Implementation of personalised risk prediction and prevention of sudden cardiac death after myocardial infarction

Personalised prevention of sudden cardiac death: from analysis of existing data to large trials

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 847999

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Project

Implementation of personalised risk prediction and prevention of sudden cardiac death after myocardial infarction

Sudden cardiac death is a major unsolved public health problem accounting for ~20% of all deaths in Europe with an estimated yearly incidence of ~350-700,000 cases. These are most frequently patients with previous myocardial infarction. In sudden cardiac death, the heart suddenly and unexpectedly stops beating. If untreated, the patient dies within minutes, but sudden cardiac death can be successfully prevented by a cardiac device, the implantable cardioverter defibrillator. The implantable cardioverter defibrillator is highly effective, but is also associated with potentially severe complications and high health care costs. Based on evidence from older (and outdated) landmark trials, current guidelines recommend prophylactic implantable cardioverter defibrillator implantation in post-myocardial infarction patients with left ventricular ejection fraction (LVEF)≤35% to prevent sudden cardiac death. However, in only a minority will the implantable cardioverter defibrillator ever deliver a lifesaving therapy. Moreover, in absolute numbers the majority of cases of sudden cardiac death occur in patients with a LVEF>35%, currently not considered for prophylactic implantable cardioverter defibrillator. Due to the devastating consequences of sudden cardiac death and the considerable health care expenditures associated with implantable cardioverter defibrillator therapy, a personalised treatment approach for prediction of sudden cardiac death and prevention by implantable cardioverter defibrillator implantation is urgently required. > > Lay Summary

The ambition of PROFID is to introduce a disruptive innovation in the prevention of sudden cardiac death in post- myocardial infarction patients by introducing – for the first time – a personalised treatment approach. PROFID aims at transforming and fundamentally improving clinical practice in this clinically high relevant field of cardiology from a “one-size-fits-all” to “individualised” treatment strategy, potentially resulting in a substantial reduction of the enormous burden that sudden cardiac death places on society as a whole and on the individual patient. > Lay Summary

In order to reach the final goal, the following main phases have been designed for the PROFID project:

Clinical prediction model development
In the first phase, a variety of data from different settings will be included in order to develop a clinical prediction model for the individual risk of sudden cardiac death. This model will be based on a collection of existing highly phenotyped data with the largest number of post- myocardial infarction patients ever in this regard (~1,000,000 patients of both sexes). The databases represent a wide variety of data sources such as national registries, institutional research databases, electronic health records and claims databases.

Clinical trials
In the second phase, two parallel randomised clinical trials will validate the utility of use of the clinical prediction model for the decision making on implantable cardioverter defibrillator implantation, while health economic analyses will assess its economic impact on health care systems. Both studies are prospective, parallel-group, randomised, open-label, multi-centre, blinded outcome assessment (PROBE), event-driven trials.

  • Trial 1: PROFID-Reduced Non-inferiority trial in reduced LVEF and low sudden cardiac death risk
    Non-inferiority controlled clinical trial without investigational product (Proof of Strategy Trial). This trial will be conducted on about 2,500 patients with a LVEF≤35% and a low risk for sudden cardiac death as predicted by the clinical prediction model that would receive an ICD according to current guidelines with randomised comparison of the ICD versus just optimal medical treatment without ICD.
  • Trial 2: PROFID-Preserved Superiority trial in preserved or moderately reduced LVEF and high sudden cardiac death risk
    Superiority controlled clinical trial without investigational product (Proof of Strategy Trial). This trial (“PROFID-Preserved”) will be conducted on more than 1,400 patients with a LVEF>35% and a high risk for sudden cardiac death as predicted by the clinical prediction model that would not receive an ICD according to current guidelines with randomised comparison of the ICD versus just optimal medical treatment without ICD.

Online web-based tool
A software tool for clinical use of the risk score will be implemented and hosted at the website of the European Society of Cardiology. The unique composition of the PROFID consortium with participation of key opinion leaders, patient organisations, large hospital chains, payers, policy makers and state authorities across Europe, will ensure implementation into routine clinical practice. > Lay Summary

For more information about the methodology of this project, please click here.

