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

Vascular disease, both occlusive and dilating, is a major contributor to
mortality and morbidity, also in The Netherlands. Techniques in both open
surgery and endovascular treatments have been refined over the past decades,
but at present are still associated with mortality and high rates of
complications and morbidity. Unfractionated heparin (UFH) is used by all
vascular surgeons worldwide during open and endovascular non-cardiac arterial
procedures (NCAP) since more than 70 years. UFH is used as a periprocedural
prophylactic antithrombotic to reduce the clotting of blood and thereby
preventing arterial thrombo-embolic complications, such as myocardial
infarction, stroke, bowel-ischemia and peripheral embolic events in
extremities. The use of heparin also has a major clinical disadvantage: the
prolonged clotting of blood may increase blood loss, lengthens time needed for
haemostasis and may cause an increase in bleeding complications. The severity
of bleeding complications can be mild such as a hematoma or pain, but may
sometimes require blood transfusions or even surgical (re-)exploration in case
of extensive and even life-threatening bleeding.
Because of the fine line between thrombosis and bleeding, vascular
interventions require precise technique and an accurate level of coagulation.
Another major disadvantage of the use of heparin as a periprocedural
prophylactic antithrombotic is the fact that heparin has a unpredictable effect
in individual patients. The molecular structure of heparin causes a variety of
its effect, creating not only a difference in efficacy between different
brands, but even between batches of the same brand. The above described
characteristics of heparin result in an unpredictable effect as an
antithrombotic in the individual patient, possibly being harmful.
In Europe, UK, and in a substantial part of the USA and the rest of the world,
heparin is administered as a standardized bolus in every patient undergoing
NCAP. Most used dosage is 5.000 IU, irrespective of sex, bodyweight, type of
procedure or duration of procedure.
In all cardiac interventions, open or endovascular and using cardio-pulmonary
bypass or not, the effect of heparin is measured routinely in every patient
worldwide. Abundant literature has 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. This results in better patient
related outcomes. Surprisingly vascular surgeons have not adopted this
measurement of the ACT during NCAP.
A study group, Consensus on Arterial Peri-Procedural Anticoagulation (CAPPA),
was formed in the Netherlands to create consensus on periprocedural
anticoagulation during non-cardiac procedures. After surveys and two published
systematic reviews, this group concluded that ACT measurement in NCAP is to be
preferred and should be introduced in daily practice. This to ensure the
individual patient of safe, tailor-made periprocedural anticoagulation. This
should lead to better results of procedures with improved patient related
outcomes and less harm for the patient.
In a consortium of 5 large training hospitals (university and teaching
hospitals) we initiated a study to evaluate the feasibility and safety of
measuring the ACT during NCAP (MANCO, NTR nr. 6973, ClinicalTrials.gov
M016-045). The infrastructure of research in these 5 hospitals proved to be
effective.
Results of more than 500 patients show that ACT measurements can be introduced
safely and adequately in daily routine in the operation room during open and
endovascular procedures. Evaluation of these data resulted in a safe and
adequate protocol to ensure patient of optimal, ACT guided heparinization
during NCAP. A goal ACT of 200-220 seconds is considered to be optimal.
Literature from mainly cardiac interventions, indicated that a fixed value of
250-300 seconds is safe. At higher ACT values more bleeding complications were
recorded. In our 500+ patients the individual base ACT value was: mean 132 sec
(+/- 16).
Next step will be to conduct a large (inter)national 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 aneurysm (AAA) surgery DSAA classification C:
aneurysm originating below the Superior Mesenteric Artery. DSAA being the Dutch
Surgical Aneurysm Audit, a Dutch registration which is mandatory for all Dutch
vascular surgeons for treated patients with an AAA. These procedures include
standardized care regarding indication, techniques and periprocedural care. The
hiatus of sound evidence on periprocedural anticoagulation and heparinization
during NCAP has been prioritized by the Dutch Board of Surgery, the Board of
Vascular Surgery, and by the Federation of Medical Specialists. These boards
have granted their full cooperation, also to expand the already existing
infrastructure of this research. The intended study will be used to create an
infrastructure and consortium of 20+ major vascular surgical centers in the
Netherlands for research. Supported by the Dutch Board of Vascular Surgery and
initiated by the already existing collaboration between the mentioned 5 large
hospitals, this will secure implementation of major clinical trials in the near
future. Part of the grant from ZonMw will be used for the founding and securing
of this infrastructure.

Primary Objective: To establish that ACT guided heparinization results in safe
and optimal anticoagulation during open AAA repair. We hypothesize that ACT
guided heparinization will result in a decrease of thrombo-embolic
complications, without a significant increase in bleeding complications when
compared to the use of standardized bolus of 5 000 IU. with one ACT-measurement
at the end of the procedure. The decrease in thrombo-embolic complications will
lead to less mortality and morbidity, lower number of re-operations or better
patency, all substantially improving patient*s quality of health, efficiency of
medical care and quality of vascular medical care. Results will be implemented
in guidelines in the Netherlands and Europe for vascular surgeons and promoted
worldwide.

Secondary Objective(s): NA

(Inter)national multi-centre RCT, reported according to CONSORT 2010 statement.
Patients will be blinded for the allocated treatment. Patients will be
randomized using a computerized program (CASTOR EDC) with a random block size
2, 4, 6. The randomization will be stratified by participating centre. Analysis
will be performed by intention to treat principle. A separate analysis per
protocol will also be performed as a sensitivity analysis. 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.

ACT guided heparinisation during open abdominal aortic aneurysm surgery

Benefits for participating is that there could be a reduction in
thrombo-embolic complications and mortality when the ACT is measured.

Risks could be that the ACT guided heparinization could lead to more bleeding
complications. The ACT of 200-220 seconds and the use of protamine is proven to
be safe.

Measurements
Extra blood samples will be drawn, under general anaesthetic, from an arterial
line in the wrist. This arterial line is part of standard procedure for this
type of surgery and is of no extra burden in the ACT guided group.
In total a maximum of 48 ml of extra blood will be drawn. This amount does not
cause problems in adults.
In patients in the non-ACT arm, one ACT measurement will be performed just
before the end of the surgery (max. 5 ml).

Participation also involves:
- complete 5 short questionnaires; pre-operative, 1 and 4 weeks, 3 and 6 months
after surgery.
- complete longer questionnaires; one at 3 months and two at 6 months after
surgery.
- patient will be called between 30-35 days (max. duration time 5 minutes), to
evaluate complications after discharge.