Reversal and Removal of Oral Antithrombotic Drugs in Patients With Active or Perceived Imminent Bleeding

Davide Cao; Nicolas Amabile; Mauro Chiarito; Victoria T. Lee; Dominick J. Angiolillo; Davide Capodanno; Deepak L. Bhatt; Michael J. Mack; Robert F. Storey; Michael Schmoeckel; C. Michael Gibson; Efthymios N. Deliargyris; Roxana Mehran

Disclosures

Eur Heart J. 2023;44(20):1780-1794.

Abstract and Introduction

Abstract

Graphical Abstract

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In case of ongoing major bleeding, rapid and effective restoration of normal hemostatic functions with reversal agents on top of standard supportive measures may be required to successfully stop the bleeding. When major bleeding risk can be anticipated (e.g. due to the need for urgent invasive surgical procedures), antithrombotic drug removal and some reversal strategies may be considered before proceeding to surgery to mitigate perioperative bleeding risk. Bold text indicates reversal agents, parentheses indicate antithrombotic drugs that are reversed. Ab, antibody; DOACs, direct oral anticoagulants; VKA, vitamin K antagonists.

Remarkable progress has been made in the pharmacological management of patients with cardiovascular disease, including the frequent use of antithrombotic agents. Nonetheless, bleeding complications remain frequent and potentially life-threatening. Therapeutic interventions relying on prompt antithrombotic drug reversal or removal have been developed to assist clinicians in treating patients with active bleeding or an imminent threat of major bleeding due to urgent surgery or invasive procedures. Early phase studies on these novel strategies have shown promising results using surrogate pharmacodynamic endpoints. However, the benefit of reversing/removing antiplatelet or anticoagulant drugs should always be weighed against the possible prothrombotic effects associated with withdrawal of antithrombotic protection, bleeding, and surgical trauma. Understanding the ischemic-bleeding risk tradeoff of antithrombotic drug reversal and removal strategies in the context of urgent high-risk settings requires dedicated clinical investigations, but challenges in trial design remain, with relevant practical, financial, and ethical implications.

Introduction

Antithrombotic drugs are mainstay therapy for the secondary prevention of patients with established cardiovascular disease, including those with coronary, cerebrovascular, and peripheral artery disease, atrial fibrillation, and venous thromboembolism. These drugs have been shown to reduce recurrent ischemic events and to provide a consistent survival benefit.^[1] Nonetheless, the use of antithrombotic therapies is encumbered by a well-recognized risk of bleeding complications,^[2] which may have catastrophic consequences.^[3]

About 40 000 tons of aspirin are produced each year worldwide.^[4] In the USA alone, >50 million patients take aspirin while >4 million are treated with oral anticoagulant therapies.^[4,5] The worldwide sales for direct-acting oral anticoagulants (DOACs) reached ~8 billion US dollars in 2015 and are continuing to grow at a rapid rate.^[6] These numbers convey the idea of how many patients are potentially exposed to the bleeding side effects of antithrombotic drugs, with prognostic implications similar to the thrombotic events they are meant to prevent.^[7]

Bleeding risk largely depends on the pharmacodynamic and pharmacokinetic attributes of each drug but persists even for those with the safest risk profiles. For instance, the widespread use of DOACs was thought to overcome the practical limitations of vitamin K antagonists (VKA) and to significantly reduce hemorrhagic complications. Nonetheless, a growing proportion of emergency department admissions are still linked to DOAC-related bleeding.^[8,9] Notably, bleeding risk is further exacerbated in cases of combination therapy with two or more antithrombotic agents, as is often the case for patients on oral anticoagulants with acute coronary syndrome (ACS) or undergoing percutaneous coronary interventions (PCI).^[10,11]

Raising awareness about the prognostic impact of bleeding prompted the search for management strategies aimed at preventing and, if necessary, treating hemorrhagic events related to antithrombotic therapies.^[12,13] This review summarizes the evidence base for and practical approaches to antithrombotic drug reversal and removal strategies in patients facing active or an imminent threat of bleeding and critically appraises the challenges in clinical trial design and interpretation when studying reversal or removal of antithrombotic drugs in different clinical settings.

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Table 1. New agents for antithrombotic drug reversal
Agent	Drug reversed	Structure	Mechanism of action	Mode of administration	Dosage(s)	Onset of action	Offset of action
Bentracimab	Ticagrelor	Human monoclonal antibody	Antigen-binding fragment	i.v. bolus (10 min) followed by loading (4 h) and maintenance (12 h) infusions	6 g bolus; 6 g loading infusion; 6 g maintenance infusion	5 min	24 h
Idarucizumab	Dabigatran	Humanized monoclonal antibody	Thrombin analogue	Two i.v. boluses or 5–10 min infusions (no longer than 15 min apart)	2 × 2.5 mg	<5 min	24–72 h
Andexanet alfa	Direct and indirect factor Xa inhibitors^a	Recombinant truncated human factor Xa variant	Decoy receptor	i.v. bolus followed by 2-h infusion	400–800 mg bolus; 480–960 mg infusion	2 min	12 h
Ciraparantag	All DOACs, heparin and fondaparinux	Small cationic molecule	Hydrogen bonding and charge–charge interactions with DOACs and heparins	i.v. bolus	100–300 mg	5–10 min	24 h

i.v., intravenous; DOACs, direct oral anticoagulants.
^aLimited efficacy for low-molecular-weight heparin.

