Direct Oral Anticoagulants Plasma Levels Measurement: Clinical Usefulness from Trials and Real-World Data

Abstract

Measurement of direct oral anticoagulants (DOACs) activity is not routinely necessary. Indeed, evaluation of DOACs plasmatic concentration is discouraged for the majority of patients, due to the lack of outcome data supporting this approach. Nevertheless, DOAC measurements may be useful in emergency situations such as serious bleeding events, need for urgent invasive procedures, and acute ischemic stroke or in managing anticoagulation in “special populations” not adequately studied in clinical trials, for example the very elderly or those at the extremes of body weight. The aim of this review is to describe and summarize the methods for DOACs activity evaluation and the settings in which their plasma level measurement may be indicated, analyzing indications from scientific societies and evidence from clinical trials, as well as real world data on the usefulness of DOACs plasma levels “monitoring.”

Keywords

direct oral anticoagulants - plasma level measurements - coagulation assays - elective procedures - extreme body weight - elderly

Publikationsverlauf

Artikel online veröffentlicht:
26. Februar 2021

• References

• 1 Hindricks G, Potpara T, Dagres N. et al; ESC Scientific Document Group. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS). Eur Heart J 2020; 2020: 1-126
• 2 Konstantinides SV, Meyer G, Becattini C. et al; ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020; 41 (04) 543-603
• 3 Afshari A, Ageno W, Ahmed A. et al; ESA VTE Guidelines Task Force. European Guidelines on perioperative venous thromboembolism prophylaxis: executive summary. Eur J Anaesthesiol 2018; 35 (02) 77-83
• 4 Caldeira D, Barra M, Pinto FJ, Ferreira JJ, Costa J. Intracranial hemorrhage risk with the new oral anticoagulants: a systematic review and meta-analysis. J Neurol 2015; 262 (03) 516-522
• 5 Favaloro EJ, Pasalic L, Lippi G. Oral anticoagulation therapy: an update on usage, costs and associated risks. Pathology 2020; 52 (06) 736-741
• 6 Connors JM. Testing and monitoring direct oral anticoagulants. Blood 2018; 132 (19) 2009-2015
• 7 Loo SY, Dell'Aniello S, Huiart L, Renoux C. Trends in the prescription of novel oral anticoagulants in UK primary care. Br J Clin Pharmacol 2017; 83 (09) 2096-2106
• 8 Melillo E, Carbone A, Rago A. et al. Update on direct oral anticoagulants in atrial fibrillation patients undergoing cardiac interventional procedures: from clinical trials to real-world evidence. J Cardiovasc Pharmacol 2020; 75 (03) 185-199
• 9 Russo V, Attena E, Di Maio M. et al. Clinical profile of direct oral anticoagulants versus vitamin K anticoagulants in octogenarians with atrial fibrillation: a multicentre propensity score matched real-world cohort study. J Thromb Thrombolysis 2020; 49 (01) 42-53
• 10 Russo V, Attena E, Mazzone C. et al. Real-life performance of edoxaban in elderly patients with atrial fibrillation: a multicenter propensity score-matched cohort study. Clin Ther 2019; 41 (08) 1598-1604
• 11 Steffel J, Verhamme P, Potpara TS. et al; ESC Scientific Document Group. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018; 39 (16) 1330-1393
• 12 Russo V, Rago A, Papa AA. et al. Use of non-vitamin K antagonist oral anticoagulants in atrial fibrillation patients with malignancy: clinical practice experience in a single institution and literature review. Semin Thromb Hemost 2018; 44 (04) 370-376
