The Emerging Role of Bivalirudin for Therapeutic Anticoagulation in Patients With Coronavirus Disease 2019 Requiring Extracorporeal Membrane Oxygenation Support: Is It Time to Change the Routine Practice?

Abstract

EXTRACORPOREAL MEMBRANE OXYGENATION (ECMO) can be helpful in patients presenting with life-threatening refractory hypoxemia secondary to acute respiratory distress syndrome (ARDS) for different reasons, including infection with the novel coronavirus disease 2019 (COVID-19). Systemic anticoagulation is challenging in the latter because of the associated hypercoagulable status in COVID-19 patients.1Guo Z Sun L Li B et al.Anticoagulation management in severe coronavirus disease 2019 patients on extracorporeal membrane oxygenation.J Cardiothorac Vasc Anesth. 2021; 35: 389-397Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Heparin commonly is used for therapeutic anticoagulation during the use of ECMO. Heparin-induced thrombocytopenia (HIT) can be challenging in patients with COVID-19 receiving ECMO support.2Bidar F Hékimian G Martin-Toutain I et al.Heparin-induced thrombocytopenia in COVID-19 patients with severe acute respiratory distress syndrome requiring extracorporeal membrane oxygenation: Two case reports.J Artif Organs. 2021; 24: 277-281Crossref PubMed Scopus (10) Google Scholar Bivalirudin, a direct thrombin inhibitor administered by continuous infusion, is a synthetic congener of the naturally occurring hirudin, secreted in the saliva of the blood-sucking leech Hirudo medicinalis. The United States Food and Drug Administration approved using bivalirudin as an anticoagulant in patients undergoing percutaneous coronary intervention. It emerges as an off-label alternative anticoagulant for postcardiotomy ECMO, with particular concerns about avoiding areas of blood stagnation to reduce the risk of ECMO circuit and intracardiac thrombosis.3Erdoes G Ortmann E Martinez Lopez De Arroyabe B et al.Role of bivalirudin for anticoagulation in adult perioperative cardiothoracic practice.J Cardiothorac Vasc Anesth. 2020; 4: 2207-2214Abstract Full Text Full Text PDF Scopus (7) Google Scholar,4Ranucci M. Bivalirudin and post-cardiotomy ECMO: A word of caution.Crit Care. 2012; 16: 427Crossref PubMed Scopus (0) Google Scholar Bivalirudin has been described for anticoagulation in 99 out of 142 patients with ARDS treated with ECMO at a referral North Italian center over 11 years from 2009; 45% of them had influenza A virus subtype H1N1 or COVID-19 pneumonia.5Pieri M Donatelli V Calabrò MG et al.Eleven years of venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome: From H1N1 to SARS-CoV-2. Experience and perspectives of a national referral center.J Cardiothorac Vasc Anesth. 2021; (S1053-0770(21)00842-9)Abstract Full Text Full Text PDF Scopus (2) Google Scholar Seelhammer et al also reported the feasibility of using bivalirudin for maintaining anticoagulation during the use of ECMO in a patient with COVID-19.6Seelhammer TG Rowse P Yalamuri S. Bivalirudin for maintenance anticoagulation during venovenous extracorporeal membrane oxygenation for COVID-19.J Cardiothorac Vasc Anesth. 2021; 35: 1149-1153Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar In this issue of the Journal of Cardiothoracic Vascular Anesthesia, Trigonis et al7Trigonis R Smith N Porter S et al.Efficacy of bivalirudin for therapeutic anticoagulation in COVID-19 patients requiring ECMO support.J Cardiothorac Vasc Anesth. 2022; 36: 414-418Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar presented the results of a retrospective case-control comparative study on the efficacy and safety of protocol-based therapeutic anticoagulation using different bivalirudin dosing rates in 42 patients receiving venovenous (VV) ECMO secondary to non-COVID-19 and COVID-19 infection. The main objective of this single-center study was to better describe the pharmacology of bivalirudin in patients with COVID-19 receiving ECMO support compared to the non-COVID patient group.7Trigonis R Smith N Porter S et al.Efficacy of bivalirudin for therapeutic anticoagulation in COVID-19 patients requiring ECMO support.J Cardiothorac Vasc Anesth. 2022; 36: 414-418Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar This study was based on the need to test the efficacy of using bivalirudin for anticoagulation in patients with COVID-19 receiving VV ECMO. Compared with the non-COVID-19 group, patients in the COVID-19 group received higher median and maximum bivalirudin infusion rates to achieve consistent activated partial thromboplastin time (aPTT) levels at a greater frequency than the non-COVID patient group despite using the same anticoagulation protocol.7Trigonis R Smith N Porter S et al.Efficacy of bivalirudin for therapeutic anticoagulation in COVID-19 patients requiring ECMO support.J Cardiothorac Vasc Anesth. 