The aim of PROFID is to develop a personalized prediction of risk for sudden cardiac death after myocardial infarction, a leading cause of death in Europe, as well as a personalized sudden cardiac death prevention by targeted implantation of an implantable cardioverter-defibrillator. The ultimate goal is to successfully prevent the majority of the catastrophic sudden cardiac death events that occur after myocardial infarction by accurate and timely identification of those patients that are at high risk for sudden cardiac death (based on multiple factors, over and above LVEF, including relevant clinical characteristics/biomarkers) followed by implantable cardioverter defibrillator implantation. Thus, PROFID aims to close the huge gap of current clinical practice with regard to protection from sudden cardiac death after myocardial infarction.> Lay Summary

Consortium

The Profid Consor­tium

The PROFID consortium consists of a multidisciplinary team of top European key opinion leaders in cardiology, the European Society of Cardiology, patient organisations, big hospital chains, a large statutory health insurance company, national/state authorities, and biomedical informatics, epidemiology, statistics and health economics experts. Thus, it represents a unique alignment of all major stakeholders from all European geographies.
Methodology

Our work packages

The ambitious research of the PROFID project and the inherent challenges associated with developing and clinically validating the risk score in a large patient population will be mitigated by a carefully designed methodology and executed through nine work packages (WPs) as described below.

In WP1, University of Manchester will incorporate the data provided by the consortium partners and apply statistical modelling and machine learning methods to define a clinical prediction model that will estimate a personal risk score for sudden cardiac death for the individual patient.

In WP2, preparations for the clinical trials, including preparation of the trials protocols, ethics approvals, collaboration policy (including each partners’ responsibilities regarding data security and governance), data management plan and clinical centre recruitment will be performed by partners CRI and LHI beginning from the start of the project (in parallel to WP1).

WP3 covers the two multinational clinical trials in post- myocardial infarction patients. Experienced clinical contract research organisation (CRO) CRI will be responsible for overall management and monitoring of the trials. Coordinator LHI will act as sponsor of the clinical trials. In WP4, CRI and LHI will ensure GCP-compliant data analysis and clinical trial closure.

In WP5, health economics analyses will be led by York to inform HTA considerations on the use of implantable cardioverter defibrillators guided by personalised risk predictions. In addition, specific national requirements for health economic assessments and decision-making on implementation and reimbursement will be determined by University of Bayreuth. York will develop the cost-effectiveness analysis model to evaluate the value for money of the risk prediction tool to guide personalised treatment decisions to prevent sudden cardiac death. To this extent, York will first analyse the (health-economics-relevant) data made available by the consortium partners with a view to derive pre-RCT input parameters for the cost-effectiveness model. The model’s inputs will be updated with estimates derived from the analyses of the data obtained in WP3 in order to derive the final version of the cost-effectiveness analysis model. A value-of-information analysis will be conducted as part of this work, to help identify the areas in which further research would be most valuable from the societal point of view.

In WP6, AMC will examine the major ethical and legal issues that need to be overcome before the predictive model can be implemented throughout Europe, including data sharing, data sovereignty, GDPR implementation, self-determination, patient autonomy and ethical aspects of implementing personalised medicine guidelines. As part of this WP, a study on the patients’ perspective on the implementation of the predictive model will be performed through an international survey of patient preferences and a comparative analysis including the handling of regional differences, as well as to normative examinations. Moreover, AMC will develop a template matrix regarding data security and data governance to provide practical ethical and legal guidance to all partners.

In WP7, ESC will ensure inclusion of the personalised risk prediction and prevention in European clinical practice guidelines depending on the project results. A freely-available user-friendly web-based application of the risk calculator will be provided via the ESC website to clinicians for the easy calculation of the individual risk score for each patient. All partners will collaborate in dissemination and communication efforts, e.g. academic partners will publish scientific papers, ESC will publish guidelines, payers will focus on reimbursement procedures and DHF will communicate project results and recommendations to patients, their families and the general public.

WP8 is dedicated to the organisational aspects of running such a large research collaboration. The tasks planned will ensure that the project’s main objectives are realised on schedule and within budgetary limits, and that activities of all partners involved are in conformity with the EC contract and the consortium agreement.

Ethics requirements
This work package sets out the ethics requirements that the project must comply with.

publications

Relevant literature and Press releases