration in the UF effluent was measured in one animal and was 98.8, with 6 L of effluent having been removed. The total recovery of dabigatran was calculated to be less than 5%. Dabigatran concentrations also did not decrease appreciably with HD on CPB following UF.
  
  
  
  UF in conjunction with CPB was ineffective at removing dabigatran. Heparin demonstrated a dabigatran-lowering effect, suggesting a possible drug interaction or assay impairment. Based on these findings, emergent cardiac surgery with UF on cardiopulmonary bypass to remove dabigatran is not advisable. Alternative forms of drug removal or reversal must be identified.
authors.affiliation: Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Walter F
authors.initials: WF
authors.lastname: DeNino
authors.affiliation: Perfusion Services, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Carter
authors.affiliation: Perfusion Services, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Sievert
authors.affiliation: Boehringer-Ingelheim Inc., Ridgefield, CT, UK.
authors.forename: Ashley
authors.initials: A
authors.lastname: Goss
authors.affiliation: Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Toole
authors.affiliation: Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Rupak
authors.initials: R
authors.lastname: Mukherjee
authors.affiliation: Department of Pharmacy Services, Medical University of South Carolina, Charleston, SC, USA uberwe@musc.edu.
authors.forename: Walter E
authors.initials: WE
authors.lastname: Uber
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000097:blood*; D002315:Cardiopulmonary Bypass; D000069604:Dabigatran / Q000097:blood* / Q000302:isolation & purification; D006493:Heparin / Q000494:pharmacology; D008297:Male; D013552:Swine; D014462:Ultrafiltration; D014914:Whole Blood Coagulation Time
chemical_list: D000991:Antithrombins; D006493:Heparin; D000069604:Dabigatran
keywords: dabigatran; hemodialysis; ultrafiltration