Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter Defibrillators in Europe

An estimated 500.000 sudden cardiac deaths (SCD) occur in the European Union
(EU) annually. Most SCDs are caused by malignant ventricular arrhythmias, which
are life threatening especially for patients with cardiovascular diseases.
Patients who have survived a severe arrhythmic cardiac event unequivocally
receive treatment with an ICD today (so-called secondary prevention). Other
patients may not yet have had a life-threatening event but have an increased
risk of future malignant ventricular arrhythmias due to markedly reduced left
ventricular (LV) function. According to two clinical trials, both published
about 10 years ago, patients with an increased risk of malignant ventricular
arrhythmias had a 31% and 23% survival benefit, respectively, if
prophylactically implanted with an ICD (so-called primary prevention). Based on
these two trials, implantation of an ICD device for primary prevention has
become an integral part of international guidelines and is widely used in
clinical routine. Today, an estimated > 100.000 ICDs are implanted in the EU
annually with device costs alone exceeding ¤2 billion. Implantation rates,
however, vary significantly between EU regions, reflecting considerable
socio-economic and health-care inequality across the EU. In addition, experts
disagree increasingly regarding the validity of the decade-old trial results as
the basis for current medical practice. The reasons of this dissent are
manifold:

(1) Randomised trials have shown no survival benefit from primary ICD
prophylaxis.
(2) ICD candidates today exhibit lower rates of malignant arrhythmias and have
better outcome without an ICD than the patients included in the seminal trials
10 years ago, most probably due to improvements in pharmacological and other
non-ICD therapy.
(3) Less than one third of patients with a prophylactically implanted ICD
device ever receive an appropriate shock from their device. The risk of death
due to non-arrhythmic cause may presently outweigh the risk of death due to
arrhythmia in these patients.
(4) Not every appropriate shock prevents SCD. Presumably less than 50% of
appropriate shocks are truly life-saving.
(5) ICDs themselves may increase mortality by yet unidentified effects.
(6) Harm and side-effects of ICD treatment may have been underestimated in
women.

To increase the effectiveness of prophylactic ICD implantation, expert
consensus demands more accurate strategies for the selection of candidate
patients. Randomised prospective trials on ICD therapy are not an option for
ethical reasons. As implantation rates depend on medical decisions as well as
on a country*s economic background, cost-effectiveness of ICD therapy has been
assessed in Markov models, however, these models are subject to variability
from the input parameters.

-To characterise total mortality risk in a prospective patient cohort of ICD
candidates newly implanted for primary prophylaxis of malignant ventricular
arrhythmias, compared to a non-randomised control group not implanted for
primary prophylaxis.
-To determine prespecified clinical baseline characteristics (confounding
variables) contributing to the risk of the primary endpoints
-To assess simple and cost-effective electrocardiographic noninvasive risk
stratification techniques
-To define subgroups within the cohort with a lower or higher benefit from ICD
treatment
-To perform blood-sampling from each patient for analyses of biomarkers and
genetic-information
-To provide outcome data as a basis for extensive health economic evaluation of
ICD use including subgroups and country-specific differences

This prospective study is open, observational, non-invasive,
non-interventional, outpatient, non-randomised, multi-centre, multi-national
and includes one blood sampling per patient for later genetic testing. No
therapeutic intervention is performed. No medicinal products, medical devices
or drug substances are tested.
The study includes patients who are eligible for primary prophylactic ICD
device implantation, whether they receive an ICD device or not. Patients who do
receive an ICD device will be followed as part of the ICD Group, while patients
who do not receive an ICD device will be followed as part of the Control Group.

Study participation includes a few additional diagnostic tests, which are part
of standard diagnostics in other patients with heart diseases and bear no
health risk. Blood sampling from one of your veins bears the risk of developing
a haematoma (bruise). The bruise can hurt for a few days but does not require
treatment, except in very rare cases. A theoretical residual risk remains of
vessel- and nerve damage or infection through the transmission of germs,
although this risk does not play a role in practical everyday life.