Preserved platelet function during cardiopulmonary bypass with aprotinin in dual antiplatelet therapy.

Dual antiplatelet therapy (DAPT), the combination of aspirin with clopidogrel,
has been shown to reduce ischaemic complications in patients presenting with
acute coronary syndrome (ACS). 1 ACS patients are often treated with urgent or
acute angiography, followed by percutaneous coronary intervention (PCI) or
coronary artery bypass grafting (CABG). In these patients, long-term
clopidogrel + aspirin therapy significantly reduces the risk of adverse
ischaemic events. 2 Although the preoperative use of aspirin alone does not
affect postoperative bleeding, its use in combination with clopidogrel can be
responsible for increased postoperative bleeding, blood products requirement,
and need for surgical re-exploration, which in turn may cause a further range
of complications. 3,4 Patients undergoing cardiac surgical procedures remain at
significant risk of major bleeding and exposure to blood products. Severe
bleeding and the need for perioperative transfusion are associated with worse
outcomes. Therefore, several blood-sparing strategies showed important decrease
in transfusion need of allogenic blood products and have been implemented in
addition of prophylactic use of antifibrinolytic agents. 4,5
However, DAPT has drawbacks as patients are prone to bleeding, especially if
urgent or acute cardiac surgery is required. It has been confirmed that
clopidogrel, in combination with aspirin before CABG, is associated with higher
postoperative bleeding and blood product use. 6
The 2015 ESC Guidelines for the management of acute coronary syndromes in
patients presenting without persistent ST-segment elevation recommend that in
patients without signs of recurrent or ongoing ischaemia, CABG should be
delayed for 5 days following interruption of ticagrelor or clopidogrel therapy
and 7 days following interruption of prasugrel therapy. Aspirin should be
continued through surgery except in patients with markedly increased bleeding
risk (e.g. redo CABG or complex combined procedures) or in patients who refuse
blood transfusion; in such patients it may be advisable to stop aspirin 3-5
days preoperatively. 7
The recent joined EACTA-EACTS guidelines recommend to stop DAPT therapy > 5
days before cardiac surgery and the use of antifibrinolytics tranexamic acid
and aprotinin during surgical procedure. 8
Aprotinin has shown to decrease bleeding and the need for transfusion in
patients undergoing CABG surgery who continued the use of combined clopidogrel
and aspirin within 5 days before surgery. 9-11 A recent prospective study,
however, confirmed that, despite the prophylactic use of tranexamic acid,
bleeding was increased by 22% in clopidogrel treated patients. 12
Therefore, aprotinin may be preferred over TXA in DAPT treated patients, and
recent publications mention DAPT treated patients as target group for the use
of aprotinin. 11,13,14
On the other hand, surgical techniques and Patient Blood Management procedures
have changed in the past decade. Therefore, the additional benefit of aprotinin
over tranexamic acid could be debated.

The risk of bleeding during cardiac surgery depends on the combination of the
type of surgical intervention on one hand, and the patient profile on the other
hand.
Clinical studies and expert opinion mention patient related independent risk
factors like preoperative anemia (Hb< 6mmol/L), low platelet count (<125.000
/mm³), acquired platelet dysfunction (mainly DAPT less then 5 days before
surgery), inherited or acquired coagulopathies, female gender, age > 70y and
low body weight. Other co-morbidities could include Hypertension, Diabetes
mellitus, peripheral vascular disease, renal insufficiency, Asthma, COPD,
unstable angina and myocardial infarction (MI).9-15
Meybohm et al published a risk stratification, based on surgical procedure,
defined as low risk (predominantly isolated coronary artery bypass graft (CABG)
or single valve surgery), medium risk (combined cardiac surgery, e.g. CABG with
valve surgery) and high risk (complex surgery, e.g. redo sternotomy, multiple
valve surgery, surgery of ascending aorta or aortic arch, or emergency
surgery). 16 Also prolonged CPB time and deep hypothermia are recognized as
surgical high risk factors. 17
The goal of this pilot study is to verify the effect size of a study
investigating the use of aprotinin versus the actual systematic use of
tranexamic acid in patients, at dual anti-platelet therapy (high risk of
bleeding), undergoing on-pump non-complex cardiac surgery (CABG or single
valve) with low risk of bleeding, in a single center prospective cohort.

