ACTION-1: study protocol for a randomised controlled trial on ACT guided heparinization during open abdominal aortic aneurysm repair {1}

Heparin 70 all (NCAP) to reduce thrombo-embolic (TEC). But also increases blood loss causing for the Heparin has an unpredictable effect in the individual The Activated Clotting Time (ACT) can measure the effect of heparin. Currently this ACT is not measured during NCAP as standard of care, contrary to during cardiac interventions, open and endovascular. A RCT will evaluate if ACT guided heparinization results in less TEC than the current standard: a single bolus of 5 000 IU of heparin and no measurements at all. A goal ACT of 200-220 seconds should be reached during ACT guided heparinization and this should decrease (mortality caused by) TEC, while not bleeding complications. This during (AAA) as this is a standardized abdominal or iliac aneurysms. Preoperative laboratory results: Hb, leucocytes, sodium, potassium, creatinine, eGFR, platelets. Presence of impaired renal function (eGFR < 40 ml/min).

optimal level of coagulation. Another major disadvantage of the use of heparin as a periprocedural prophylactic antithrombotic, is the fact that heparin has an unpredictable effect in individual patients. (12) The molecular structure of heparin causes a variety of its effect, creating not only a difference in e cacy between different brands, but even between batches of the same brand. (13) In most countries heparin is administered as a standardized bolus in every patient undergoing NCAP. The most often used dosage is 5 000 IU, irrespective of sex, bodyweight, type of procedure or duration of procedure. Interventional radiologists often use a dose of less than 5 000 IU. (9,10) In all cardiac interventions worldwide, open or endovascular and using cardio-pulmonary bypass or not, the effect of heparin is measured routinely. Many studies have shown that the activated clotting time (ACT) is the preferred test to measure the effect of heparin and that using this test increases safety of these cardiac interventions. (14,15) This results in better patient related outcomes. Surprisingly vascular surgeons have not adopted this measurement of the ACT during NCAP. This ACT measurement could ensure the individual patient of safe, tailor-made periprocedural anticoagulation. (16)(17)(18)(19)(20)(21)(22)(23). This should lead to better results of procedures, with improved patient-related outcomes and less harm for the patient {6b}.
To evaluate the implementation of routine ACT measurements during NCAP, a prospective registry was instituted in 4 major vascular centers in The Netherlands (MANCO, NTR nr. 6973, ClinicalTrials.gov M016-045). All ACT measurements were performed according to a standardized protocol using the same device: Hemostasis Management System Plus (HMS) by Medtronic®, with high-range ACT cartridges (HR-ACT). The percentage of successful measurements was 99% and results were reproducible and comparable between the different hospitals. The validation and standardization of the HMS for ACT measurements are extensively proven in the literature during cardiac interventions. (24,25) Similar studies were performed with other cartridges (low-range ACT) for the HMS and other brands of ACT measurement systems. Results (on le, manuscript in preparation) show that the HMS and the HR-ACT guarantee the most stable, reproducible and comparable results during NCAP. Results of the MANCO study, in more than 700 patients, show that ACT measurements can be introduced safely and adequately in daily routine in the operation room and angio-suite, both during open and endovascular NCAP. Evaluation of these data resulted in a safe and adequate protocol to ensure the patient of optimal, ACT guided heparinization during NCAP. A goal ACT of 200-220 seconds is considered to be optimal. A systematic review was conducted by our research group, in which only 4 studies could be found that investigated the relation between ACT values and clinical outcomes.(26) Two studies did not nd a relationship between ACT value and bleeding complications. (19,23) Saw et al. found that an ACT > 300 seconds was associated with increased combined event rate (death, stroke or MI) in carotid artery stenting. (21) Kasapis et al. found increased bleeding in peripheral endovascular interventions when the ACT was > 250 seconds. (16) In the MANCO study the effect of the standardized bolus of 5 000 IU was evaluated by measuring the ACT. (27) Results showed that large individual patient variability in the response to heparin was present.
The mean baseline ACT in all patients was 129 ± 18 s and the mean ACT 5 minutes after the initial bolus of heparin was 191 ± 36 seconds. After the initial dose of 5 000 IU heparin only 33% and 6% of patients reached an ACT of 200 and 250 seconds, respectively.
Despite the use of heparin, ATEC occurred in 17 patients (9%). The lowest number of ATEC and hemorrhagic complications occurred in the group of patients with an ACT between 200 and 250 seconds. Conclusions: A standardized bolus of 5 000 IU heparin does not lead to adequate and safe heparinization in non-cardiac arterial procedures. Patient response to heparin shows a large individual variability. Therefore, routine ACT measurements are necessary to ascertain adequate anticoagulation. Further research is needed to investigate if heparin dosing based on the ACT could result in less arterial thromboembolic complications, without increasing hemorrhagic complications.
Next step was to design a large international multicenter trial to provide level 1 evidence that ACT guided heparinization will result in less thrombo-embolic complications, without more bleeding complications than unmonitored heparinization with the use of a standardized bolus. This will be evaluated during open abdominal aortic aneurysm (AAA) surgery DSAA classi cation C: aneurysm originating below the Superior Mesenteric Artery. DSAA being the Dutch Surgical Aneurysm Audit, a Dutch registration that is mandatory for all Dutch vascular surgeons who treat patients with an AAA. (28) In this registry details are stored regarding indication, techniques and periprocedural care. The reason to choose open AAA repair for this RCT, is that this procedure is subject to standardized care in all hospitals around Europe, also by following the 2019 European Society of Vascular Surgery Guidelines on Management of Patients with an AAA. (29) During a trajectory of 2 years funding was applied for at ZorgOnderzoek Nederland Medische Wetenschappen (ZonMw, https://www.zonmw.nl) in close collaboration with the Dutch Surgical Association and Dutch Vascular Surgery board. ZonMw's principal commissioners are the Dutch Ministry of Public Health, Welfare and Sport (VWS) and the Netherlands Organization for Scienti c Research (NWO). ZonMw also increasingly works on behalf of other parties, such as local authorities, health funds, health care insurers, private companies, and professional associations. After an extensive (international) peer-reviewed process, a grant of 1.6 million euros was granted for the ACTION-1 trial: ACT guided heparinization during open abdominal aortic aneurysm repair.
One of the main demands of ZonMw was to execute a pilot study. Results of this pilot study in 46 patients with open AAA repair resulted in a decrease of TEC from 22% in the 5 000 IU group to 7% in the ACT guided group. No increase in bleeding complications or mortality was detected (no mortality in both groups, E-CABG class 1 bleeding in 39% in the 5000 IU group versus 36% in the ACT guided group). (30,31) In the ACT guided group the use of protamine at the end of surgery was also described in a protocol. (32,33) Because of the limited number of included patients, no statistical signi cance was reached. This underlines the importance of performing a RCT.

