Antithrombotic drug removal from whole blood using Haemoadsorption with a porous polymer bead sorbent

Ritu Tripathi, Jesus Morales, Victoria Lee, C Michael Gibson, Michael J Mack, David J Schneider, James Douketis, Frank W Sellke, Magnus E Ohman, Vinod H Thourani, Robert F Storey, Efthymios N Deliargyris, Ritu Tripathi, Jesus Morales, Victoria Lee, C Michael Gibson, Michael J Mack, David J Schneider, James Douketis, Frank W Sellke, Magnus E Ohman, Vinod H Thourani, Robert F Storey, Efthymios N Deliargyris

Abstract

Aim: To evaluate the ability of the DrugSorb™-AntiThrombotic Removal (ATR) haemoadsorption device utilizing porous polymer bead sorbent technology to remove three commonly used antithrombotic drugs from whole blood.

Methods and results: We evaluated the removal of apixaban, rivaroxaban, and ticagrelor by the DrugSorb-ATR haemoadsorption device in a benchtop clinical scale model using bovine whole blood. Blood spiked at clinically relevant concentrations of an antithrombotic agent was continuously circulated through a 300-mL DrugSorb-ATR haemoadsorption device at a flow rate of 300 mL/min. Drug concentration was monitored over 6 h to evaluate drug removal. Results were compared with a control circuit without the haemoadsorption device. Removal rates at 30, 60, 120, and 360 minutes were: apixaban: 81.5%, 96.3%, 99.3% >99.8%; rivaroxaban: 80.7%, 95.1%, 98.9%, >99.5%; ticagrelor: 62.5%; 75%, 86.6%, >95% (all P <0.0001 vs. control). Blood pH and haematological parameters were not significantly affected by the DrugSorb-ATR haemoadsorption device when compared with the control circuit.

Conclusion: DrugSorb-ATR efficiently removes apixaban, rivaroxaban, and ticagrelor in a clinical-scale benchtop recirculation circuit with the bulk of removal occurring in the first 60 minutes. The clinical implications of these findings are currently investigated in patients undergoing on-pump cardiothoracic surgery in two US pivotal trials (ClinicalTrials.gov Identifiers: NCT04976530 and NCT05093504).

Keywords: Apixaban; Extracorporeal; Haemoadsorption; Porous polymer beads; Rivaroxaban; Ticagrelor.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

Figures

Figure 1
Figure 1
Schematic representation of antithrombotic drug adsorption at the surface of porous polymer beads. The DrugSorb-ATR system incorporates a cartridge filled with biocompatible highly porous polymer beads that can actively remove hydrophobic target compounds via haemoadsorption. The extensive network of pores on the surface of each polymer bead is optimally sized for particular target molecules, and internal channels provide a vast surface area for adsorption. Beads are produced using solid state chemistry and rely on hydrophobic interactions for adsorption, rather than employing ligands, antibodies, cells, or other biologics. Pore size is such that adsorption of larger molecules (e.g. antibodies and albumin) is minimized and cells are excluded.
Figure 2
Figure 2
Schematic representation of experimental recirculation circuit. The circuit includes either a 300 mL DrugSorb-ATR device (treatment) or a tubing connector (control). Drawing not to scale.
Figure 3
Figure 3
Percent removal of antithrombotic drugs. Results represent mean ± SD, n = 5. There is a statistically significance difference between treatment and control (P <0.001, student's t-test) at each time point other than t = 0 min.
Figure 4
Figure 4
Therapeutic ranges and remaining plasma concentrations of (A) Apixaban, (B) Rivaroxaban and (C) Ticagrelor over 6 h of haemoperfusion. The grey shaded region represents the therapeutic window for each drug based on its clinical use. DrugSorb-ATR was able to reduce the drug concentration below the trough plasma level within 30–60 minutes for all drugs tested. Results presented as mean ± SD, n = 5.