• 13 Baglin T, Hillarp A, Tripodi A, Elalamy I, Buller H, Ageno W. Measuring oral direct inhibitors (ODIs) of thrombin and factor Xa: a recommendation from the Subcommittee on Control of Anticoagulation of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2013; 11 (04) 756-760
• 14 Douxfils J, Mani H, Minet V. et al. Non-VKA oral anticoagulants: accurate measurement of plasma drug concentrations. BioMed Res Int 2015; 2015: 345138
• 15 Gosselin RC, Adcock DM, Bates SM. et al. International Council for Standardization in Haematology (ICSH) recommendations for laboratory measurement of direct oral anticoagulants. Thromb Haemost 2018; 118 (03) 437-450
• 16 Douxfils J, Ageno W, Samama CM. et al. Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians. J Thromb Haemost 2018; 16 (02) 209-219
• 17 Levy JH, Ageno W, Chan NC, Crowther M, Verhamme P, Weitz JI. Subcommittee on Control of Anticoagulation. When and how to use antidotes for the reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost 2016; 14 (03) 623-627
• 18 Lessire S, Douxfils J, Pochet L. et al. Estimation of rivaroxaban plasma concentrations in the perioperative setting in patients with or without heparin bridging. Clin Appl Thromb Hemost 2018; 24 (01) 129-138
• 19 Yin OQP, Antman EM, Braunwald E. et al. Linking endogenous factor Xa activity, a biologically relevant pharmacodynamic marker, to edoxaban plasma concentrations and clinical outcomes in the ENGAGE AF-TIMI 48 trial. Circulation 2018; 138 (18) 1963-1973
• 20 Padayattil Jose S, Banzato A, Carraro P. et al. Point of Care Testing (POCT) to assess drug concentration in patients treated with non-vitamin K antagonist oral anticoagulants (NOACs). Thromb Res 2018; 163 (January): 100-104
• 21 Al-Aieshy F, Malmström RE, Antovic J. et al. Clinical evaluation of laboratory methods to monitor exposure of rivaroxaban at trough and peak in patients with atrial fibrillation. Eur J Clin Pharmacol 2016; 72 (06) 671-679
• 22 Hawes EM, Deal AM, Funk-Adcock D. et al. Performance of coagulation tests in patients on therapeutic doses of dabigatran: a cross-sectional pharmacodynamic study based on peak and trough plasma levels. J Thromb Haemost 2013; 11 (08) 1493-1502
• 23 Mani H, Herth N, Kasper A. et al. Point-of-care coagulation testing for assessment of the pharmacodynamic anticoagulant effect of direct oral anticoagulant. Ther Drug Monit 2014; 36 (05) 624-631
• 24 Ebner M, Birschmann I, Peter A. et al. Point-of-care testing for emergency assessment of coagulation in patients treated with direct oral anticoagulants. Crit Care 2017; 21 (01) 32
• 25 Ansell J, Zappe S, Jiang X. et al. A novel whole blood point-of-care coagulometer to measure the effect of direct oral anticoagulants and heparins. Semin Thromb Hemost 2019; 45 (03) 259-263
• 26 Harder S, Santos SMD, Krozer V, Moll J. Surface acoustic wave-based microfluidic coagulation device for monitoring anticoagulant therapy. Semin Thromb Hemost 2019; 45 (03) 253-258
• 27 Billoir P, Barbay V, Joly LM, Fresel M, Chrétien MH, Le Cam Duchez V. Anti-Xa oral anticoagulant plasma concentration assay in real life: rivaroxaban and apixaban quantification in emergency with LMWH calibrator. Ann Pharmacother 2019; 53 (04) 341-347
• 28 Tomaselli GF, Mahaffey KW, Cuker A. et al. 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol 2017; 70 (24) 3042-3067
• 29 Christensen H, Cordonnier C, Kõrv J. et al. European Stroke Organisation Guideline on reversal of oral anticoagulants in acute intracerebral haemorrhage. Eur Stroke J 2019; 4 (04) 294-306