Method/design
This study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines. (34) Study design {8} The ACTION-1 trial is a multicenter RCT designed to compare the outcomes of ACT guided heparinization to a standardized bolus of 5000 IU of heparin, during open AAA repair.
Patients undergoing open AAA repair, meeting eligibility criteria, will be included in the trial after giving written informed consent.
The following Dutch vascular centers (academic and large community training hospitals){9} are currently, or in upcoming months, participating in the ACTION-1 trial: Dijklander Ziekenhuis Hoorn, Amsterdam UMC location VUmc, Amsterdam UMC location AMC, Rijnstate Ziekenhuis Arnhem, Elisabeth-TweeSteden Independent Central Adjudication Committee (ICAC) will be blinded for the intervention {17a}. Blinding will follow all legal demands for unblinding in case of patient safety, as deemed as such by attending medical personnel {17b}. Also, the Data Safety Monitoring Board (DSMB) can decide to unblind.

Study objectives {7}
To establish that ACT guided heparinization results in safe and optimal anticoagulation during open AAA repair. The hypothesis is that ACT guided heparinization will result in a decrease of TEC, without a signi cant increase in bleeding complications when compared to the use of a non-ACT guided standardized bolus of 5 000 IU. The decrease in TEC will lead to less mortality and morbidity, lower number of re-operations or better patency, all substantially improving patient's quality of health, e ciency of medical care and quality of vascular medical care.

