ACTION-1: ACT Guided Heparinization During Open Abdominal Aortic Aneurysm Repair.

Sponsor

Dijklander Ziekenhuis (Other)

Overall Status

Recruiting

CT.gov ID

NCT04061798

Collaborator

ZonMw: The Netherlands Organisation for Health Research and Development (Other), Amsterdam UMC, location VUmc (Other), Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) (Other)

750

Enrollment

Locations

Arms

Anticipated Duration (Months)

39.5

Patients Per Site

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Aim of the ACTION-1 study is to determine whether ACT guided heparinization decreases thrombo-embolic complications (TEC) and mortality after elective open AAA surgery, without causing more bleeding complications.

Condition or Disease	Intervention/Treatment	Phase
Abdominal Aortic Aneurysm Surgery Arterial Disease	Drug: ACT guided heparinization Drug: 5 000 IU of heparin	Phase 4

Detailed Description

Heparin is used during open abdominal aortic aneurysm (AAA) surgery to reduce thrombo-embolic complications (TEC): such as myocardial infarction, stroke, peripheral embolic events and the related mortality. On the other hand, heparin may increase blood loss, causing harm for the patient.

Heparin has an unpredictable effect in the individual patient. The effect of heparin can be measured by using the Activated Clotting Time (ACT). ACT measurement in open AAA repair could be introduced to ensure the individual patient of safe, tailor-made anticoagulation with a goal ACT of 200-220 seconds. A randomized controlled trial (RCT) has to prove that ACT guided heparinization would result in fewer TEC and lower mortality than a standardized bolus of heparin of 5 000 international units (IU), the current gold standard. ACT guided heparinization results in higher doses of heparin during operation and this should not result in significantly more bleeding complications of importance.

The ACTION-1 study will evaluate the effect of weight dosed heparinization during open abdominal aortic aneurysm surgery.The study will be an international multi-centre single blind randomized controlled trial. Patients will be randomized using a computerized program (CASTOR EDC) with a random block size of a maximum of 8. The randomization will be stratified by participating centre. Separate evaluation of results and if complications can be labelled as TEC, will be performed by an Independent Central Adjudication Committee. The 3 members of this Committee will be blinded with regard to if the patient was randomized for ACT guided heparinization or standard bolus of 5 000 IU without ACT measurements.

In the intervention group, heparin is given to reach an ACT of 200-220 seconds. Based on the ACT, an additional dose of heparin will be administered. 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). Depending on the ACT value near the end of surgery, protamine will be given to neutralize the effect of heparin.

In the comparative group, a single dose of 5 000 IU of heparin will be given 3-5 minutes before clamping of the aorta. No ACT measurements will be performed, except for one ACT measurement after re-establishing blood flow and removing all clamps. Depending on that ACT value near the end of surgery, the local protamine can be given to neutralize the effect of heparin.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

750 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Intervention group: 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. 5 minutes after administration of heparin, ACT measurement is performed. Comparative group: A single dose of 5 000 IU of heparin is given 3-5 minutes before clamping of the aorta. No ACT measurements are performed, except for one ACT measurement after re-establishing blood flow and removing all clamps.Intervention group: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. 5 minutes after administration of heparin, ACT measurement is performed.Comparative group:A single dose of 5 000 IU of heparin is given 3-5 minutes before clamping of the aorta. No ACT measurements are performed, except for one ACT measurement after re-establishing blood flow and removing all clamps.

Masking:

Single (Participant)

Masking Description:

Patients will be randomized using a computerized program (CASTOR EDC) with a random block size of a maximum of 8. The randomization will be stratified by participating centre. The participant is blinded to the allocated treatment. Separate evaluation of results and if complications can be labelled as TEC, will be performed by an Independent Central Adjudication Committee. The 3 members of this Committee will be blinded to the allocated treatment. Since the care provider and investigator have to do the ACT measuring, it is impossible to blind them to the allocated treatment.

