Periodic Reporting for period 3 - PROFID (Implementation of personalised risk prediction and prevention of sudden cardiac death after myocardial infarction)
Reporting period: 2023-01-01 to 2024-06-30
The risk-benefit of routine defibrillator implantation for primary prevention of sudden cardiac death (SCD) in post myocardial infarction (MI) patients with reduced left ventricular ejection fraction (LVEF) has substantially changed since the conduction of landmark trials that established this therapy. 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 MI with reduced LVEF under contemporary optimal medical treatment (OMT) appears imperative. Additionally, a personalised approach is highly desired.
The major objectives of PROFID amongst others are:
-Re-evaluate in a randomised trial the current clinical practice of routine prophylactic cardioverter-defibrillator (ICD) implantation for primary prevention of SCD in the setting of contemporary OMT in patients who have survived an MI.
-Assess by AI techniques the predictive role of novel risk markers for SCD with the aim of a personalised risk stratification
-Address ethical and legal aspects, including patients’ perspective on randomised therapy strategies for SCD prevention;
-Evaluate the economic impact to guide treatment decisions in this patient population;
-Update corresponding European clinical guidelines on SCD prevention and ICD implantation.
The major objectives of PROFID amongst others are:
-Re-evaluate in a randomised trial the current clinical practice of routine prophylactic cardioverter-defibrillator (ICD) implantation for primary prevention of SCD in the setting of contemporary OMT in patients who have survived an MI.
-Assess by AI techniques the predictive role of novel risk markers for SCD with the aim of a personalised risk stratification
-Address ethical and legal aspects, including patients’ perspective on randomised therapy strategies for SCD prevention;
-Evaluate the economic impact to guide treatment decisions in this patient population;
-Update corresponding European clinical guidelines on SCD prevention and ICD implantation.
The PROFID team developed and validated a Clinical Prediction Model for predicting the SCD risk of individuals with previous MI with the aim to assess the expected benefit of ICD implantation for SCD prevention across the whole range of LVEF (WP1). The primary finding of this analysis was that consideration of a large number and variety of clinical parameters collected during routine care showed a poor predictive performance for the risk of SCD in patients with previous MI or ischemic cardiomyopathy with reduced LVEF <50%. CMR imaging did also not improve risk prediction for SCD after myocardial infarction in the largest pooled patient cohort collected to date. Based on these results, the trial design was adapted accordingly. The PROFID EHRA trial investigates whether in post-MI patients with symptomatic heart failure and reduced LVEF ≤35% who receive OMT, OMT without ICD implantation is not inferior to OMT with ICD implantation with respect to all-cause mortality. More than 600 hospitals in 12 countries in Europe were classified as potentially eligible for study participation and key opinion leader-physicians in these countries were nominated.
Since 2023, the main focus was on the start and implementation of the PROFID EHRA clinical trial (WP2/WP3), including ethics committee submissions; identification, contracting and preparation of study sites as well as activating study sites for patient enrolment, which started in November 2023. Until June 2024, ethics committee approvals have been obtained in 7 European countries and 24 study sites are open for recruitment. The predictive role of novel SCD risk markers will be prospectively assessed by AI analysis of the 12-lead electrocardiogram and by use of AI techniques in two optional PROFID EHRA sub studies, focusing on genomics and cardiac MRI.
The clinical trial has been renamed from “PROFID” to "PROFID EHRA" in 2023 to emphasise the close collaboration with and the strong support of the European Heart Rhythm Association (EHRA). Furthermore, since 1 January 2024, Charité - Universitätsmedizin Berlin has taken over the role of project coordinator and sponsor of the clinical study.
As part of the health economic analysis (WP5), the national health technology assessment organizations and their respective manuals for the countries participating in the PROFID EHRA trial have been compared. A budget impact analysis, which aims to assess whether the introduction of the “PROFID approach” leads to cost changes for the healthcare system in each participating country, is ongoing. The health economics protocol for the PROFID EHRA trial was finalized.
Ethical guidance on consent and related issues (WP6) is of major importance. A “Report on ethical and legal aspects of personal medicine, AI and machine learning” was written, which presents results regarding trust in health data research. A guidance document addressing novel ethical issues and a manuscript on non-inferiority trials' ethics was prepared as well. For setting up the planned PROFID EHRA Incidental Findings Committee, an associated charter was prepared. In addition, an interview study on patient views regarding AI's potential impact on decision-making and patient care was conducted.
The work performed within WP7 has been pivotal in further advancing the international recognition of the PROFID project and especially the PROFID EHRA trial, through intense and various strategic promotion and dissemination efforts. Outstanding visibility was achieved at all EHRA and ESC Congresses held since the start of the project, as well as numerous further national and international congresses and events.
The results of WP1 are reported in a manuscript that was accepted for publication in a leading Cardiology journal.
Since 2023, the main focus was on the start and implementation of the PROFID EHRA clinical trial (WP2/WP3), including ethics committee submissions; identification, contracting and preparation of study sites as well as activating study sites for patient enrolment, which started in November 2023. Until June 2024, ethics committee approvals have been obtained in 7 European countries and 24 study sites are open for recruitment. The predictive role of novel SCD risk markers will be prospectively assessed by AI analysis of the 12-lead electrocardiogram and by use of AI techniques in two optional PROFID EHRA sub studies, focusing on genomics and cardiac MRI.
