European Ambulance Acute Coronary Syndrome Angiox Trial: EUROMAX

Randomised clinical studies have confirmed primary coronary intervention to be
the ideal therapy for patients with ST segment elevation acute coronary
syndrome. Rapid diagnosis of the clinical symptom complex, initiation of an
antithrombotic treatment based on acetylsalicylic acid, clopidogrel and
unfractioned heparin, rapid transport of the patient to a cardiac cath lab to
carry out a diagnostic coronary angiography and the subsequent therapy
depending on the diagnosis in line with current European guidelines, are
essential to ensure long-term success of the treatment. Early use of
anti-coagulants, known as thrombin inhibitors, that prevent the development and
activation of thrombin, , has been proven to be capable of preventing
thromboembolic complications, particularly with the concomitant use of platelet
aggregation inhibitors. The thrombin inhibitor bivalirudin, under the trade
name of Angiox®, is authorized throughout Europe for the treatment of patients
with acute coronary syndrome (instable angina pectoris and non-ST segment
elevation acute coronary syndrome), who are suitable for early coronary
intervention, and also as an intravenous anticoagulant during percutaneous
coronary intervention. In the HORIZONS AMI study, involving over 3,600 study
patients with ST segment elevation acute coronary syndrome, bivalirudin was
compared with a standard therapy of unfractioned heparin and GP IIa/IIIb
inhibitors and was shown to be safe with the same level of efficacy (p=0.006
for "net adverse clinical outcomes"). In this EUROMAX study, the efficacy and
safety of early administration of bivalirudin is to be tested, starting while
the patient with ST segment elevation acute coronary syndrome is transferred to
the cardiac cath lab. The study objective is to test if early administration of
bivalirudin in patients with ST segment elevation acute coronary syndrome
results in a better 30 day treatment outcome than the current standard therapy
of unfractioned heparin with or without a GP IIa/IIIb inhibitor. EUROMAX is a
European, multi-centre, multi-national, prospective, randomised, open-label,
phase IIB study, with a planned study population of 3680.

The purpose of the trial is to show that the early administration of
bivalirudin improves 30 day outcomes when compared to the current standard of
care in patients with STE-ACS, with an onset of symptoms of >20 minutes and <12
hours, intended for a primary PCI management strategy, presenting either via
ambulance or to centres where PCI is not performed.

Multi-centre, multi-national, prospective, randomised, open-label, comparison
of bivalirudin to other guideline based current therapies (excluding
bivalirudin).

Patients who have had symptoms of an ST segment elevation acute coronary
syndrome for more than 20 minutes within the last 12 hours, who are to be
transferred to a suitably equipped clinic for primary coronary intervention,
are informed about the study and once they have given their written consent are
randomized in a ratio of 1:1 into either the treatment with bivalirudin or the
corresponding standard therapy.

All patients also receive acetylsalicylic acid for at least one year and a
P2Y12 receptor blocker in accordance with standard clinical practice. The
treatment with bivalirudin is continued during the diagnostic coronary
angiography and, if primary coronary intervention is required, up to 4 hours
after the end of the procedure. If no coronary intervention is carried out, the
Bivalirudin administration is continued at a low dose for up to 72 hours, at
the study investigator's discretion. The dose and treatment term in the
standard therapy control arm correspond to the routine requirements in line
with European guidelines. The patients otherwise receive the standard therapy
for the treatment of an ST segment elevation acute coronary syndrome. If a
patient meets the study inclusion criteria, the study will be explained to him
in the ambulance or the primary hospital and he will be asked to sign the
written informed consent declaration. The patients are then randomized and will
receive the assigned study medication. On arrival in the cardiac cath lab the
diagnostic coronary angiography and if necessary in the same session the
coronary intervention can be carried out as planned, according to standard
clinic routine. Participation in the study will not extend the patient's
in-patient hospital stay. All patients are regularly clinically monitored
during their stay in the clinic. Further follow-up check-ups are carried out
after 30 days and after one year.
In the context of this study a total of 75 ml at 5 timepoints are drawn from
each patient.

Angiox® has been used in over two million patients to date. It is, however,
possible that not all side effects and risks of Angiox® have been investigated.
One common side effect of the treatment with bivalirudin (occurring in more
than 1 in 10 patients) is bleeding; this can occur anywhere in the body and can
cause the following complications: anaemia (low red blood cell count),
haematoma (a collection of blood outside the vessels), bleeding and bruising at
the injection site and a lower platelet count (thrombocytopenia). Blood
coagulation can also be affected. In rare cases (in fewer than one in 1,000
patients) bleeding can lead to death or to irreversible disability. The risk of
bleeding is increased if Angiox® is used concomitantly with other blood
thinning drugs, and in some 3% of cases (3 in 100 patients) blood or blood
product transfusion are required. One common undesirable event (occurring in
one to ten in 100 patients) is the formation of a blood clot (thrombosis), that
can lead to severe or fatal complications, such as a heart attack. An allergic
reaction to Angiox® is also possible. This can manifest in the form of a rash
(hives), itching all over the body or shortness of breath. These are rare side
effects (one in 1,000 to one in 100 patients) that can be very serious or even
fatal. These include headache, change in blood pressure, change in the heart
rate, nausea and/or vomiting, backache, thoracic pain, shortness of breath,
rash. The most common side effect in the control arm of the study with the use
of heparin is bleeding. This can be at the injection site, in the stool, in the
urine or any other part of the body. Another possible side effect is the
tendency to haematomas. Bleeding in the brain and heparin-induced
thrombocytopenia (fall in the blood platelet count) have also been observed. At
the sites where blood is taken pain, burning, swelling, bleeding, blood clots,
pallor and rarely inflammation or nerve damage can occur. Overall, no more than
75 ml of blood will be drawn from each patient during the course of the study.
Pregnant or breastfeeding women are not allowed to take part in the study. As
with any medication rare, previously unobserved side effects can occur. The
patient is monitored for side effects, and given the appropriate treatment if
problems arise. It is also necessary for the patient to inform the study
investigator about any health problems or health impairment or if he is feeling
generally unwell or there is a change in the treatment during the trial, even
if it does not appear to be likely that it is connected to receiving the study
preparation. The study doctor will decide on suitable measures to take. An
independent expert group will also constantly monitor the safety of the study
and side effects of the study medication during study participation and for the
entire study duration. It is possible that early administration of Angiox®
(bivalirudin) can inhibit bleeding more safely and with better patient
tolerance than heparin. While it cannot be guaranteed that the patient will
benefit from taking part in this study, the experience gained may be very
beneficial for future patients with a heart attack.