Sample size calculation {14}
In the DSAA (2014 to 2016) the rate of serious complications was 29% for all patients. According to the Society for Vascular Surgery AAA 2018 guidelines the incidence of TEC is between 15 and 36%. In our preliminary MANCO trial, the incidence of TEC was 14%. For our power calculation the incidence of TEC is set at 14%. The vast majority of mortality after open AAA repair stems from TEC. A mortality rate of 5% after open AAA repair is derived from DSAA. Hypothesis is that decrease of TEC will result in a lower mortality of 3%. Bleeding complications derived from the literature and from our MANCO trial and ACTION pilot study: 18-39% (scored according to E-CABG classi cation). (30) Derived from data from our pilot study and from literature, the hypothesis is that ACT guided heparinization will lower the rate of TEC to 8%. The expected incidence for the combined endpoint of TEC and mortality is therefore set at 19% for the 5 000 IU group and 11% for the ACT guided group. Using a continuity corrected chi-square test with a two-sided alpha of 5%, 337 patients are needed in each group to achieve a power of 80%. Including a drop out of 10%, a total of 750 patients are needed for the combined primary endpoints of TEC and mortality.
In our pilot study no increase in bleeding complications was found for open AAA repair (E-CABG class 1 bleeding was 39% versus 36%). Nevertheless, it is important that excessive bleeding does not occur in the intervention group. Therefore, a non-inferiority calculation was performed. Bleeding complications and TEC are different and have a different impact on patients. Bleeding complications Grade 1 E-CABG have less impact on mortality and quality of life than TEC. The expectation is an improvement in combined TEC and mortality of 8%, the non-inferiority for bleeding complications is set at 11%.
Expecting 32% bleeding complications in the standard group and 33% in the intervention group and a non-inferiority limit of 43% (11% limit difference) with a power of 80% and a one-sided alpha of 5%, 272 patients required in each group. Therefore the 750 patients included are su cient to also evaluate the non-inferiority for bleeding complications.
Main study parameter/endpoint e cacy {12} Combined incidence of all TEC and all-cause mortality within 30 days or during the same admission in hospital. TEC are any complication as caused by thrombus or embolus perioperatively, including but not exclusively: myocardial infarction, leg ischemia, deep venous thrombosis, colon ischemia, TIA/stroke, graft thrombosis, peroperative thrombus requiring embolectomy or redo of an anastomosis, thrombus or embolus in organs or lower limbs and other peripheral thrombosis.
Main study parameter/endpoint safety {12} Incidence of bleeding complications according to E-CABG classi cation, grade 1 and higher: per-or postoperative transfusion of 2 or more units of red blood cells, transfusion of platelets, transfusion of fresh frozen plasma or reoperation for bleeding during hospital stay. (30,31) Secondary study parameters/endpoints {12} Secondary endpoints: complications (non-TEC), within 30 days postoperative or in the same admission, as de ned by DSAA and suggested standards for reports on aneurysmal disease: all complications requiring re-operation, longer hospital stay, all other complications. Incidence of kidney injury as de ned by RIFLE criteria: rise of serum creatinine > 100% or decrease of eGFR with 50%.(35) Allergic reactions. ACT values (in intervention group), total heparin administration, protamine administration. Peroperative blood loss, blood transfusions either autologous or homologous, other blood products administration, total operative time, aortic clamping time, use of adjunctive hemostatic products, length of hospital (including ICU) stay. Health status as measured with the EQ-5D-5L. Economic and healthcare costs evaluation by IMCQ and IPCQ and addition of out-of-pocket expenses.

Other study parameters {12}
Preoperative parameters Patient demographics: sex, smoking history, body length and weight and body mass index, medical history (general, cardiac, pulmonary, diabetes, surgical), medication, all previous vascular interventions. Blood pressure and pulse at outpatient visit, ECG reports. Diameter and anatomical classi cation of abdominal or iliac aneurysms. Preoperative laboratory results: Hb, leucocytes, sodium, potassium, creatinine, eGFR, platelets. Presence of impaired renal function (eGFR < 40 ml/min).