References

    1. McCarty D, Robinson A. Factor Xa inhibitors: a novel therapeutic class for the treatment of non-valvular atrial fibrillation. Ther Adv Cardiovasc. Dis. 2016;10:37–49.
    1. Eikelboom J, Merli G. Bleeding with direct oral anticoagulants vs. warfarin: clinical experience. Am J Emerg Med 2016;34:3–8.
    1. Lippi G, Mattiuzzi C, Adcock D, Favaloro EJ. Oral anticoagulants around the world: an updated state-of-the art analysis. Ann Blood 49–49, 2018;3. doi:10.21037/aob.2018.12.04
    1. Troy A, Anderson TS. National trends in use of and spending on oral anticoagulants among US medicare beneficiaries from 2011 to 2019. JAMA Health Forum 2021;2:e211693–e211693.
    1. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, Investigators P, Freij A, Thorsen M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–1057.
    1. Collet JP, Thiele H, Barbato E, Barthelemy O, Bauersachs J, Bhatt DL, Dendale P, Dorobantu M, Edvardsen T, Folliguet T, Gale CP, Gilard M, Jobs A, Juni P, Lambrinou E, Lewis BS, Mehilli J, Meliga E, Merkely B, Mueller C, Roffi M, Rutten FH, Sibbing D, Siontis GCM, Group ESCSD . 2020 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2021;42:1289–1367.
    1. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ, Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimsky P, Group ESCSD . 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the european society of cardiology (ESC). Eur Heart J 2018;39:119–177.
    1. Dayoub EJ, Seigerman M, Tuteja S, Kobayashi T, Kolansky DM, Giri J, Groeneveld PW. Trends in platelet adenosine diphosphate P2Y12 receptor inhibitor use and adherence among antiplatelet-naive patients after percutaneous coronary intervention, 2008–2016. JAMA Intern Med 2018, 2018;178:943–950.
    1. Verheugt FW, Clemmensen P, Mehran R, Agewall S, Pocock SJ, Goldstein S, Torp-Pedersen C, Simoons ML, Borer JS, Khder YM, Burton P, Deliargyris E, McMurray JJ, Berkowitz SD, Stough WG, Zannad F. Antithrombotic outcome trials in acute coronary syndromes: seeking the optimal balance between safety and efficacy. Eur Heart J 2013;34:1621–1629.
    1. Sunkara T, Ofori E, Zarubin V, Caughey ME, Gaduputi V, Reddy M. Perioperative management of direct oral anticoagulants (DOACs): a systemic review. Health Serv. Insights 2016;9s1:25–36.
    1. Sousa-Uva M, Storey R, Huber K, Falk V, Leite-Moreira AF, Amour J, Al-Attar N, Ascione R, Taggart D, Collet JP, ESCWGoC Surgery, ESCWGo Thrombosis. Expert position paper on the management of antiplatelet therapy in patients undergoing coronary artery bypass graft surgery. Eur Heart J 2014;35:1510–1514.
    1. Lawton JS, Tamis-Holland JE, Bangalore S, Bates ER, Beckie TM, Bischoff JM, Bittl JA, Cohen MG, DiMaio JM, Don CW, Fremes SE, Gaudino MF, Goldberger ZD, Grant MC, Jaswal JB, Kurlansky PA, Mehran R, Metkus TS Jr., Nnacheta LC, Rao SV, Sellke FW, Sharma G, Yong CM, Zwischenberger BA. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the american college of cardiology/ circulation, american heart association joint committee on clinical practice guidelines. Circulation 2022;145:e18–e114.
    1. Pagano D, Milojevic M, Meesters MI, Benedetto U, Bolliger D, von Heymann C, Jeppsson A, Koster A, Osnabrugge RL, Ranucci M, Ravn HB, Vonk ABA, Wahba A, Boer C. 2017 EACTS/EACTA guidelines on patient blood management for adult cardiac surgery. Eur J Cardiothorac Surg 2018, 2018;53:79–111.