2022; 36: 414-418Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar In this study,7Trigonis R Smith N Porter S et al.Efficacy of bivalirudin for therapeutic anticoagulation in COVID-19 patients requiring ECMO support.J Cardiothorac Vasc Anesth. 2022; 36: 414-418Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar the authors collected the data from patients over 1 year, starting from June 2019. Of note, the first case of COVID-19 infection was identified in the United States, the authors’ center-based country, on January 22, 2020. This study did not include any randomization or blinding. Another retrospective study in the United States included a single group of 33 patients with COVID-19 receiving bivalirudin while on ECMO over 9 months from February 2020.8Bissell BD Gabbard T Sheridan EA et al.Evaluation of bivalirudin as the primary anticoagulant in patients receiving extracorporeal membrane oxygenation for SARS-CoV-2-associated acute respiratory failure.Ann Pharmacother. 2021 Jul 29; (Online ahead of print)10600280211036151https://doi.org/10.1177/10600280211036151Crossref Scopus (5) Google Scholar The 2 studies7Trigonis R Smith N Porter S et al.Efficacy of bivalirudin for therapeutic anticoagulation in COVID-19 patients requiring ECMO support.J Cardiothorac Vasc Anesth. 2022; 36: 414-418Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar,8Bissell BD Gabbard T Sheridan EA et al.Evaluation of bivalirudin as the primary anticoagulant in patients receiving extracorporeal membrane oxygenation for SARS-CoV-2-associated acute respiratory failure.Ann Pharmacother. 2021 Jul 29; (Online ahead of print)10600280211036151https://doi.org/10.1177/10600280211036151Crossref Scopus (5) Google Scholar had similar institutional protocols for changing the rate of bivalirudin infusion and a therapeutic target of aPTT of 60- to-80 seconds, but with different aPTT ranges for changing the bivalirudin infusion rate. Compared with Bissell et al,8Bissell BD Gabbard T Sheridan EA et al.Evaluation of bivalirudin as the primary anticoagulant in patients receiving extracorporeal membrane oxygenation for SARS-CoV-2-associated acute respiratory failure.Ann Pharmacother. 2021 Jul 29; (Online ahead of print)10600280211036151https://doi.org/10.1177/10600280211036151Crossref Scopus (5) Google Scholar patients in the study of Trigonis et al7Trigonis R Smith N Porter S et al.Efficacy of bivalirudin for therapeutic anticoagulation in COVID-19 patients requiring ECMO support.J Cardiothorac Vasc Anesth. 2022; 36: 414-418Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar needed lower peak bivalirudin infusion rates to maintain the target aPTT (0.08 v 0.36 µg/kg/h, respectively) and had higher ECMO survival rate (84% v 52%, respectively), more prolonged stays in the intensive care unit (median 29 v 25 days, respectively), and a higher incidence of bleeding complications (21% v 12%, respectively). The former study included more patients. The vast difference between the peak infusion rates of bivalirudin in these 2 studies7Trigonis R Smith N Porter S et al.Efficacy of bivalirudin for therapeutic anticoagulation in COVID-19 patients requiring ECMO support.J Cardiothorac Vasc Anesth. 2022; 36: 414-418Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar,8Bissell BD Gabbard T Sheridan EA et al.Evaluation of bivalirudin as the primary anticoagulant in patients receiving extracorporeal membrane oxygenation for SARS-CoV-2-associated acute respiratory failure.Ann Pharmacother. 2021 Jul 29; (Online ahead of print)10600280211036151https://doi.org/10.1177/10600280211036151Crossref Scopus (5) Google Scholar raises a concern on the need for a well-designed dose-response study to evaluate the optimum infusion rate to maintain the balance between the risks of thrombosis and bleeding. The incidence of intracranial, intraocular, and gastrointestinal bleeding, defined as an acute blood loss for which the patient was transfused for hemoglobin level less than 7 g/dL or associated hemodynamic compromise, and deep venous thrombosis were similar in the 2 groups.7Trigonis R Smith N Porter S et al.Efficacy of bivalirudin for therapeutic anticoagulation in COVID-19 patients requiring ECMO support.J Cardiothorac Vasc Anesth. 2022; 36: 414-418Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar However, caution should be exercised in interpreting the safety of using bivalirudin in patients with COVID-19. First, this study7Trigonis R Smith N Porter S et al.Efficacy of bivalirudin for therapeutic anticoagulation in COVID-19 patients requiring ECMO support.J Cardiothorac Vasc Anesth. 