Periodic Reporting for period 2 - PROFID (Implementation of personalised risk prediction and prevention of sudden cardiac death after myocardial infarction)
Reporting period: 2021-07-01 to 2022-12-31
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 (CPM) 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. We considered 24 datasets from 13 countries containing clinical information and a large variety of other variables. Seven datasets included additionally variables from cardiac magnetic resonance (CMR) imaging. 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. The SCD rates were lower than expected, being low in patients with severe LVEF impairment and very low in patients with moderately impaired or preserved LVEF.
Based on these results, the PROFID trial design was adapted. The trial investigates whether in post-MI patients with symptomatic heart failure and reduced LVEF ≤35% who receive OMT, OMT without ICD implantation (index group) is not inferior to OMT with ICD implantation (control group) with respect to all-cause mortality. The trial has been registered at ClinicalTrials.gov (NCT05665608). We have classified more than 500 hospitals in 12 countries in Europe as potentially eligible for study participation and nominated key opinion leader-physicians in these countries. The predictive role of the most promising novel SCD risk markers will be prospectively assessed by use of AI techniques in the trial and in sub studies. We expect the trial to start in April 2023.
We continued to focus on developing a conceptual cost-effectiveness model structure, preparatory work in terms of health economics analysis plan development, and the evaluation of health technology assessment methods in the PROFID partner countries. Additionally, adjustments of the previous developed data extraction tool were performed and a budget impact analysis (BIA) was conducted with the aim to assess whether the introduction of a personalized medicine approach leads to cost changes for the healthcare systems.
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. Furthermore, a paper about trust specific to machine learning and artificial intelligence is currently been written. A systematic review on professionals’ attitudes towards ML/AI and the impact on professional autonomy has been conducted as well. Patient interviews in Germany and the Netherlands were conducted in order to gauge patients’ perspectives on AI-driven ICD care.
The communication and dissemination efforts within the project aimed to promote PROFID and its outcomes in a deliberate and efficient way. PROFID was featured in late breaking science sessions at the ESC Congress 2021 and 2022, the world’s largest cardiovascular congress as well as the EHRA Congress 2022, the annual meeting of the European Heart Rhythm Association and thus achieved outstanding visibility.
Based on these results, the PROFID trial design was adapted. The trial investigates whether in post-MI patients with symptomatic heart failure and reduced LVEF ≤35% who receive OMT, OMT without ICD implantation (index group) is not inferior to OMT with ICD implantation (control group) with respect to all-cause mortality. The trial has been registered at ClinicalTrials.gov (NCT05665608). We have classified more than 500 hospitals in 12 countries in Europe as potentially eligible for study participation and nominated key opinion leader-physicians in these countries. The predictive role of the most promising novel SCD risk markers will be prospectively assessed by use of AI techniques in the trial and in sub studies. We expect the trial to start in April 2023.
We continued to focus on developing a conceptual cost-effectiveness model structure, preparatory work in terms of health economics analysis plan development, and the evaluation of health technology assessment methods in the PROFID partner countries. Additionally, adjustments of the previous developed data extraction tool were performed and a budget impact analysis (BIA) was conducted with the aim to assess whether the introduction of a personalized medicine approach leads to cost changes for the healthcare systems.
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. Furthermore, a paper about trust specific to machine learning and artificial intelligence is currently been written. A systematic review on professionals’ attitudes towards ML/AI and the impact on professional autonomy has been conducted as well. Patient interviews in Germany and the Netherlands were conducted in order to gauge patients’ perspectives on AI-driven ICD care.
The communication and dissemination efforts within the project aimed to promote PROFID and its outcomes in a deliberate and efficient way. PROFID was featured in late breaking science sessions at the ESC Congress 2021 and 2022, the world’s largest cardiovascular congress as well as the EHRA Congress 2022, the annual meeting of the European Heart Rhythm Association and thus achieved outstanding visibility.
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 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 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 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 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.