Primary Purpose:

Treatment

Official Title:

ACTION-1: ACT Guided Heparinization During Open Abdominal Aortic Aneurysm Repair, a Randomised Trial.

Actual Study Start Date :

Mar 2, 2020

Anticipated Primary Completion Date :

Jan 1, 2024

Anticipated Study Completion Date :

Nov 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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. 5 minutes after administration of heparin, ACT measurement is performed.	Drug: ACT guided heparinization If the ACT is <180 sec., an additional dose of heparin of 60 IU/kg is administered. If the ACT is 180-200 sec., 30 IU/kg. If the ACT is >200 sec., no extra heparin is given. 5 min. after every administration of heparin the ACT is measured. If the ACT is >200 sec, the next ACT measurement is performed every 30 min., until the end of the procedure or until new heparin administration is required. After each new dose of heparin, an ACT measurement is performed after 5 min. and the above- described protocol of ACT measurements will be repeated. After re-establishing blood flow and removing all clamps, the ACT is measured. If the ACT at closure is 200-250 sec., 2500 IU of protamine should be administered. If >250 sec., 5000 IU protamine. If 180-200 sec., 1000 IU protamine. 5 min. after the administration of protamine, the ACT is measured. The ACT should preferably be below 180 sec. If the ACT is still more than 200 sec., protamine should be administered again.
Active Comparator: 5 000 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, except for one ACT measurement after re-establishing blood flow and removing all clamps. Depending on that ACT value near the end of surgery, the local protamine can be given to neutralize the effect of heparin. Only on clarified indications extra doses of heparin or protamine are permitted, at the discretion of the attending vascular surgeon. Indications could be clot formation intravascular or in a prosthesis, excessive bleeding or prolonged operation duration. Deviations from protocol should be clearly stated with reasoning in the operative report.	Drug: 5 000 IU of heparin A single dose of 5 000 IU of heparin is given 3-5 min before clamping of the aorta. No ACT measurements are performed, except for one ACT measurement after re-establishing blood flow and removing all clamps. Only on clarified indications extra doses of heparin or protamine are permitted, at the discretion of the attending vascular surgeon. Indications could be clot formation intravascular or in a prosthesis, excessive bleeding or prolonged operation duration. Deviations from protocol should be clearly stated with reasoning in the operative report. If the ACT at closure is between 200 and 250 s, 2500 IU protamine should be administered. If the ACT is higher than 250 s, 5000 IU protamine should be administered. If the ACT is between 180 and 200 s, 1000 IU protamine should be administered. Five minutes after the administration of protamine, the ACT is measured. The ACT should preferably be below 180 s. If the ACT is still more than 200 s, protamine should be administered again.

Arm

Intervention/Treatment

Experimental: 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. 5 minutes after administration of heparin, ACT measurement is performed.

Drug: ACT guided heparinization

If the ACT is <180 sec., an additional dose of heparin of 60 IU/kg is administered. If the ACT is 180-200 sec., 30 IU/kg. If the ACT is >200 sec., no extra heparin is given. 5 min. after every administration of heparin the ACT is measured. If the ACT is >200 sec, the next ACT measurement is performed every 30 min., until the end of the procedure or until new heparin administration is required. After each new dose of heparin, an ACT measurement is performed after 5 min. and the above- described protocol of ACT measurements will be repeated. After re-establishing blood flow and removing all clamps, the ACT is measured. If the ACT at closure is 200-250 sec., 2500 IU of protamine should be administered. If >250 sec., 5000 IU protamine. If 180-200 sec., 1000 IU protamine. 5 min. after the administration of protamine, the ACT is measured. The ACT should preferably be below 180 sec. If the ACT is still more than 200 sec., protamine should be administered again.

Active Comparator: 5 000 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, except for one ACT measurement after re-establishing blood flow and removing all clamps. Depending on that ACT value near the end of surgery, the local protamine can be given to neutralize the effect of heparin. Only on clarified indications extra doses of heparin or protamine are permitted, at the discretion of the attending vascular surgeon. Indications could be clot formation intravascular or in a prosthesis, excessive bleeding or prolonged operation duration. Deviations from protocol should be clearly stated with reasoning in the operative report.