2022; 36: 414-418Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar was not powered to test the incidence of bivalirudin-induced complications. Second, the authors did not consider the Extracorporeal Life Support Organization criteria for identifying major and minor bleeding events (Table 1). Third, no data is available on the volume of blood derivatives transfused or the rates of significant circuit or component clots, necessitating a change of the ECMO circuit or circuit component.Table 1The ELSO Criteria for Identifying Major and Minor Bleeding EventsSeverity of BleedingCriteriaMajor bleedingClinically overt bleeding is associated with any of the following:Hemoglobin falls of at least 2 g/dL in 24 hoursA greater than 20 mL/kg over 24 hoursTransfusion requirement of 1 or more 10 mL/kg PRBC transfusions over that same periodRetroperitoneal bleeding.Pulmonary bleeding.Intracranial bleeding.Bleeding that requires surgical intervention.Minor bleedingA less than 20 mL/kg/d requires transfusion of one 10 mL/kg PRBCs transfusion or less.Developed from The ELSO Anticoagulation Guideline.9Lequier L, Annich G, Al-Ibrahim O, et al. The ELSO Anticoagulation Guideline. Available at: https://www.elso.org/portals/0/files/elsoanticoagulationguideline8-2014-table-contents.pdf. Accessed October 31, 2021.Google ScholarAbbreviations: ELSO, extracorporeal life support organization; PRBC, packed red blood cell. Open table in a new tab Developed from The ELSO Anticoagulation Guideline.9Lequier L, Annich G, Al-Ibrahim O, et al. The ELSO Anticoagulation Guideline. Available at: https://www.elso.org/portals/0/files/elsoanticoagulationguideline8-2014-table-contents.pdf. Accessed October 31, 2021.Google Scholar Abbreviations: ELSO, extracorporeal life support organization; PRBC, packed red blood cell. Bivalirudin would be a good alternative to heparin use during the use of ECMO in patients with HIT3Erdoes G Ortmann E Martinez Lopez De Arroyabe B et al.Role of bivalirudin for anticoagulation in adult perioperative cardiothoracic practice.J Cardiothorac Vasc Anesth. 2020; 4: 2207-2214Abstract Full Text Full Text PDF Scopus (7) Google Scholar,10Brown MA Najam F Pocock ES et al.A comparison of bivalirudin and heparin for patients on extracorporeal membrane oxygenation.Thromb Res. 2020; 190: 76-78Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar; however, in the study of Trigonis et al,7Trigonis R Smith N Porter S et al.Efficacy of bivalirudin for therapeutic anticoagulation in COVID-19 patients requiring ECMO support.J Cardiothorac Vasc Anesth. 2022; 36: 414-418Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar patients were not tested for HIT as bivalirudin was used routinely for all patients receiving ECMO at the authors’ center. That would limit the generalizability of the present results among different worldwide centers where the use of bivalirudin is only limited to the patients with HIT because of its high cost. Several previous studies compared the use of unfractionated heparin and bivalirudin for anticoagulation during the use of ECMO, but they have variable designs and numbers of included patients.11Kaseer H Soto-Arenall M Sanghavi D et al.Heparin vs. bivalirudin anticoagulation for extracorporeal membrane oxygenation.J Card Surg. 2020; 35: 779-786Crossref PubMed Scopus (38) Google Scholar, 12Giuliano K Bigelow BF Etchill EW et al.Extracorporeal membrane oxygenation complications in heparin- and bivalirudin-treated patients.Crit Care Explor. 2021; 3: e0485Crossref PubMed Google Scholar, 13Berlioz B Kaseer HS Sanghavi DK et al.Bivalirudin resistance in a patient on venovenous extracorporeal membrane oxygenation with a therapeutic response to argatroban.BMJ Case Rep. 2020; 13e232262Crossref PubMed Scopus (4) Google Scholar Seelhammer et al14Seelhammer TG Bohman JK Schulte PJ et al.Comparison of bivalirudin versus heparin for maintenance systemic anticoagulation during adult and pediatric extracorporeal membrane oxygenation.Crit Care Med. 2021; 49: 1481-1492Crossref PubMed Scopus (35) Google Scholar demonstrated a lower mortality rate in the adult group receiving bivalirudin than the use of heparin for anticoagulation in a large retrospective study, including 424 patients requiring ECMO in which 21% were pediatric. However, this difference was not reported among pediatric patients. Rivosecchi et al15Rivosecchi RM Arakelians AR Ryan J et al.Comparison of anticoagulation strategies in patients requiring venovenous extracorporeal membrane oxygenation: Heparin versus Bivalirudin.Crit Care Med. 2021; 49: 1129-1136PubMed Google Scholar reported significant decreases in the incidence of major bleeding events and ECMO circuit thrombotic complications and volume of packed red blood cells, fresh frozen plasma, and platelet transfusion in 133 patients who received bivalirudin for anticoagulation during the use of ECMO compared with 162 patients who received heparin. Smaller studies failed to report similar differences in terms of bleeding or thrombotic complications.11Kaseer H Soto-Arenall M Sanghavi D et al.Heparin vs. bivalirudin anticoagulation for extracorporeal membrane oxygenation.J Card Surg. 2020; 35: 779-786Crossref PubMed Scopus (38) Google Scholar, 12Giuliano K Bigelow BF Etchill EW et al.Extracorporeal membrane oxygenation complications in heparin- and bivalirudin-treated patients.Crit Care Explor. 