Ethical considerations
If patients meet the inclusion criteria, they will be fully informed about the trial and provided with a patient information form and have the opportunity to ask questions. Patients willing to participate will sign the informed consent form. This study will be conducted in accordance with the Good Clinical Practice (GCP) guidelines, the principles of the Declaration of Helsinki and with the Medical Research Involving Human Subjects Act (WMO). The medical ethical committee in Amsterdam (2019.732 -NL6675902919) has approved the study protocol, as well as local institutional boards of each participating center. All legal European demands concerning insurances for possible harm from trial participation are met and all separate trial study sites have insurance as legally demanded by Dutch Government for non-trial harm for participating patients {30}.
Safety and quality control Independent Central Adjudication Committee The ICAC is instituted to decide whether complications are rightfully labelled as TEC in the CRF. Two vascular surgeons and 1 registered Intensive-Care specialist will form this committee, none of them being a member of the ACTION-1 project group. This committee will gather 30 days after 100, 200, 500 inclusions and 6 weeks after the last inclusion.
They are blinded for the intervention and will judge the complication parts of the CRFs of all included patients.
In case of disagreement within this committee, the majority will be decisive. In case this committee decides that they need further clari cation on a speci c complication, this will be provided by the project group with data from the original electronic patient le of the patient.

Data safety monitoring board {21 a,b}
Despite the fact that this study is labeled as moderate risk, a full DSMB is installed. The DSMB is composed of three independent experts: a vascular surgeon, a cardio-thoracic surgeon and a clinical epidemiologist and biostatistician.
A safety review will be performed by an independent statistician (T. van der Ploeg, PhD) and reviewed by the data safety monitoring committee after the results are available for 100, 200 and 500 patients. This is a safety review, which looks at the combination of several outcomes as opposed to a traditional interim analysis with speci ed stopping rules.
In case of strong concerns about safety, the safety monitoring committee can advise to stop the study.
Furthermore, Serious Adverse Events (SAE) will be reported to the data and safety monitoring committee.
A total of three safety reviews are planned: A rst interim analysis is planned when approximately 100 subjects have been enrolled. This will provide data sample size calculations, and safety assessments.
A second interim analysis is planned when approximately 200 subjects have been enrolled. This will provide data sample size calculations, and safety assessments.
A third interim analysis is planned when approximately 500 subjects have been enrolled. This will provide data sample size calculations, and safety assessments.
Additional ad-hoc interim analyses may be conducted to support decision making concerning the current clinical study, the sponsor's clinical development projects in general or in case of any safety concerns. Independent personnel who are not directly involved in conducting the study will perform the interim analyses and review of the unblinded outputs.
The DSMB should consider stopping the study if the following conditions are met: Stopping rule for safety is: a difference in all-cause mortality within 30 days after surgery or during the same admission between intervention and control group with P value smaller than 0.05 in disadvantage of the intervention group.
a difference in life threatening bleeding (E-CABG classi cation grade 2 or higher: transfusion of 5 or more units of red blood cells or reoperation for bleeding) between intervention and control group with P value smaller than 0.05 in disadvantage of the intervention group. a difference in the composite of all-cause mortality or life threatening bleeding (E-CABG classi cation grade 2 or higher: transfusion of 5 or more units of red blood cells or reoperation for bleeding) between intervention and control group with P value smaller than 0.05 in disadvantage of the intervention group.
Stopping rules for e cacy: The DSMB should only under exceptional circumstances advise to terminate the trial under overwhelming e cacy of the act guided heparin group over the control group: the DSMB could consider stopping when a difference in incidence of TEC and mortality within 30 days after surgery or during the same admission between intervention and control group with P value smaller than 0.001 occurs, according to Haybittle-Peto boundary.
No further dissemination of interim results should occur, in particular not with individuals involved in treating the study's subjects or assessing clinical data.
While monitoring guidelines have been provided, the DSMB uses all available evidence and its collective judgement to base its recommendation to stop or modify the study.
Adverse, severe adverse events and suspected unexpected serious adverse reactions {22} Adverse events are de ned as any undesirable experience occurring to a subject during the study, whether or not considered related to the intervention. All adverse events, within 30 days postoperative or in the same admission, reported spontaneously by the subject or observed by the investigator will be recorded.
A SAE is de ned as any untoward medical occurrence or effect that results in death, is life threatening (at the time of the event), requires hospitalization or prolongation of existing inpatients' hospitalization, results in persistent or signi cant disability or incapacity, or any other important medical event that did not result in any of the outcomes listed above due to medical or surgical intervention but could have been based upon appropriate judgement by the investigator. An elective hospital admission will not be considered as a serious adverse event.
All SAE will be reported by the local principal investigator to the sponsor within 24 hours of the study site staff becoming aware of the event. The sponsor will report all the SAE in a line listing, which will be reported once every six months to the medical ethical committee.
Adverse reactions are all untoward and unintended responses to an investigational product related to any dose administered. Unexpected adverse reactions are suspected unexpected serious adverse reactions (SUSAR) if the following three conditions are met: the event must be serious; and there must be a certain degree of probability that the event is a harmful and an undesirable reaction to the medicinal product under investigation, regardless of the administered dose; and the adverse reaction must be unexpected, that is to say, the nature and severity of the adverse reaction are not in agreement with the product information as recorded in the Summary of Product Characteristics.
All SUSARs will be reported by the sponsor to the DSMB and to the accredited medical ethical committee via 'Toetsingonline' on the website of the Central Committee on Research involving Human Subjects (CCMO, www.ccmo.nl).
Independent monitoring and extensive quality control including all extensive legal demands for major trials with pharmaceuticals are met by an international acclaimed bureau: Julius Clinical (https://www.juliusclinical.com).