• 30 Powers WJ, Rabinstein AA, Ackerson T. et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2019; 50 (12) e344-e418
• 31 Veitch AM, Vanbiervliet G, Gershlick AH. et al. Endoscopy in patients on antiplatelet or anticoagulant therapy, including direct oral anticoagulants: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guidelines. Gut 2016; 65 (03) 374-389
• 32 Touzé E, Gruel Y, Gouin-Thibault I. et al. Intravenous thrombolysis for acute ischaemic stroke in patients on direct oral anticoagulants. Eur J Neurol 2018; 25 (05) 747-e52
• 33 Godier A, Dincq AS, Martin AC. et al. Predictors of pre-procedural concentrations of direct oral anticoagulants: a prospective multicentre study. Eur Heart J 2017; 38 (31) 2431-2439
• 34 Pernod G, Albaladejo P, Godier A. et al; Working Group on Perioperative Haemostasis. Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: proposals of the working group on perioperative haemostasis (GIHP)—March 2013. Arch Cardiovasc Dis 2013; 106 (6-7): 382-393
• 35 Faraoni D, Levy JH, Albaladejo P, Samama CM. Groupe d'Intérêt en Hémostase Périopératoire. Updates in the perioperative and emergency management of non-vitamin K antagonist oral anticoagulants. Crit Care 2015; 19 (01) 203
• 36 Connolly SJ, Crowther M, Eikelboom JW. et al; ANNEXA-4 Investigators. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med 2019; 380 (14) 1326-1335
• 37 Drouet L, Bal Dit Sollier C, Steiner T, Purrucker J. Measuring non-vitamin K antagonist oral anticoagulant levels: when is it appropriate and which methods should be used?. Int J Stroke 2016; 11 (07) 748-758
• 38 Marsch A, Macha K, Siedler G. et al. Direct oral anticoagulant plasma levels for the management of acute ischemic stroke. Cerebrovasc Dis 2019; 48 (1-2): 17-25
• 39 Seiffge DJ, Hooff RJ, Nolte CH. et al; NOACISP Study Group*. Recanalization therapies in acute ischemic stroke patients: impact of prior treatment with novel oral anticoagulants on bleeding complications and outcome. Circulation 2015; 132 (13) 1261-1269
• 40 Seiffge DJ, Traenka C, Polymeris AA. et al. Intravenous thrombolysis in patients with stroke taking rivaroxaban using drug specific plasma levels: experience with a standard operation procedure in clinical practice. J Stroke 2017; 19 (03) 347-355
• 41 Kepplinger J, Prakapenia A, Barlinn K. et al. Standardized use of novel oral anticoagulants plasma level thresholds in a new thrombolysis decision making protocol. J Thromb Thrombolysis 2016; 41 (02) 293-300
• 42 Purrucker JC, Haas K, Rizos T. et al; RASUNOA Investigators (Registry of Acute Stroke Under New Oral Anticoagulants). Coagulation testing in acute ischemic stroke patients taking non-vitamin K antagonist oral anticoagulants. Stroke 2017; 48 (01) 152-158
• 43 Doherty JU, Gluckman TJ, Hucker WJ. et al. 2017 ACC expert consensus decision pathway for periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation: a report of the American College of Cardiology Clinical Expert Consensus Document Task Force. J Am Coll Cardiol 2017; 69 (07) 871-898