Table 2. Ongoing trials on antithrombotic reversal/removal strategies in patients with major bleeding or undergoing non-deferrable surgery
Study name	Design	n	Aim(s)	Population	Intervention(s)	Primary outcome(s)
Reversal strategy
REVERSE-IT (NCT04286438)	Prospective single-arm study	200	To evaluate the efficacy of ticagrelor reversal with bentracimab	Patients with uncontrolled major or life-threatening bleeding or who require urgent surgery or invasive procedure within 3 days of last ticagrelor intake	Bentracimab 18 g (up to 36 g) IV infusion over 16 (up to 24) h	1. Minimum % inhibition of platelet reactivity units within 4 h of infusion initiation2. Achievement of effective hemostasis within 4 h of infusion initiation
ANNEXA-I (NCT03661528)	Randomized placebo-controlled trial	1200	To determine the efficacy and safety of andexanet compared to usual care in patients presenting with acute intracranial hemorrhage	Patients presenting with acute intracranial hemorrhage within 6 h of symptom onset and within 15 h of taking an oral factor Xa inhibitor	Andexanet alfa IV bolus and infusion	Achievement of effective hemostasis within 12 h of infusion initiation
Removal strategy
START-T (NCT04976530)	Randomized sham-controlled trial	120	To evaluate the efficacy of intraoperative ticagrelor removal during cardiopulmonary bypass	Patients undergoing on-pump cardiothoracic surgery within 48 h of last ticagrelor intake	Sorbent hemoperfusion system (DrugSorb-ATR) integrated into the cardiopulmonary bypass circuit	Perioperative bleeding up to 48 h post-operation
STAR-D (NCT05093504)	Randomized sham-controlled trial	120	To evaluate the efficacy of intraoperative apixaban or rivaroxaban removal during cardiopulmonary bypass	Patients undergoing on-pump cardiothoracic surgery within 30 h of last apixaban or rivaroxaban intake	Sorbent hemoperfusion system (DrugSorb-ATR) integrated into the cardiopulmonary bypass circuit	Perioperative bleeding up to 48 h post-operation

IV, intravenous; BARC, Bleeding Academic Research Consortium.

Table 3. Challenges to efficacy and safety endpoints of trials on reversal/removal strategies
Surrogate efficacy endpoints (bleeding)			Safety endpoints (thrombosis)
Laboratory measurements • Lack of evidence showing correlation between pharmacodynamic parameters and improvement in clinical outcomes • Limited ability of dichotomous laboratory cut-offs to predict multifactorial clinical events • Thresholds to define increased bleeding risk and therapeutic window not validated for most laboratory tests • Non-universal access to specialized coagulation and platelet function assays • Specialized assays highly dependent on technical expertise • Wide variability of the reagent sensitivity of non-specialized assays • Poor agreement between different tests • Pharmacodynamic outcomes generally not sufficient for regulatory approval	Imaging • Standardized protocols for multiple imaging assessments in urgent/emergency settings • Dissociation between hematoma expansion and clinical or functional outcomes • Identifying accurate predictors of hematoma expansion • Potential need for repeated contrast media administration	Clinical parameters • Dissociation between the clinical course and the extent of bleeding • Lack of validated criteria to define achievement of effective hemostasis • Confounding effects of concomitant bleeding management treatments, major invasive procedures, and patient comorbidities • Use of blood products and volume expanders subject to interindividual variability • Definition of the time window to assess reversal/removal effects on bleeding	Hard clinical endpoints • Difficulty in establishing association between thrombotic events and reversal/removal treatment effects in the absence of a control arm • Confounding effect of early termination of antithrombotic therapy, ongoing bleeding, major invasive procedures, and non-specific hemostatic management • Practical challenges in conducting large, adequately powered studies for hard safety endpoints in an urgent/emergency setting	Surrogate endpoints • Limited ability of prothrombotic markers levels to predict thrombotic events or document hypercoagulability and thrombotic rebound • Thresholds to define increased thrombotic risk not validated for most prothrombotic markers • Confounding effect of ongoing bleeding, trauma, major invasive procedures, non-specific hemostatic management, and patient comorbidities

Authors and Disclosures

Davide Cao^1–3, Nicolas Amabile⁴, Mauro Chiarito^2,5, Victoria T. Lee⁶, Dominick J. Angiolillo⁷, Davide Capodanno⁸, Deepak L. Bhatt⁹, Michael J. Mack¹⁰, Robert F. Storey¹¹, Michael Schmoeckel¹², C. Michael Gibson¹³, Efthymios N. Deliargyris¹⁴ and Roxana Mehran¹*