Inclusion criteria {10}
Inclusion criteria are: able to speak and read in local language of trial hospital; patients older than 18 years scheduled for elective, open repair of an iliac or abdominal aortic aneurysm distal of the SMA (DSAA segment C); Implantation of a tube or bifurcation prosthesis; trans-abdominal or retroperitoneal surgical approach of aneurysm; able and willing to provide written informed consent.

Exclusion criteria {10}
Exclusion criteria are: not able to provide written informed consent; previous open or endovascular intervention on the abdominal aorta (previous surgery on other parts of the aorta or iliac arteries is not an exclusion criterion); history of coagulation disorders, heparin induced thrombocytopenia (HIT), allergy for heparin or thrombocyte pathology; impaired renal function with EGFR below 30 ml/min; acute open AAA surgery; hybrid interventions; connective tissue disorders; dual anti-platelet therapy, which cannot be discontinued; life expectancy less than 2 years; in ammatory, mycotic or infected aneurysms; allergy for protamine or sh protein.

Recruitment {15}
Patients scheduled to undergo open AAA repair, will be informed about the study by their attending vascular surgeon in outpatient clinic of participating hospitals about the study and the informed consent procedure will be explained. Informed consent will only be obtained by medical personnel who are GCP licensed. Also, a mandatory training by research-staff has to completed and the Site Initiation Visit (SIV) completed {26a}. This SIV is performed by an external, independent trial research organization: Julius Clinical. A total of 750 patients with an abdominal aortic aneurysm requiring open aneurysm repair, will be included in the ACTION-1 study, after signing informed consent ( gure 1). An EQ-5D-5L questionnaire is handed out to the patient after receiving informed consent. The patient returns the form by post to the investigators, or bring the form when admitted for surgery, for baseline values. Figure 2 shows the participant timeline {13} and gure 3 shows the study schedule.

Randomization {16 a,b,c}
Randomization will take place just before the start of surgery by one of the researchers of the sponsor, using a computerized program (CASTOR EDC) with a random block size of 2, 4, 6. The randomization will be strati ed by participating center.

