PROFID EHRA
PRevention Of sudden cardiac death aFter myocardial Infarction by Defibrillator im-
plantation

Patients who have survived a myocardial infarction (MI) are at increased risk
for sudden cardiac death (SCD), mostly caused by life-threatening ventricular
tachyarrhythmias such as ventricular tachycardia and ventricular fibrillation.
A severely reduced left ventricular ejection fraction (LVEF) as a rough overall
measure of impaired heart function after MI was shown to indicate a higher risk
for SCD. Based on this observation, two landmark randomised trials, MADIT II
and SCD-HeFT, were conducted between end of the 1990s and early 2000s. These
trials compared the survival of patients with severely reduced LVEF, either
after MI or due to other causes of heart failure, who received a defibrillator
with the
survival of patients being on medical therapy alone. These two trials reported
a significantly better survival of patients in the defibrillator arm and led to
international guideline recommendations for routine implantation of
defibrillators in survivors of MI with severely impaired LVEF as a means for
primary prevention of SCD. Indeed, in these trials and in other studies from
this period, therapies delivered by the defibrillators were reported in a
substantial portion of patients. Since then, the management of these patients
has changed dramatically with the advent of a series of novel drug classes that
reduce not only mortality but specifically SCD leading to a substantial
decrease of the sudden death rates as
well as of the rates of appropriate defibrillator therapies implanted for
primary prevention of SCD. At the same time, the complication rates associated
with the defibrillator therapy remain significant without obvious decrease.
Thus, there is meanwhile a whole bulk of evidence that the risk-benefit of
defibrillator implantation for primary prevention of SCD in patients with
severely reduced LVEF has substantially changed since the conduction of these
two landmark trials 20-25 years ago.
A personalised prediction of the SCD risk would be desirable, but remains not
feasible up to now and various attempts have not found their way into clinical
practice. Cardiovascular imaging or genetics seem to be promising but their
value has not been established mainly due to the relevant paucity of respective
data.

To demonstrate that in post-MI patients with symptomatic heart failure who
receive optimal medical therapy (OMT) for this condition, and with reduced LVEF
<=35%, OMT without implantable cardioverter defibrillator (ICD) implantation
(index group) is not inferior to OMT with ICD implantation (control group) with
respect to all-cause mortality within about 2.5 years of observation.
A secondary objective of the trial is to explore the potential of novel and
promising risk markers for personalised risk prediction of SCD. For this
purpose, two sub-studies will be conducted: a cardiac Magnetic Resonance
Imaging (cMRI) sub-study and a genomics sub-study, each of them in a subset of
participating study sites with adequate potential. In addition, an artificial
intelligence-based analysis of the twelve-lead Electrocardiograms (ECGs)
collected in the main study at baseline and at follow-ups will be performed.

PROFID EHRA is a non-commercial, investigator-driven, prospective,
parallel-group, randomised, open-label, blinded outcome assessment (PROBE),
multi-centre, non-inferiority trial without dedicated investigational medical
device (Proof of Strategy Trial) with two groups with 1:1 randomisation. The
randomisation to one of the treatment strategy groups is the only study
intervention, all medical treatment (drugs, devices, procedures) used within
this trial is at the discretion of the treating physicians and represent
clinical routine. It will be conducted in about 12 European countries with
about 180 clinical sites actively participating.

No investigational medical product is defined to be used within PROFID EHRA but
only the therapeutic strategy (ICD versus no ICD) is a pre-defined study
treatment and allocated by random group (Proof of Strategy Trial). The marketed
devices to be implanted will be decided by the treating physician based on the
clinical situation of the individual study patient and in line with local
policies in routine clinical care for device implantation.

see risk- benefit assessment (study protocol, 3.3)