• 44 Rossini R, Tarantini G, Musumeci G. et al; Italian Society of Interventional Cardiology (SICI-GISE), Italian Society for the Study of Haemostasis and Thrombosis (SISET), Italian Society of Anesthesia and Intensive Care Medicine (SIAARTI), Italian Society of Surgery (SIC), Italian Society for Cardiac Surgery (SICCH), Italian Society of Vascular and Endovascular Surgery (SICVE), Italian Society of Urology (SIU), Italian Orthopaedic Society (SIOT), Italian Society of Thoracic Surgeons (SICT), Italian Federation of Scientific Societies of Digestive System Diseases (FISMAD), Italian Society of Digestive Endoscopy (SIED), Italian Association of Hospital Gastroenterology and Digestive Endoscopy (AIGO), Italian Association of Gastroenterology and Digestive Endoscopy (SIGE), Italian Society of Maxillofacial Surgery (SICMF), Italian Society of Reconstructive Plastic Surgery and Aesthetics (SICPRE), Italian Society of Gynecology and Obstetrics (SIGO), Italian Society of Neurosurgery (SINch), Italian Association of Hospital Pulmonologist (AIPO), Italian Society of Periodontology (SIdP), Italian Society of Ophthalmology (SOI), Italian Association of Hospital Otorhinolaryngologist (AOOI), Italian Association of Hospital Surgeons (ACOI), Association of Obstetricians Gynecologists Italian Hospital (AOGOI). A multidisciplinary approach on the perioperative antithrombotic management of patients with coronary stents undergoing surgery: surgery after stenting 2. JACC Cardiovasc Interv 2018; 11 (05) 417-434
• 45 Barba R, Marco J, Martín-Alvarez H. et al; RIETE investigators. The influence of extreme body weight on clinical outcome of patients with venous thromboembolism: findings from a prospective registry (RIETE). J Thromb Haemost 2005; 3 (05) 856-862
• 46 Russo V, Attena E, Di Maio M. et al. Non-vitamin K vs vitamin K oral anticoagulants in patients aged > 80 year with atrial fibrillation and low body weight. Eur J Clin Invest 2020; 50 (11) e13335
• 47 Park CS, Choi EK, Kim HM, Lee SR, Cha MJ, Oh S. Increased risk of major bleeding in underweight patients with atrial fibrillation who were prescribed non-vitamin K antagonist oral anticoagulants. Heart Rhythm 2017; 14 (04) 501-507
• 48 De Caterina R, Lip GYH. The non-vitamin K antagonist oral anticoagulants (NOACs) and extremes of body weight-a systematic literature review. Clin Res Cardiol 2017; 106 (08) 565-572
• 49 Martin K, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost 2016; 14 (06) 1308-1313
• 50 Martin K, Moll S. Direct oral anticoagulant drug level testing in clinical practice: a single institution experience. Thromb Res 2016; 143: 40-44
• 51 Piran S, Traquair H, Chan N, Bhagirath V, Schulman S. Peak plasma concentration of direct oral anticoagulants in obese patients weighing over 120 kilograms: a retrospective study. Res Pract Thromb Haemost 2018; 2 (04) 684-688
• 52 Tittl L, Endig S, Marten S, Reitter A, Beyer-Westendorf I, Beyer-Westendorf J. Impact of BMI on clinical outcomes of NOAC therapy in daily care—results of the prospective Dresden NOAC Registry (NCT01588119). Int J Cardiol 2018; 262: 85-91
• 53 Barsam SJ, Patel JP, Roberts LN. et al. The impact of body weight on rivaroxaban pharmacokinetics. Res Pract Thromb Haemost 2017; 1 (02) 180-187
• 54 Russo V, Paccone A, Rago A. et al. Apixaban in a morbid obese patient with atrial fibrillation: a clinical experience using the plasmatic drug evaluation. J Blood Med 2020; 11: 77-81
• 55 Russo V, Rago A, Laezza N. et al. Edoxaban in elderly patient with morbid obesity and atrial fibrillation: the role of plasma levels evaluation for selecting the appropriate dose. Monaldi Arch Chest Dis 2020; 90 (01) 110-112
• 56 Russo V, Bottino R, Rago A. et al. Clinical performance of nonvitamin K antagonist oral anticoagulants in real-world obese patients with atrial fibrillation. Semin Thromb Hemost 2020; 46 (08) 970-976
• 57 Heeringa J, van der Kuip DAM, Hofman A. et al. Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J 2006; 27 (08) 949-953