Primary objective
To determine whether aprotinin can reverse the increased postoperative blood
loss, induced by dual anti-platelet therapy in elective non-complex cardiac
surgery.

Secondary objective
To determine whether aprotinin reduces transfusion of allogenic blood products
in patients on dual antiplatelet therapy undergoing simple cardiac surgery and
to determine whether its use is safe and well-tolerated.

This phase II study is a single-center, investigator initiated, randomized,
single-blind controlled study. This study will be conducted in subjects who are
undergoing elective complex cardiac surgery. Simple cardiac surgery is defined
as CABG or single valve surgery. This study will be performed at a single
center in Zwolle, the Netherlands, by the departments of Cardiothoracic Surgery
and Cardiothoracic Anesthesia and Intensive Care. The study comprises an
intervention group of 29 subjects and a control group of 29 subjects totalling
58 study subjects. Recruitment should require approximately 9 months for the 58
subjects to be enrolled in the study. Baseline examination (including signing
of the Informed Consent Document (ICD)) of potential subjects will begin in
March 2020 and the data of the last included patient should be completed
including follow-up at the end of March 2021 (12 months). Including analysis of
the results, the study duration will be approximately 12 months.
Observation of each individual subject will include detailed evaluation from
the day of baseline examination (Day *3 to *1) to 30 days post-surgery for
SF-36, EuroQoL and SAE recordings. Data for the primary efficacy endpoint will
be collected within 24 hours of administration of study medication.

6.1 Description of study medication
Aprotinin.
Aprotinine is classified as an antihaemorragic drug subclass, protease
inhibitor, ATC-code B02AB01.

Aprotinin is a non-specific serine protease inhibitor with antifibrinolytic
properties. By forming reversible stoichiometric enzyme inhibitor complexes
aprotinin inhibits human trypsin, plasmin, plasmakallikrein. Aprotinin has a
wider therapeutic range compared to tranexamic acid because, besides preventing
of formation of plasmin by blocking tPA (tissue plasminogen activator), it also
inhibits plasmin directly.
Additionally, aprotinine has beneficial effects when using cardiopulmonaire
bypass (CPB), by low intrinsic anticoagulation (inhibition of trombin and
thrombin generation by tissuefactor), anti-inflammatory action, reduction of
pulmonary and cardiac oxidative stress and the protection against inactivation
of platelets, preserving platelet function.

6.2 Summary of findings from clinical studies
Several studies have described the effect of aprotinin compared to tranexamic
acid. The estimated effect size in the reduction of postoperative blood loss
from a few studies is represented in table 1 (see protocol)


There have been 2 studies describing the effect of aprotinin in dual
anti-platelet therapy.9,10 However, these studies were placebo controlled and
did not have tranexamic acid in the control group.
A recent meta-analysis compared the safety of aprotinin with tranexamic acid
and amino-caproic acid.18 The findings of this analysis are summarized in
figure 1.( see protocol)

6.3 Description of route of administration
Aprotinin is administered intravenously, and in the reservoir of the
extracorporeal circuit. The estimated extra volume should be taken into account
and be corrected for, with regard to total volume balance.

6.4 Description of dosage
After a test dose of 10,000 KIU the remaining loading dose is administered, a
total of 1 milj. KIU. Following this loading dose, a continued infusion is
given, 250,000 KIU hourly. An additional 1 milj KIU is added to the priming
solution of the extracorporeal circuit.

6.5 Preparation and labelling
Aprotinin is stored at room temperature. Under sterile conditions, aprotinin is
either administered directly from the vials as a loading dose (intravenously or
pump priming solution), or transferred into a sterile 50ml syringe, for
continuous infusion.

1. There is no extra time burden. Participants complete the same questionaires
as other patients.
2. After induction of Anesthesia, 5 ml of blood will be drawn for the verify
now test. This is not a routine test and therefore an extra burden.
3. Participants are at risk for side effects of the study medication. These are
listed under "Intervention".
4. Patiënts receiving aprotinine have an increased risk on myocardial
infarction compared to the standard therapy.