Treatment details {11a}
ACT-guided heparinization Heparin is given to reach an ACT of 200-220 seconds. At the start of the procedure, before any heparin is given, a baseline ACT measurement is performed. 3-5 minutes before clamping of the aorta, 100 IU/kg bodyweight of heparin is administrated intravenously. If patients weighing more than 150 kg, a maximum heparin dose of 15.000 IU heparin is administered to prevent overdose. 5 minutes after administration of heparin, ACT measurement is performed. If the ACT is below 180 seconds, an additional dose of heparin of 60 IU/kg is administered. If the ACT is between 180 and 200 seconds, an additional dose of heparin of 30 IU/kg is administered, and if the ACT is 200 seconds or longer, no extra heparin is given.
Five minutes after every administration of heparin the ACT is measured. If the ACT is 200 seconds or longer, the next ACT measurement is performed every 30 minutes, until the end of the procedure or until new heparin administration is required (because of ACT < 200 seconds). After each new dose of heparin, an ACT measurement is performed after 5 minutes and the above described protocol of ACT measurements will be repeated. After re-establishing blood ow and removing all clamps, the ACT is measured. Depending on that ACT value near the end of surgery, protamine is given to neutralize the effect of heparin.
If the ACT at closure is between 200 and 250 seconds, 2500 IU protamine should be administered. If the ACT is higher than 250 seconds, 5000 IU protamine should be administered, and if between 180 and 200 seconds, 1000 IU protamine. Five minutes after the administration of protamine, the ACT is measured.
The ACT should preferably be below 180 seconds. If the ACT is still more than 200 seconds, protamine should be administered again using to the above-mentioned protocol. When an additional dose of protamine is required, ACT measurement is performed 5 minutes after that administration.

IU of heparin
A single dose of 5 000 IU of heparin is given 3-5 minutes before clamping of the aorta. No ACT measurements are performed. Only on clari ed indications extra doses of heparin or protamine are permitted, at the discretion of the attending vascular surgeon. Deviations from protocol will be clearly stated with reasoning in the operative report.
Patients with additional doses of heparin or protamine outside protocol will not be excluded from the trial. Evaluation will be performed according to intention-to-treat analysis but also a per-protocol analysis will be performed and, if indicated, a sensitivity analysis.

Follow-up and quality of life measurements
Postoperative treatment, blood tests and outpatient clinic visits will be according to local protocols. The patients will be sent 3 kind of surveys; the EQ-5D-5L for quality of life evaluation, after 1 week, 4 weeks, After thirty days, all postoperative variables will be collected into the electronic database. All study parameters are standard care and can be reproduced from electronic patient les. Extensive standard operating procedures (SOP) are present to secure that data is properly scored.
All data will be collected at each participating center using the eCRF in the electronic database Castor EDC. Castor complies with all applicable laws and regulations with regard to ICHG GCP and the General Data Protection Regulation (GDPR). Each participating center will maintain a key list. This key list stays in the local hospital and will not be shared. After completion of the study, all study documents will be stored on site for 25 years. After completion of the trial, all raw data will be made available for others, following the mandatory policy of ZonMw. No contractual agreements are made that limit any access for other investigators {29}.
Statistical analysis {20 a,b,c} Descriptive statistics of continuous variables will be presented as means with standard deviations (SD) or medians with inter-quartile ranges (IQR) depending on the distribution of the data.
Categorical data will be presented as proportions and numbers. The statistical e cacy analysis will be conducted according to the intention-to-treat principle. A separate per protocol analysis will be performed additionally as a sensitivity analysis. All analyses will be performed with the latest version of the Statistical Package for Social Sciences (SPSS, SPSS Inc., Armonk, NY, USA).
The analysis of primary e cacy and safety outcomes will be performed on an intention-to-treat basis and in a hierarchical fashion. If statistical analysis shows that there is a statistically signi cant difference in the primary e cacy endpoint statistical analysis of the primary safety study parameter will be performed. If there is no signi cant difference between study groups in primary e cacy endpoint, assessment of primary safety endpoint will be considered exploratory.

Primary e cacy study parameter
The primary endpoint is the composite of the incidence of all TEC, including myocardial infarction, leg ischemia, deep venous thrombosis, colon ischemia, stroke, graft thrombosis, thrombo-embolic complications in kidney or spleen and other peripheral thrombosis and all-cause mortality within 30 days after surgery or during the same admission. Also, peroperative thrombosis requiring additional actions peroperatively (i.e., embolectomy, atherectomy or re-do of an anastomosis because of thrombus). The statistical e cacy analysis will be conducted with a chi-square test for proportions. Differences in the incidence of this composite endpoint between the intervention and control group will be expressed as the absolute risk difference with 95% con dence interval.
Primary safety study parameter Incidence of bleeding complications according to E-CABG classi cation, grade 1 and higher.(31) For the bleeding complications a non-inferiority test will be used. We test the hypothesis that the difference in bleeding between the intervention group and the control group is below the a priori speci ed boundary of 11%. This will be tested using a one-sided t test with an alpha of 0.025, with the null hypothesis that the number of bleedings is above the threshold margin and the alternative hypothesis that is below the threshold margin. If the con dence interval for the bleeding complications does not include the noninferiority limit in the per-protocol analysis and the intention-to-treat analysis non-inferiority for bleeding complications is established.

