The risk-benefit of routine defibrillator implantation for primary prevention of sudden cardiac death (SCD) in patients with severely reduced left ventricular ejection fraction (LVEF) has substantially changed. Due to the inherent risks and considerable costs of the defibrillator, a novel randomised adequately powered assessment of the potential benefit or harm of the defibrillator in survivors of myocardial infarction (MI) with reduced LVEF under contemporary optimal medical therapy (OMT) is urgently needed. The PROFID trial aims to reassess the role of routine prophylactic ICD implantation in patients with reduced LVEF ≤ 35% after myocardial infarction under contemporary OMT and is designed to be as close to routine clinical care as possible. The start of the PROFID clinical trial is a huge milestone.

Gerhard, can you give us a short update on the PROFID trial?

Gerhard Hindricks: “Based on the findings of the extensive PROFID data analysis, we adjusted the design of the PROFID trial programme and we are now focusing on one trial, the PROFID trial, in order to address existing outdated data which do no longer represent current therapies. During the last months we have extensively prepared the start of the PROFID trial and we expect first-patient-in in summer 2023.”

Thomas, what have been your main tasks and achievements during the last six months?

Thomas Fetsch: “During the last six months, the main tasks focussed on updating the study documents for the adapted PROFID trial and planning the two additional sub-studies “cMRI” and “Genomics”. In addition, extensive site management is still underway to contract at least 180 actively participating study sites necessary to enrol around 3,600 patients. Study sites which already agreed participation in the two previously planned trials had to be contacted again and informed about the adapted study design, but additional study sites in other European countries were meanwhile invited to participate. We also carefully created necessary documents and argumentation lines reaching out for ethics approval. A non-inferiority trial like PROFID always raises ethical and statistical questions. Therefore, we are proud to report the first approvals by major Ethics Committees in Spain and Germany as the most important successes so far.”

Philipp, you are the national coordinator for the PROFID trial in Germany. What are your responsibilities and expectations?

Philipp Sommer: “We expect Germany to be one of the strongest contributors to this study. I will take care of connecting the centers with CRI, the Clinical Research Organisation of PROFID, and be available for all kind of concerns – including questions on inclusion and exclusion criteria, follow-up and AE/SAE (adverse events/ serious adverse events). Furthermore I will try to motivate centers in their screening and inclusion activities to complete enrolment of this really important study as soon as possible.”

Gerhard, what is the biggest challenge during the PROFID trial?

Gerhard Hindricks: “We are facing very tight timelines. Therefore the support of each country and every study site participating in the PROFID trial is very important and highly appreciated, as substantial recruitment rates per site and month will be constantly needed throughout the trial.”

The PROFID trial is comparing treatment of ICD implantation and optimal medical therapy (OMT) with treatment with OMT only. How is OMT defined?

Thomas Fetsch: “All study patients present with a history of MI, symptomatic heart failure and significantly reduced LVEF, thus, all study patients require OMT as baseline treatment regardless of random group allocation. It is essential that the study sites follow corresponding medical guidelines for OMT such as the 2021 ESC guidelines for heart failure and the 2019 ESC guidelines for chronic coronary syndromes. Consequently, OMT varies individually depending on each patient’s clinical status and cannot be defined universally.”

The PROFID trial, like any clinical trial, will include patients selected according to inclusion and exclusion criteria. To what extent will the study results be generalisable?

Gerhard Hindricks: “The inclusion and exclusion criteria of the study are actually broad and reflect very well the population seen in clinical practice, so that no significant patient groups are excluded. Therefore, I don’t expect any substantial deviation of the study population from the target population in routine clinical care. A clear aim of PROFID is maximal generalizability of study results.”

The PROFID data analysis did not lead to a risk prediction model as originally planned. Do you have any plans in order to keep AI and personalised risk prediction in the PROFID project?

Gerhard Hindricks: “Yes, indeed. The PROFID trial as a very large randomized trial offers a unique opportunity to address this issue. We plan to explore the potential of novel and promising risk markers for personalised risk prediction of sudden cardiac death. For this purpose and as Thomas already mentioned, we are currently working on the set up of two optional sub-studies, a cardiac Magnetic Resonance Imaging sub-study and a sub-study on Genomics. In addition, we will perform an artificial intelligence-based analysis of the twelve-lead ECGs. Furthermore, our great partners of WP5, responsible for the health economic analysis, and WP6, responsible for the examination of ethical and legal aspects of personalised ICD implantation, continue their research about personalised risk predictions.”

Philipp, what is in your opinion most important in order to run the PROFID trial successfully in Germany? What kind of support do you need?

Philipp Sommer: First, overcoming the concerns by some cardiologists will be key. We have to realize that 1) we are no longer living in times of MADIT II enrolment and 2) we can actively harm patients with implantation of ICD. Having these two major points in mind it should be very clear that we need to redo the studies from the last century in order to avoid overtreatment in the future and to respect the limited resources of our health care system. PROFID will answer the question if still today patients need to be protected for SCD only because of impaired left ventricular function.”

Gerhard, what are the next steps in the PROFID project?

Gerhard Hindricks: “It is crucial that the PROFID trial starts as soon as possible in all 13 participating countries in order to enrol almost 3,600 patients and we also need to focus on the finalisation of the  set-up of the optional sub-studies. Therefore, all our efforts are currently focusing on starting the trial in all participating countries.”