    1. Doherty JU, Gluckman TJ, Hucker WJ, Januzzi JL Jr., Ortel TL, Saxonhouse SJ, Spinler SA. 2017 ACC expert consensus decision pathway for periprocedural management of anticoagulation in patients with non-valvular atrial fibrillation: a report of the american college of cardiology clinical expert consensus document task force. J Am Coll Cardiol 2017;69:871–898.
    1. Douketis JD, Healey JS, Brueckmann M, Fraessdorf M, Spyropoulos AC, Wallentin L, Oldgren J, Reilly P, Ezekowitz MD, Connolly SJ, Yusuf S, Eikelboom JW. Urgent surgery or procedures in patients taking dabigatran or warfarin: analysis of perioperative outcomes from the RE-LY trial. Thromb Res 2016;139:77–81.
    1. Godier A, Taylor G, Gaussem P. Inefficacy of platelet transfusion to reverse ticagrelor. N Engl J Med 2015;372:196–197.
    1. Jacobs JW, Booth GS. Blood shortages and changes to massive transfusion protocols: survey of hospital practices during the COVID-19 pandemic. Transfus Apher Sci 61, 2022:103297.
    1. Budovich A, Zargarova O, Nogid A. Role of apixaban (eliquis) in the treatment and prevention of thromboembolic disease. P T 2013;38:206–231.
    1. Sillen H, Cook M, Davis P. Determination of unbound ticagrelor and its active metabolite (AR-C124910XX) in human plasma by equilibrium dialysis and LC-MS/MS. J Chromatogr B 2011;879:2315–2322.
    1. Bratsos S. Pharmacokinetic properties of rivaroxaban in healthy human subjects. Cureus 2019;11:e5484.
    1. Poli EC, Alberio L, Bauer-Doerries A, Marcucci C, Roumy A, Kirsch M, De Stefano E, Liaudet L, Schneider AG. Cytokine clearance with cytosorb(R) during cardiac surgery: a pilot randomized controlled trial. Crit Care 2019;23:108.
    1. Friesecke S, Trager K, Schittek GA, Molnar Z, Bach F, Kogelmann K, Bogdanski R, Weyland A, Nierhaus A, Nestler F, Olboeter D, Tomescu D, Jacob D, Haake H, Grigoryev E, Nitsch M, Baumann A, Quintel M, Schott M, Kielstein JT, Meier-Hellmann A, Born F, Schumacher U, Singer M, Kellum J, Brunkhorst FM. International registry on the use of the cytosorb (R) adsorber in ICU patients: study protocol and preliminary results. Med Klin Intensivmed Notfmed 2019;114:699–707.
    1. Gulilat M, Tang A, Gryn SE, Leong-Sit P, Skanes AC, Alfonsi JE, Dresser GK, Henderson SL, Rose RV, Lizotte DJ, Teft WA, Schwarz UI, Tirona RG, Kim RB. Interpatient variation in rivaroxaban and apixaban plasma concentrations in routine care. Can J Cardiol 2017;33:1036–1043.
    1. Mazzeffi MA, Lee K, Taylor B, Tanaka KA. Perioperative management and monitoring of antiplatelet agents: a focused review on aspirin and P2Y12 inhibitors. Korean J Anesthesiol 2017;70:379–389.
    1. US Food and Drug Administration . Cardiopulmonary bypass oxygenators 510(k) submissions - Final Guidance for industry and FDA staff.
    1. US Food and Drug Administration . Bioanalytical method validation guidance for industry.
    1. Frost C, Nepal S, Wang J, Schuster A, Byon W, Boyd RA, Yu Z, Shenker A, Barrett YC, Mosqueda-Garcia R, LaCreta F. Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor xa inhibitor, in healthy subjects. Br J Clin Pharmacol 2013;76:776–786.
    1. Mueck W, Stampfuss J, Kubitza D, Becka M. Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet 2014;53:1–16.
    1. Koertge A, Wasserkort R, Wild T, Mitzner S. Extracorporeal haemoperfusion as a potential therapeutic option for critical accumulation of rivaroxaban. Blood Purif. 2018;45:126–128.