Secondary study parameter(s)
Secondary endpoints include all complications as de ned by DSAA and suggested standards for reports on aneurysmal disease. Health status measured with the EQ-5D-5L questionnaire. Differences in categorical outcomes between the intervention and control group will be expressed as the absolute risk difference with 95% con dence interval. Differences in continuous outcomes will be tested with the student's t-test in case of a normal distribution or the Mann-Whitney U-test in case the data do not follow the normal distribution. The level of signi cance is set at a two-sided p-value < 0.05.

Other study parameters
Peroperative blood loss, blood transfusions either autologous or homologous, other blood products administration, total operative time, clamping time, use of adjunctive hemostatic products, length of hospital (including ICU) stay and health status. ACT values measured. Amount of heparin and protamine used. The outcomes of the rst 5 patients from all participating hospitals will be analyzed and compared with the outcomes of patients included later. Data on previous heparin protocol will be collected per hospital. Analyses will be conducted to determine whether the previously used heparin protocol affects the outcomes.

ECONOMIC EVALUATION:
Cost effectiveness analysis (CEA) General considerations: We hypothesize that ACT guided heparinization could lower the rate of TEC and TEC related mortality to in total 11% and that the quality of life can be increased from 73% to 76%. The economic evaluation of ACT guided heparinization against standard care with a standardized bolus of heparin will be performed as cost-utility analyses and a cost effectiveness analysis from a societal perspective with the costs per quality adjusted life year (QALY) and the costs per prevented complication as the primary economic outcomes. The cost-utility analysis can be used for policy making and composition of a guideline. The cost-effectiveness analysis (CEA) relates to the clinical outcome parameter and may be used for prioritization or bench marking of strategies that enhance surgical patient safety. The CEA and CUA will be based on a time horizon of 6 months. All related complications are within the time horizon of 6 months and patients will be recovered from the surgery. For on-going complications such as leg amputations, colostomy, permanent neurological de cits, dialysis a CEA and CUA with a lifelong time horizon will be made using extrapolation and model-based techniques. For this time horizon discounting of effects and costs will be performed as stated in the most recent guidelines for cost analysis.(36) To account for uncertainties in the lifelong time horizon, a probabilistic sensitivity analysis will be performed.
Incremental cost-effectiveness ratios will be calculated as the difference in costs per QALY gained and as the difference in costs prevented complications. Sampling variability will be accounted for by biascorrected and accelerated non-parametric bootstrapping. Results will be reported along with their 95% con dence intervals and displayed graphically with cost-effectiveness planes and with costeffectiveness acceptability curves. One-way and multi-way sensitivity analyses will be done for the unit costs of the most common complications. Some missing data can be expected, if missing data is at random, this will be handled through multiple imputations with predictive mean matching.

Cost analysis
Medical costs, patient costs and productivity losses will be included in the evaluation. The medical costs cover the costs of surgery and related complications, anesthesia, theatre, peri-operative materials, inpatient stay at the ICU and the wards and medications. The patient costs include out-of-the pocket expenses like over-the-counter medication and health care related travel costs. Productivity losses are costs resulting from being absent and decreased productivity during work. Hospital health care utilization will be retrieved from CRFs and hospital information systems. Data on out-of-hospital health care will be gathered with the iMTA Medical Consumption Questionnaire (iMCQ) adjusted to the study setting. The productivity losses will be documented with the iMTA Productivity Cost Questionnaire (iPCQ). Questions on out-of-pocket expenses will be added to these patient questionnaires. Costs will be price indexed based on consumer price indices (CPI).
Costs will be calculated for individual patients as the product sum of the resource use and the respective unit costs. The iMCQ questionnaire will be send 13 and 26 weeks after surgery, the iPCQ only 26 weeks after surgery.