The clinical trial has been renamed from “PROFID” to "PROFID EHRA" in 2023 to emphasise the close collaboration with and the strong support of the European Heart Rhythm Association (EHRA). Furthermore, since 1 January 2024, Charité - Universitätsmedizin Berlin has taken over the role of project coordinator and sponsor of the clinical study.
As part of the health economic analysis (WP5), the national health technology assessment organizations and their respective manuals for the countries participating in the PROFID EHRA trial have been compared. A budget impact analysis, which aims to assess whether the introduction of the “PROFID approach” leads to cost changes for the healthcare system in each participating country, is ongoing. The health economics protocol for the PROFID EHRA trial was finalized.
Ethical guidance on consent and related issues (WP6) is of major importance. A “Report on ethical and legal aspects of personal medicine, AI and machine learning” was written, which presents results regarding trust in health data research. A guidance document addressing novel ethical issues and a manuscript on non-inferiority trials' ethics was prepared as well. For setting up the planned PROFID EHRA Incidental Findings Committee, an associated charter was prepared. In addition, an interview study on patient views regarding AI's potential impact on decision-making and patient care was conducted.
The work performed within WP7 has been pivotal in further advancing the international recognition of the PROFID project and especially the PROFID EHRA trial, through intense and various strategic promotion and dissemination efforts. Outstanding visibility was achieved at all EHRA and ESC Congresses held since the start of the project, as well as numerous further national and international congresses and events.
The results of WP1 are reported in a manuscript that was accepted for publication in a leading Cardiology journal.
Expected results until the end of the project
The PROFID project is expected to change the daily clinical practice of SCD prevention. The risk-benefit assessment of defibrillator therapy has most likely changed dramatically. No randomised comparisons between OMT and defibrillator therapy on top of contemporary OMT after MI were conducted in the last 20 years. Thus, successful completion of the PROFID EHRA trial will ensure that a large group of patients does not have to unnecessarily undergo an invasive and costly ICD implantation procedure. Furthermore, valuable insight into the predictive role of novel risk markers will be gained without all inherent limitations of retrospective analyses. This may allow a personalised SCD risk stratification in the future.
Socio-economic impact and patients' perspective
It is estimated that approx. 45,000 defibrillator implantations for primary prevention of SCD after MI are performed annually in the European Union with estimated associated costs exceeding 500 million €. The data that will be generated across several European countries will facilitate the evidence-based decision making approach for prevention of SCD by ICD implantation for post-MI patients with a LVEF ≤35%. It is expected, that with successful completion of the PROFID EHRA trial, a large group of patients will no longer have to undergo the invasive and costly procedure of ICD implantation, which is associated with a considerable complication risk, leading to overall increased population health. If this is the case, it can be expected that a more nuanced treatment policy would result both in no additional financial burden (and very possibly significant savings) for healthcare systems across Europe and increased population health outcomes (through the efficient reallocation of the budget for the currently inefficiently implemented ICD implantation). The prospective assessment of novel risk markers may allow a more personalised approach.
Patients' perspective is essential and will be assessed with different approaches. This knowledge can be used to improve research and treatment processes according to the interests and preferences of patients, will support the investigation of ethical and legal issues and result in creating an acceptable ethical framework for an adapted approach to ICD implantation.
The PROFID project is expected to change the daily clinical practice of SCD prevention. The risk-benefit assessment of defibrillator therapy has most likely changed dramatically. No randomised comparisons between OMT and defibrillator therapy on top of contemporary OMT after MI were conducted in the last 20 years. Thus, successful completion of the PROFID EHRA trial will ensure that a large group of patients does not have to unnecessarily undergo an invasive and costly ICD implantation procedure. Furthermore, valuable insight into the predictive role of novel risk markers will be gained without all inherent limitations of retrospective analyses. This may allow a personalised SCD risk stratification in the future.
Socio-economic impact and patients' perspective
It is estimated that approx. 45,000 defibrillator implantations for primary prevention of SCD after MI are performed annually in the European Union with estimated associated costs exceeding 500 million €. The data that will be generated across several European countries will facilitate the evidence-based decision making approach for prevention of SCD by ICD implantation for post-MI patients with a LVEF ≤35%. It is expected, that with successful completion of the PROFID EHRA trial, a large group of patients will no longer have to undergo the invasive and costly procedure of ICD implantation, which is associated with a considerable complication risk, leading to overall increased population health. If this is the case, it can be expected that a more nuanced treatment policy would result both in no additional financial burden (and very possibly significant savings) for healthcare systems across Europe and increased population health outcomes (through the efficient reallocation of the budget for the currently inefficiently implemented ICD implantation). The prospective assessment of novel risk markers may allow a more personalised approach.
Patients' perspective is essential and will be assessed with different approaches. This knowledge can be used to improve research and treatment processes according to the interests and preferences of patients, will support the investigation of ethical and legal issues and result in creating an acceptable ethical framework for an adapted approach to ICD implantation.