    1. Husted SE, Storey RF, Bliden K, Tantry US, Høimark L, Butler K, Wei C, Teng R, Gurbel PA. Pharmacokinetics and pharmacodynamics of ticagrelor in patients with stable coronary artery disease: results from the ONSET-OFFSET and RESPOND studies. Clin Pharmacokinet 2012;51:397–409.
    1. Jaspers T, Shudofsky K, Huisman MV, Meijer K, Khorsand N. A meta-analysis of andexanet alfa and prothrombin complex concentrate in the treatment of factor Xa inhibitor-related major bleeding. Res Pract Thromb Haemos 2021;5:e12518.
    1. Kustos SA, Fasinu PS. Direct-acting oral anticoagulants and their reversal agents-an update. Medicines 2019;6:103.
    1. Pollack CV Jr., Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kam CW, Kamphuisen PW, Kreuzer J, Levy JH, Royle G, Sellke FW, Stangier J, Steiner T, Verhamme P, Wang B, Young L, Weitz JI. Idarucizumab for dabigatran reversal - Full cohort analysis. N Engl J Med 2017;377:431–441.
    1. Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, Yue P, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Demchuk AM, Pallin DJ, Concha M, Goodman S, Leeds J, Souza S, Siegal DM, Zotova E, Meeks B, Ahmad S, Nakamya J, Milling TJ Jr., Investigators A-. Full study report of andexanet alfa for bleeding associated with factor xa inhibitors. N Engl J Med 2019;380:1326–1335.
    1. Angheloiu GO, Gugiu GB, Ruse C, Pandey R, Dasari RR, Whatling C. Ticagrelor removal from human blood. JACC: Basic to Translational Science 2017;2:135–145.
    1. Mendes V, Colombier S, Verdy F, Bechtold X, Schlaepfer P, Scala E, Schneider A, Kirsch M. Cytosorb (R) haemoadsorption of apixaban during emergent cardio-pulmonary bypass: a case report. Perfusion 2021;36:873–875.
    1. Hassan K, Bruning T, Caspary M, Wohlmuth P, Pioch H, Schmoeckel M, Geidel S. Haemoadsorption of rivaroxaban and ticagrelor during acute type a aortic dissection operations. Ann Thorac Cardiovasc Surg 2022. doi:10.5761/atcs.oa.21-00154
    1. Hassan K, Kannmacher J, Wohlmuth P, Budde U, Schmoeckel M, Geidel S. Cytosorb adsorption during emergency cardiac operations in patients at high risk of bleeding. Ann Thorac Surg 2019;108:45–51.
    1. Salis S, Mazzanti VV, Merli G, Salvi L, Tedesco CC, Veglia F, Sisillo E. Cardiopulmonary bypass duration is an independent predictor of morbidity and mortality after cardiac surgery. J Cardiothorac Vasc Anesth 2008;22:814–822.
    1. Klein M, Dauben HP, Schulte HD, Gams E. Centrifugal pumping during routine open heart surgery improves clinical outcome. Artif Organs 1998;22:326–336.
    1. Tettey M, Aniteye E, Sereboe L, Edwin F, Kotei D, Tamatey M, Entsuamensah K, Amuzu V, Frimpong-Boateng K. Predictors of post-operative bleeding and blood transfusion in cardiac surgery. Ghana Med J 2009;43:71–76.
    1. Scott BH, Seifert FC, Glass PSA, Grimson R. Blood use in patients undergoing coronary artery bypass surgery: impact of cardiopulmonary bypass pump, haematocrit, gender, age, and body weight. Anesth & Analg 2003;97:958–963.
    1. Miana LA ea. Risk factors of post-operative bleeding after adult cardiac surgery. Brasileira de Cirurgia Cardiovascular 2004;19:280–286.
    1. Garau I, Marz A, Sehner S, Reuter DA, Reichenspurner H, Zollner C, Kubitz JC. Haemadsorption during cardiopulmonary bypass reduces interleukin 8 and tumor necrosis factor alpha serum levels in cardiac surgery: a randomized controlled trial. Minerva Anestesiol 2019;85:715–723.

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