Drug: 5 000 IU of heparin

A single dose of 5 000 IU of heparin is given 3-5 min before clamping of the aorta. No ACT measurements are performed, except for one ACT measurement after re-establishing blood flow and removing all clamps. Only on clarified indications extra doses of heparin or protamine are permitted, at the discretion of the attending vascular surgeon. Indications could be clot formation intravascular or in a prosthesis, excessive bleeding or prolonged operation duration. Deviations from protocol should be clearly stated with reasoning in the operative report. If the ACT at closure is between 200 and 250 s, 2500 IU protamine should be administered. If the ACT is higher than 250 s, 5000 IU protamine should be administered. If the ACT is between 180 and 200 s, 1000 IU protamine should be administered. Five minutes after the administration of protamine, the ACT is measured. The ACT should preferably be below 180 s. If the ACT is still more than 200 s, protamine should be administered again.

Outcome Measures

Primary Outcome Measures

Combined incidence of all thrombo-embolic complications (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, transient ischemic attack (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. Incidence of bleeding complications according to European multicenter study on Coronary Artery Bypass Grafting (E-CABG) classification, 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.

Secondary Outcome Measures

Complications (non-TEC). [Within 30 days or during the same admission in hospital]
All complications requiring re-operation, longer hospital stay, all other complications. Incidence of kidney injury as defined by RIFLE criteria: rise of serum creatinine > 100% or decrease of estimated Glomerular Filtration Rate (eGFR) with 50%.32 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 haemostatic products, length of hospital (including ICU) stay. Health status as measured with the EQ-5D-5L. Economic and healthcare costs evaluation by the institute for Medical Technology Assessment (iMTA) Medical Consumption Questionnaire(IMCQ) and iMTA Productivity Cost Questionnaire (IPCQ) and addition of out-of-pocket expenses.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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 Superior Mesenteric Artery (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:

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.
Inflammatory, mycotic or infected aneurysms.
Allergy for protamine or fish protein

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Gelre Ziekenhuizen	Apeldoorn	Gelderland	Netherlands	7334DZ
2	Rijnstate	Arnhem	Gelderland	Netherlands	6815 AD
3	Slingeland Ziekenhuis	Doetinchem	Gelderland	Netherlands	7009BL
4	AUMC Location VUmc	Amsterdam	Noord Holland	Netherlands	1081 HV
5	AUMC Location AMC	Amsterdam	Noord Holland	Netherlands	1105AZ
6	Elisabeth TweeSteden Ziekenhuis	Tilburg	Noord-Braband	Netherlands	5022 GC
7	Amphia	Breda	Noord-Brabant	Netherlands	4818 CK
8	Catharina Ziekenhuis	Eindhoven	Noord-Brabant	Netherlands	5623 EJ
9	Dijklander Ziekenhuis	Hoorn	Noord-Holland	Netherlands	1624NP
10	Medisch Spectrum Twente	Enschede	Overijssel	Netherlands	7512 KZ
11	Isala	Zwolle	Overijssel	Netherlands	8025 AB
12	Haaglanden Medisch Centrum	Den Haag	Zuid-Holland	Netherlands	2597AX
13	Groene Hart	Gouda	Zuid-Holland	Netherlands	2803 HH
14	Leiden Universitair Medisch Centrum	Leiden	Zuid-Holland	Netherlands	2333 ZA
15	Alrijne	Leiderdorp	Zuid-Holland	Netherlands	2353 GA
16	Maasstad Ziekenhuis	Rotterdam	Zuid-Holland	Netherlands	3079 DZ
17	Ziekenhuisgroep Twente	Almelo		Netherlands
18	Universitair Medisch Centrum Groningen	Groningen		Netherlands
19	St. Antonius ziekenhuis	Nieuwegein		Netherlands	3435 CM