• 58 Russo V, Carbone A, Rago A, Golino P, Nigro G. Direct oral anticoagulants in octogenarians with atrial fibrillation: it is never too late. J Cardiovasc Pharmacol 2019; 73 (04) 207-214
• 59 Proietti R, Joza J, Arensi A. et al. Novel nonpharmacologic approaches for stroke prevention in atrial fibrillation: results from clinical trials. Med Devices (Auckl) 2015; 8: 103-114
• 60 Danna P, Proietti R, Sagone A. et al. Does left atrial appendage closure with a cardiac plug system reduce the stroke risk in nonvalvular atrial fibrillation patients? A single-center case series. Pacing Clin Electrophysiol 2013; 36 (03) 347-353
• 61 Reilly PA, Lehr T, Haertter S. et al; RE-LY Investigators. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014; 63 (04) 321-328
• 62 Eikelboom JW, Wallentin L, Connolly SJ. et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 2011; 123 (21) 2363-2372
• 63 Chaussade E, Hanon O, Boully C. et al. Real-life peak and trough dabigatran plasma measurements over time in hospitalized geriatric patients with atrial fibrillation. J Nutr Health Aging 2018; 22 (01) 165-173
• 64 Blickstein D, Younes S, Nakav S. Attempted suicide with rivaroxaban. Ann Hematol 2016; 95 (12) 2093-2094
• 65 Repplinger DJ, Hoffman RS, Nelson LS, Hines EQ, Howland M, Su MK. Lack of significant bleeding despite large acute rivaroxaban overdose confirmed with whole blood concentrations. Clin Toxicol (Phila) 2016; 54 (08) 647-649
• 66 Gunes G, Malkan UY, Aksu S. et al. Massive life-threatening hemorrhages due to toxic oral intake of 3750 mg dabigatran etexilate as a suicide attempt and the clinical management. Blood 2014; 124 (21) 5091-5091
• 67 Stepanian A, Dragoni A, Malissin I. et al. Self-poisoning with direct oral anticoagulants: a series of five cases admitted to the intensive care unit. Poster presented at ISTH2017 - poster session; 2017
• 68 Spiller HA, Mowry JB, Aleguas Jr A. et al. An observational study of the factor Xa inhibitors rivaroxaban and apixaban as reported to eight Poison centers. Ann Emerg Med 2016; 67 (02) 189-195
• 69 Shaw JR, Woodfine JD, Douketis J, Schulman S, Carrier M. Perioperative interruption of direct oral anticoagulants in patients with atrial fibrillation: a systematic review and meta-analysis. Res Pract Thromb Haemost 2018; 2 (02) 282-290
• 70 Douketis JD, Spyropoulos AC, Duncan J. et al. Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant. JAMA Intern Med 2019; 179 (11) 1469-1478
• 71 Steinberg BA, Peterson ED, Kim S. et al; Outcomes Registry for Better Informed Treatment of Atrial Fibrillation Investigators and Patients. Use and outcomes associated with bridging during anticoagulation interruptions in patients with atrial fibrillation: findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Circulation 2015; 131 (05) 488-494
• 72 Colonna P, von Heymann C, Santamaria A. et al. Routine clinical practice in the periprocedural management of edoxaban therapy is associated with low risk of bleeding and thromboembolic complications: the prospective, observational, and multinational EMIT-AF/VTE study. Clin Cardiol 2020; 43 (07) 769-780
• 73 Nazha B, Pandya B, Cohen J. et al. Periprocedural outcomes of direct oral anticoagulants versus warfarin in nonvalvular atrial fibrillation meta-analysis of phase III trials. Circulation 2018; 138 (14) 1402-1411
• 74 Gorla R, Dentali F, Crippa M. et al. Perioperative safety and efficacy of different anticoagulation strategies with direct oral anticoagulants in pulmonary vein isolation: a meta-analysis. JACC Clin Electrophysiol 2018; 4 (06) 794-806