¹Center for Interventional Cardiovascular Research and Clinical Trials, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1030, New York, NY 10029–6574, USA; ²Department of Biomedical Sciences, Humanitas University, Pieve Emanuele-Milan, Italy; ³Department of Cardiology, Humanitas Gavazzeni, Bergamo, Italy; ⁴Department of Cardiology, Institut Mutualiste Montsouris, Paris, France; ⁵Department of Cardiology, IRCCS Humanitas Research Hospital, Rozzano-Milan, Italy; ⁶PAVmed Inc., New York, NY, USA; ⁷Division of Cardiology, University of Florida College of Medicine, Jacksonville, FL, USA; ⁸Division of Cardiology, Azienda Ospedaliero Universitaria Policlinico 'G. Rodolico-San Marco', University of Catania, Catania, Italy; ⁹Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, NY, USA; ¹⁰Department of Cardiac Surgery, Baylor Scott and White Health, Plano, TX, USA; ¹¹Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK; ¹²Department of Cardiac Surgery, Asklepios Klinik St. Georg, Hamburg, Germany; ¹³Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; and ¹⁴CytoSorbents Corporation, Princeton, NJ, USA

Corresponding author
Tel: +1 212 659 9649, Fax: +1 (646) 537 8547, Email: roxana.mehran@mountsinai.org; Twitter: @Drroxmehran

Author contributions
Davide Cao, Nicolas Amabile, Mauro Chiarito, Victoria T. Lee, Dominick J. Angiolillo, Davide Capodanno, Deepak L. Bhatt, Michael J. Mack, Robert F. Storey, Michael Schmoeckel, C. Michael Gibson, Efthymios N. Deliargyris, and Roxana Mehran.

Conflict of interest
Dr. Amabile reports proctoring fees Abbott, Boston Scientific; consulting fees from Shockwave Medical, Abbott, Boston Scientific; institutional research grants from Abbott Vascular, and Boston Scientific.
Dr. Lee is a former employee of CytoSorbents Inc. Dr. Angiolillo has received payment as an individual for: a) Consulting fee or honorarium from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; b) Participation in review activities from CeloNova and St. Jude Medical. Institutional payments for grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli-Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, Renal Guard Solutions and the Scott R. MacKenzie Foundation.
Dr. Capodanno reports personal fees from Amgen, Arena, Biotronik, Daiichi Sankyo, Sanofi, Terumo; consulting fees paid to the institution from Medtronic.
Dr. Bhatt discloses the following relationships - Advisory Board: AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Stasys; Board of Directors: AngioWave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Consultant: Broadview Ventures; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald's Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Takeda.
Dr. Mack has served as the co-principal investigator or study chair for clinical trials sponsored by Abbott, Edwards Lifesciences, Medtronic and CytoSorbent.
Dr. Storey reports institutional research grants/support from AstraZeneca, Cytosorbents, GlyCardial Diagnostics and Thromboserin; and personal fees from Alnylam, AstraZeneca, Bayer, Bristol Myers Squibb/Pfizer, CSL Behring, Cytosorbents, GlyCardial Diagnostics, Hengrui, Idorsia, Intas Pharmaceuticals, Medscape, Novartis, PhaseBio, Portola, Sanofi Aventis and Thromboserin.
Dr. Schmoeckel reports institutional research grants (CyTation study, STAR registry) and personal fees from Cytosorbents.
Dr. Gibson discloses the following relationships as relevant to this work: research grant support from Cytosorbent, Portola (for past studies of Andexanet), and PhaseBio (spouse).
Dr. Deliargyris is an employee of CytoSorbents Inc.
Dr. Mehran reports institutional research grants from Abbott, Abiomed, Applied Therapeutics, Arena, AstraZeneca, Bayer, Biosensors, Boston Scientific, Bristol-Myers Squibb, CardiaWave, CellAegis, CERC, Chiesi, Concept Medical, CSL Behring, DSI, Insel Gruppe AG, Medtronic, Novartis Pharmaceuticals, OrbusNeich, Philips, Transverse Medical, Zoll; personal fees from ACC, Boston Scientific, California Institute for Regenerative Medicine (CIRM), Cine-Med Research, Janssen, WebMD, SCAI; consulting fees paid to the institution from Abbott, Abiomed, AM-Pharma, Alleviant Medical, Bayer, Beth Israel Deaconess, CardiaWave, CeloNova, Chiesi, Concept Medical, DSI, Duke University, Idorsia Pharmaceuticals, Medtronic, Novartis, Philips; Equity <1% in Applied Therapeutics, Elixir Medical, STEL, CONTROLRAD (spouse); Scientific Advisory Board for AMA, Biosensors (spouse).
The other authors have nothing to disclose.