2021; 3: e0485Crossref PubMed Google Scholar Future research also needs to consider the concern on the reported resistance to bivalirudin in patients receiving ECMO.15Rivosecchi RM Arakelians AR Ryan J et al.Comparison of anticoagulation strategies in patients requiring venovenous extracorporeal membrane oxygenation: Heparin versus Bivalirudin.Crit Care Med. 2021; 49: 1129-1136PubMed Google Scholar The authors also reported double the cost of using bivalirudin in patients with COVID-19 in addition to the expected added costs of longer times on using ECMO and intensive care unit stays than those patients with non-COVID-19 ARDS.7Trigonis R Smith N Porter S et al.Efficacy of bivalirudin for therapeutic anticoagulation in COVID-19 patients requiring ECMO support.J Cardiothorac Vasc Anesth. 2022; 36: 414-418Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Ranucci et al demonstrated that compared with heparin use, there was a trend toward a lower cost of using bivalirudin in adults and a statistically significantly lower cost in pediatric patients receiving postcardiotomy ECMO.16Ranucci M Ballotta A Kandil H et al.Bivalirudin-based versus conventional heparin anticoagulation for postcardiotomy extracorporeal membrane oxygenation.Crit Care. 2011; 15: R275Crossref PubMed Scopus (163) Google Scholar A cost-analysis study is needed to define the affordability of routine using bivalirudin anticoagulation for ECMO patients with COVID-19. The aPTT is widely accepted as the standard test to monitor bivalirudin therapy during the use of ECMO. Thromboelastometry (ROTEM)-included-intrinsic (INTEM) coagulation pathway had a moderate correlation with simultaneously measured aPTT with bivalirudin anticoagulation in pediatric patients on either ECMO or a ventricular assist device.17Teruya J Hensch L Bruzdoski K et al.Monitoring bivalirudin therapy in children on extracorporeal circulatory support devices: Thromboelastometry versus routine coagulation testing.Thromb Res. 2020; 186: 54-57Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar Contradictory discordance between the 2 methods was reported in critically ill adult patients receiving ECMO support.18Prakash S Wiersema UF Bihari S et al.Discordance between ROTEM® clotting time and conventional tests during unfractionated heparin-based anticoagulation in intensive care patients on extracorporeal membrane oxygenation.Anaesth Intensive Care. 2016; 44: 85-92Crossref PubMed Scopus (25) Google Scholar The role of using rotational thromboelastrometry to monitor bivalirudin therapy for adult patients with COVID-19 on ECMO is unclear. In conclusion, although using bivalirudin has merit in maintaining therapeutic anticoagulation in patients with COVID-19 who need ECMO support, it might be a bit early to change the routine use of unfractionated heparin for patients without HIT. Larger prospective randomized-controlled studies are required to corroborate the findings of Trigonis et al7Trigonis R Smith N Porter S et al.Efficacy of bivalirudin for therapeutic anticoagulation in COVID-19 patients requiring ECMO support.J Cardiothorac Vasc Anesth. 2022; 36: 414-418Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar and confirm the safety and efficacy of bivalirudin compared with heparin in patients with COVID-19 receiving ECMO support. None. Efficacy of Bivalirudin for Therapeutic Anticoagulation in COVID-19 Patients Requiring ECMO SupportJournal of Cardiothoracic and Vascular AnesthesiaVol. 36Issue 2PreviewThe Coronavirus Disease 2019 (COVID-19) pandemic has been associated with cases of refractory acute respiratory distress syndrome (ARDS) sometimes requiring support with extracorporeal membrane oxygenation (ECMO). Bivalirudin can be used for anticoagulation in patients on ECMO support, but its efficacy and safety in patients with COVID-19 is unknown. The authors set out to compare the pharmacologic characteristics and dosing requirements of bivalirudin in patients requiring ECMO support for ARDS due to COVID-19 versus ARDS from other etiologies. Full-Text PDF