• 75 Beyer-Westendorf J, Gelbricht V, Förster K. et al. Peri-interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry. Eur Heart J 2014; 35 (28) 1888-1896
• 76 Schulman S, Carrier M, Lee AYY. et al; Periop Dabigatran Study Group. Perioperative management of dabigatran: a prospective cohort study. Circulation 2015; 132 (03) 167-173
• 77 Radaelli F, Fuccio L, Paggi S. et al; Bowell Group. Periendoscopic management of direct oral anticoagulants: a prospective cohort study. Gut 2019; 68 (06) 969-976
• 78 Russo V, Rago A, Proietti R. et al. Efficacy and safety of the target-specific oral anticoagulants for stroke prevention in atrial fibrillation: the real-life evidence. Ther Adv Drug Saf 2017; 8 (02) 67-75
• 79 Ruff CT, Giugliano RP, Braunwald E. et al. Association between edoxaban dose, concentration, anti-Factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet 2015; 385 (9984): 2288-2295
• 80 Siddiqui F, Hoppensteadt D, Jeske W, Iqbal O, Tafur A, Fareed J. Factor Xa inhibitory profile of apixaban, betrixaban, edoxaban, and rivaroxaban does not fully reflect their biologic spectrum. Clin Appl Thromb Hemost 2019; 25: 1076029619847524
• 81 Sennesael AL, Larock AS, Douxfils J. et al. Rivaroxaban plasma levels in patients admitted for bleeding events: insights from a prospective study. Thromb J 2018; 16 (01) 28
• 82 Gulilat M, Tang A, Gryn SE. et al. Interpatient variation in rivaroxaban and apixaban plasma concentrations in routine care. Can J Cardiol 2017; 33 (08) 1036-1043
• 83 Testa S, Tripodi A, Legnani C. et al; START-Laboratory Register. Plasma levels of direct oral anticoagulants in real life patients with atrial fibrillation: results observed in four anticoagulation clinics. Thromb Res 2016; 137: 178-183
• 84 Savage RL, Castellano M, Tatley MV. International reports of unexpected low plasma concentrations of dabigatran suggest that more frequent measurements will add value. Semin Thromb Hemost 2017; 43 (06) 635-638
• 85 Testa S, Paoletti O, Legnani C. et al. Low drug levels and thrombotic complications in high-risk atrial fibrillation patients treated with direct oral anticoagulants. J Thromb Haemost 2018; 16 (05) 842-848
• 86 Albaladejo P, Samama CM, Sié P. et al; GIHP-NACO Study Group. Management of severe bleeding in patients treated with direct oral anticoagulants: an observational registry analysis. Anesthesiology 2017; 127 (01) 111-120
• 87 Goto E, Horinaka S, Ishimitsu T, Kato T. Factor Xa inhibitors in clinical practice: comparison of pharmacokinetic profiles. Drug Metab Pharmacokinet 2020; 35 (01) 151-159
• 88 Suwa M, Morii I, Kino M. Rivaroxaban or apixaban for non-valvular atrial fibrillation: efficacy and safety of off-label under-dosing according to plasma concentration. Circ J 2019; 83 (05) 991-999
• 89 Seiffge DJ, Kägi G, Michel P. et al; Novel Oral Anticoagulants in Stroke Patients study group. Rivaroxaban plasma levels in acute ischemic stroke and intracerebral hemorrhage. Ann Neurol 2018; 83 (03) 451-459
• 90 Helin TA, Pakkanen A, Lassila R, Joutsi-Korhonen L. Laboratory assessment of novel oral anticoagulants: method suitability and variability between coagulation laboratories. Clin Chem 2013; 59 (05) 807-814
• 91 Birnie DH, Healey JS, Wells GA. et al. Continued vs. interrupted direct oral anticoagulants at the time of device surgery, in patients with moderate to high risk of arterial thrombo-embolic events (BRUISE CONTROL-2). Eur Heart J 2018; 39 (44) 3973-3979