Personalised Risk scOre For Implantation of Defibrillators in Patients With Preserved LVEF>35% and a High Risk for Sudden Cardiac Death

The objective of the study is to demonstrate that in post-MI patients with preserved LVEF\>35% but high risk for SCD according to a personalised risk score, the implantation of an ICD (index group) is superior to optimal medical therapy (control group) with respect to all-cause mortality.

Sudden cardiac death (SCD) is a major public health problem, causing \~50% of cardiac fatalities and accounting for \~20% of all deaths in Europe. Identification of patients that are at risk for SCD and would benefit from ICD implantation is challenging. A predictor for increased risk of SCD after MI is a severely impaired heart function as expressed by a reduced left ventricular ejection fraction (LVEF). Based on this and on historical landmark trials, which found improved survival in patients with severely reduced LVEF who received an ICD, current clinical guidelines recommend prophylactic ICD implantation in post-MI patients with a LVEF ≤35% to improve overall survival by prevention of SCD. The current use of LVEF as sole patient stratification tool to guide treatment decisions for ICD implantation in patients with prior coronary event, as is currently recommended by clinical guidelines and performed in clinical practice, has significant limitations and results in substantial over- and undertreatment of patients. In particular, there is conclusive evidence that the majority of SCD cases occur in patients with only moderately reduced or preserved LVEF. Thus, with current guidelines most of patients that will develop SCD are not protected by means of ICD implantation.

The objective of the study is to demonstrate that in post-MI patients with preserved LVEF\>35% but high risk for SCD according to a personalised risk score, the implanta-tion of an ICD (index group) is superior to optimal medical therapy (control group) with respect to all-cause mortality.

PROFID-Preserved is a non-commercial, investigator-driven, prospective, parallel-group, randomised, open-label, blinded outcome assessment (PROBE), multi-centre, superiority trial without dedicated investigational medical device (Proof of Strategy Trial) with two groups with 1:1 randomi-sation. It will be conducted in about 12 European countries with more than 150 clinical sites participating.

This study is an event driven trial and the number of randomised patients is estimated to be 1,440, required to collect 297 first primary outcome events within 30 months of mean follow-up.

Total study duration:

Enrolment of 30 months. All patients will be followed until 297 valid primary endpoints are reached (event-driven trial) which is expected about 15 months after last patient in. Total study duration of 47 months is expected which might be adapted based on a blinded interim analysis of the overall occurrence of the primary endpoint.

Individual study duration:

Expected median follow-up time will be about 30 months per patient with a minimum follow-up time of 15 months and a maximum follow-up time of presumably 45 months.

Eligibility Criteria:
Inclusion Criteria:

* Age ≥18 years.
* Documented history of myocardial infarction either as ST segment elevation myocardial infarction (STEMI) or as non-ST segment elevation myocardial infarction (NSTEMI).
* LVEF \> 35% at transthoracic echocardiography or cardiac magnetic resonance imaging (MRI).
* Predicted personalised annual risk of SCD according to the clinical risk calculator \>3%.
* Signed informed consent.

Exclusion Criteria:

* Class I or IIa indication for implantation of an ICD for secondary prevention of sudden cardiac death and ventricular tachycardia (according to the 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death, see Appendix V).
* Ventricular tachycardia induced in an electrophysiologic study.
* Unexplained syncope when ventricular arrhythmia is suspected as the cause of syncope.
* Conclusive clinical indication for CRT (class I or IIa indication according to the 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure)
* Carrying any implanted cardiac pacemaker, defibrillator or CRT device.
* Violation of instruction for use (IFU) of the selected ICD device by at least one of the random group treatments.
* Hospitalised with unstable heart failure with NYHA class IV within 1 month prior to enrolment.
* Acute coronary syndrome or cardiac revascularization therapy by coronary angioplasty or coronary artery bypass grafting within 3 months prior to enrolment.
* Cardiac valve surgery or percutaneous cardiac valvular intervention such as transcatheter aortic valve replacement or transcatheter mitral valve repair performed within 3 months prior to enrolment.
* On the waiting list for heart transplantation.
* Any known disease that limits life expectancy to less than 1 year.
* Participation in another clinical trial, either within the 3 months prior to enrolment or still on-going (participation in sub-studies connected to this trial is permitted).
* Previous participation in PROFID-Preserved.
* Drug abuse or clinically manifest alcohol abuse.