Patient outcome analysis
Patients will be asked to complete the EQ-5D-5L health status questionnaire at baseline, 1 week, 4 weeks, 13 and 26 weeks after surgery. These forms can be completed online or at home by the patients and send to the investigators by post. These questionnaires will be included in the CRFs. The EQ-5D-5L scoring pro les can be converted into a health utility score based on general population based Dutch tariffs. (37) QALYs will be calculated for each patient using linear interpolation between the successive health utility assessments over time.
Publication of data {31a,b,c} During the informed consent procedure, participants can indicate whether they want to be informed about the results of the study. The results will be shared after, the last patient completed the 6 months surveys.
Results will also be published in a peer-reviewed journal and will be described on clinicaltrials.gov.
Persons with substantive contributions to the design, conduct, interpretation, and reporting of this trial will be recognized through the granting of authorship on the nal trial report.
Participant level dataset will be shared under pre-de ned conditions and contract.

Discussion
The ACTION-1 trial is conducted to investigate if ACT guided heparinization might lead to better (patient related) outcomes than a standardized bolus of 5 000 IU of heparin without measuring its effect. The trial will be executed during open AAA repair in 18 large Dutch Vascular Centers (University and non-University) and 2 major centers in Germany and Denmark.
One of the possible concerns on operational issues might be the inclusion rate. Although the incidence of open AAA repair has declined considerably during the past decades due to the "EVAR rst" policy, a stabilization or even small increase in open AAA repair is present. The much-discussed recent NICE Guidelines on AAA treatment and the strong recommendation issued by the Dutch Board of Vascular Apart from the inclusion issue, some vascular surgeons may experience "cold feet" when their patient is randomized to an arm of the study that is not their preferred heparin regimen. Although our study group has proven convincingly that no evidence is present on either 5 000 IU or ACT guided heparinization, the strong believe and year-long routine of the individual surgeon can be hard to put aside.(26,27) Therefore, it might be anticipated that protocol deviations could occur on this aspect. For example: surgeon not administering a second dose of heparin if ACT is below 200 seconds in the ACT group, or extra gift of heparin outside protocol if the patient is randomized in the 5 000 IU group. The frequency of this reluctance to adhere to the protocol is deemed to be low and equal in both groups. Before the de nite participation of each vascular center a 30-minute presentation and discussion was held in which it was underlined that no evidence is present on either heparin regimen. Also, the strong support of the Board of Dutch Vascular Surgeons and the Board of Dutch Medical Specialists, contributes to creating equipoise amongst participating surgeons. To further enhance this feeling, it is emphasized in the protocol that individual surgeons are allowed to deviate from the protocol if this is deemed necessary for patient safety. Furthermore, during all procedures in ACTION-1, one of the trained team members will be present in the operating room during the duration of the entire procedure. The team member will randomize the patient when anesthesia is completed and the team member will perform all ACT measurements, if applicable, to exclude as much as possible any incorrect measurements or inconsistencies regarding ACT measurements. Also, the attending team member will record all variables present in the eCRF. In this manner maximal exclusion of bias can be achieved. During the two years of netuning the protocol for ACTION-1 and in the process of extensive, repeated international peer-reviewing by the funding agency ZonMw, all possible protocol and operational issues were discussed and, hopefully, anticipated.

Trial status
Medical Ethics Committee and CCMO approval was obtained on 21-st of February 2020 {24}. The current protocol of the ACTION-1 study is version 12, 10-11-2020 {3}. All major protocol modi cations and amendments will be submitted to the Medical Ethics Committee, shared with the participating hospitals and published on clinicaltrials.gov. The recruitment of the study began in March 2020. At the current date 61 patients have been included already despite delay in the preparation of participating hospitals due to the corona-crisis. The completion of the study is expected in December 2024, with a 6 moths extension period granted by ZonMw due to corona-crisis. We are willing to provide a model consent form on request.

Availability of data and materials
Participant level dataset will be shared under pre-de ned conditions and contract.

Competing interests:
No nancial or other competing interests are present for principal investigators for the overall trial and for each study site.