Activated Clotting Time Guided Heparinisation During Open Abdominal Aortic Aneurysm Repair (ACTION-1) - Rationale and Design of a Randomised Trial

Unfractionated heparin has been used by vascular surgeons worldwide for more than 70 years during non-cardiac arterial procedures (NCAP) to prevent clot formation and reduce thromboembolic complications (TEC), for example, arterial thrombosis, peripheral emboli, myocardial infarction, colonic ischaemia, deep venous thrombosis, and stroke.1Wanhainen A. Verzini F. van Herzeele I. Allaire E. Bown M. Cohnert T. et al.Editor’s Choice – European Society for Vascular Surgery (ESVS) 2019 Clinical Practice Guidelines on the Management of Abdominal Aorto-iliac Artery Aneurysms.Eur J Vasc Endovasc Surg. 2019; 57: 1-97Abstract Full Text Full Text PDF PubMed Scopus (1494) Google Scholar,2Wiersema A. Bruijninckx C. Reijnen M. Vos J. van Delden O. Vahl A. et al.Perioperative prophylactic antithrombotic strategies in vascular surgery: current practice in the Netherlands.J Cardiovasc Surg. 2015; 56: 119-144PubMed Google Scholar In this Research Letter, shortcomings and high variation in current intra-operative heparin use, the need for scientific evidence, and the design of a randomised controlled trial (RCT) are discussed. A major disadvantage of intra-operative heparin use is the increased risk of bleeding. A fine balance must be found between reduction of TEC and increased bleeding risk. Another disadvantage is the unpredictable effect of heparin in the individual patient. Heparin is often administered as a single dose of 5 000 IU, independent of patient characteristics, and without monitoring intra-operative heparinisation.2Wiersema A. Bruijninckx C. Reijnen M. Vos J. van Delden O. Vahl A. et al.Perioperative prophylactic antithrombotic strategies in vascular surgery: current practice in the Netherlands.J Cardiovasc Surg. 2015; 56: 119-144PubMed Google Scholar During cardiac interventions, the activated clotting time (ACT) is predominantly used to monitor heparinisation and aid in a patient specific anticoagulation strategy. To evaluate the feasibility and safety of measuring ACT during NCAP, a consortium was initiated (measuring the ACT during non-cardiac arterial procedures [MANCO], NTR: NL6788, clinicaltrials.gov: NCT03426293). Analyses from this prospective patient registry suggested that a standardised dose of 5 000 IU heparin does not provide adequate anticoagulation, resulting in TEC in 9% of patients. Further research showed that a weight based protocol with a starting dose of 100 IU/kg was more appropriate to reach adequate anticoagulation levels. A target ACT ≥ 200 seconds resulted in the lowest frequency of TEC (4.3%). To limit bleeding complications, a target ACT of 200 – 220 seconds seemed optimal,3Doganer O. Jongkind V. Blankensteijn J.D. Yeung K.K. Wiersema A.M. A standardized bolus of 5000 IU of heparin does not lead to adequate heparinization during non-cardiac arterial procedures.Ann Vasc Surg. 2021; 71: 280-287Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar,4Doganer O. Roosendaal L.C. Wiersema A.M. Blankensteijn J.D. Yeung K.K. Jongkind V. Weight based heparin dosage with activated clotting time monitoring leads to adequate and safe anticoagulation in non-cardiac arterial procedures.Ann Vasc Surg. 2022; 84: 327-335Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar which has been used to create the ACT guided heparinisation protocol (Fig. 1). In a pilot study, this protocol was shown to be safe, with no increase in bleeding complications, while the incidence of TEC remained low (data to be published). These results laid the foundation for a RCT: ACT guided heparinisation during open abdominal aortic aneurysm (AAA) repair (ACTION-1, NTR: NL8421, clinicaltrials.gov: NCT04061798). The present study focuses on open AAA repair as a single procedure, due to the relatively high incidence of TEC. The aim of this international, multicentre, single blind RCT is to establish whether ACT guided heparinisation results in safe and more optimal coagulation than 5 000 IU as a single bolus during open AAA repair. Inclusion criteria are patients older than 18 years, undergoing elective open repair of an AAA or iliac aneurysm originating below the superior mesenteric artery. Patients are randomised between a single bolus of 5 000 IU heparin, and ACT guided heparinisation. In the intervention group, 100 IU/kg heparin is administered three to five minutes before clamping the aorta, and ACT is measured according to a standardised protocol (Fig. 1). In the control group, a single dose of 5 000 IU heparin is administered before clamping the aorta and no ACT measurements are performed, except for a single measurement at the end of the procedure, when blood flow is re-established. Depending on the ACT at closure, protamine should be administered in both treatment groups. All ACT measurements are standardised using the Hemostasis Management System Plus (Medtronic, Minneapolis, MN, USA), using High Range ACT cartridges. The primary outcomes are combined incidence of all TEC and all cause mortality at 30 days or during the same admission (primary efficacy endpoint) and the incidence of bleeding complications, according to the E-CABG classification (European registry for Coronary Artery Bypass Grafting): administration of two or more units of red blood cells (primary safety endpoint).5Brascia D. Reichart D. Onorati F. Perrotti A. Ruggieri V.G. Bounader K. et al.Validation of bleeding classifications in coronary artery bypass grafting.Am J Cardiol. 2017; 119: 727-760Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar An Independent Central Adjudication Committee evaluates whether a complication is correctly labelled as TEC. Based on an expected decrease of the combined endpoint of TEC and reduced mortality from 19% to 11% in the ACT guided group (power: 80%, alpha: 5%, dropout: 10%), the calculated sample size is 750 patients. The study has been explained in detail in a previous protocol publication.6Wiersema A.M. Roosendaal L.C. Koelemaij M.J.W. Tijssen J.G.P. van Dieren S. Blankensteijn J.D. et al.ACTION-1: study protocol for a randomised controlled trial on ACT-guided heparinization during open abdominal aortic aneurysm repair.Trials. 2021; 22: 2-7Crossref PubMed Scopus (1) Google Scholar The ACTION-1 trial started in March 2020 and will be completed in November 2024. On 24 November 2022, 20 hospitals in the Netherlands and two hospitals in Germany were participating in the study, and 206 patients had been included. New participating centres in Europe are being recruited to increase the collaborative network and to reach the targeted sample size on the scheduled date. A Data Safety Monitoring Board for the ACTION-1 trial concluded that this trial was considered safe for the patients and was allowed to continue after a safety review of the first 100 patients. The next safety reviews will be performed after 200 patients, when follow up is completed and after 500 patients. The purpose of the ACTION-1 trial is to expand knowledge regarding intra-operative anticoagulation strategies during open AAA surgery. None. ZonMw (Dutch governmental organisation for research, development and funding in healthcare): grant 848043004, and Medtronic (Minneapolis, MN, USA). ZonMw and Medtronic did not influence the study or the decision to write nor submit this research letter.