Sudden cardiac arrest (SCA) is one of the top causes of mortality in industrialised societies. SCA is the sudden failure of the heart to pump blood through the body, caused by cardiac arrhythmia (ventricular fibrillation, VF) most commonly secondary to coronary heart disease (CHD), i.e., acute myocardial infarction and myocardial ischemia. This devastating condition is responsible for 50% of cardiac deaths, which corresponds to 2 million deaths in Europe. Much progress has been made to reduce the burden of SCA for society through improved CHD management, development of community-based cardiopulmonary resuscitation, and increased use of implantable cardioverter defibrillators. Still, SCA remains the cause of 15–20% of deaths in Western societies and 20% of all natural deaths in Europe. If left untreated, SCA is fatal within minutes. Since SCA often occurs unexpectedly outside the hospital setting, it is a challenge to provide timely and effective treatment. Therefore, SCA occurs mostly in individuals who have never been examined by a cardiologist. The knowledge to predict an individual’s risk of SCA is lacking and individuals are unaware of their personal risk to experience SCA. Therefore, prediction and prevention of SCA is challenging and patients rely on first-response treatment. The treatment in the first minutes after SCA provided by citizens, police officers, firefighters and Emergency Medical Services is critical for survival.
Strikingly, there are large regional differences in survival rates after SCA across Europe. The EuReCa ONE study investigated survival chances after cardiopulmonary resuscitation in out-of-hospital cardiac arrest patients in 27 countries across Europe. The survival percentage ranged from 1.1% (Romania) to 30.8% (Switzerland). These numbers indicate that regional differences in individual risk, prevention and treatment have a major impact on an individual’s chance to experience SCA and the chance of survival after a SCA event. Therefore, to prevent SCA and to improve survival rates across all European countries it is imperative to investigate:
➢ Inherited, acquired, and environmental risk factors of SCA across European regions;
➢ Regional differences in preventive measures and first-response treatment strategies and their effectiveness.
The Mission & The Challenges
The PARQ mission is to implement this knowledge to develop prevention and treatment guidelines to reduce the differences in survival rates and the overall burden of SCA across Europe. The first step in achieving this challenging goal is to collect and share data across all European regions and learn from differences in prevention and treatment strategies. Hence, sufficiently large cohorts of SCA patients with detailed clinical and environmental data are required. Although efforts to collect clinical data and biological samples exist at the national and international level, co-ordination between these study networks is lacking. The harmonization of data collection and analysis should be improved to enforce collaboration and data sharing between cohorts. In addition, the different European countries and regions are not equally well represented in existing research efforts. Hence, there is a need for a pan-European network to connect all stakeholders in SCA and resuscitation science and develop standards for research activities.
The PARQ Action will be built on two pillars. Read more below.
Multiple risk factors are associated with SCA occurrence. In each individual, a unique interaction of inherited, acquired and environmental risk factors determines the risk of ventricular fibrillation leading to SCA. Inherited risk factors may arise from variation in genes that control cardiac electrophysiology. Also gender accounts for variation in SCA risk; men have a higher chance of suffering from SCA, but women are less likely to be resuscitated and have lower chances of survival. In addition, acquired risk factors, such as myocardial ischemia, type II diabetes as well as environmental factors (in particular, socio-economic factors that may be related to psychosocial stress) can contribute to SCA. Inclusion of inherited, acquired and environmental factors as integral components of SCA occurrence and outcome is critical to establish new guidelines and preventive actions with cross-border relevance. In summary, designing individualized prevention and treatment strategies requires elucidation of the complex interplay of risk factors. Ongoing initiatives including large European cohort studies aim to unravel the interactions of inherited, acquired, and environmental risk factors.
- Cohort integration: Although efforts to collect clinical data and biological samples exist at national and international levels, co-ordination and harmonization between such study networks is lacking. The PARQ Action will provide the network to discuss standards for harmonization of data collection and analysis to enforce collaboration and data sharing between cohorts. In addition, the Action will include European countries and regions that are not equally well represented in existing research efforts, with a strong focus on Eastern Europe.
- Data collection and analysis: Standards will be developed for collection, storage and analysis of genomic data, pharmacological data, electrocardiogram (ECG) measurements, socioeconomic data and resuscitation data using the Utstein-style guidelines. These guidelines refer to an established consensus process, endorsed by the international resuscitation community, to facilitate and structure resuscitation research and publication. The Action members offer expertise in state-of-the-art genetic analysis methods (genome-wide association studies, genetic imputation methods, whole genome sequencing analysis) and will select the optimal methods for data handling. To support the complex bioinformatics analyses of large-scale phenotype and genotype data across Europe, the Action has access to existing parallelization frameworks for SCA data analysis. Such frameworks will facilitate use of statistical tools and analyses in parallel in different environments, including computer cluster and cloud environments. In addition, the Action will include medical ethics experts to evaluate ethical issues related to use and exchange of information and personal data of SCA patients from different EU countries.
- Inclusion of general practitioner (GP) files: SCA strikes individuals who are often unaware of their health risk and who are not monitored by cardiologists. Importantly, the recognition of individuals at risk must be improved. Novel insights could be derived from clinical information present in personal health records and GP files. The PARQ Action has formulated the unique ambition to include clinical information from GP files, to strengthen research on identification of relevant but so far unsuspected SCA risk factors. These GP files will be fully exploited using data mining methods developed by consortium members, which utilize advanced machinelearning algorithms that do not require an up-front selection of variables, but identify useful variables themselves based on the data. Data mining has the power to improve prediction models, in part because temporal information, so far untapped, is utilized, e.g., the number of GP visits preceding the study endpoint and/or the evolution over time from nonspecific signs/symptoms towards ever more specific signs/symptoms. In addition, the data mining algorithms may reveal signs/symptoms at GP visits which are so far unsuspected to be associated with SCA. We will first apply the pipeline we have described before to extract potential predictors. Thereafter, we apply advanced machine learning algorithms to create risk scores for patients. Machine learning methods to be used include decision tree algorithms, and support vector machines, and random forests algorithms. A dedicated GP task-force will design a strategic plan for collection, harmonization, safe handling and storage of GP data per Action Member country.
Multiple factors influence the chances of survival after SCA. The first minutes after SCA critically impact patient prognosis, yet the first care often occurs in an out-of-hospital setting. The delay between SCA and first-response treatment is the most important determinant of survival. European Resuscitation Council guidelines for resuscitation have been established and include instructions for first-response treatment: early recognition and call for help; early cardiopulmonary resuscitation, early defibrillation and standardized post-resuscitation treatment. Still, large disparities between SCA survival rates across Europe exist. To understand how these differences arise, other determinants of survival, such as patient characteristics and regional differences in SCA management, should be considered.
- The resuscitation science community has implemented Utstein guidelines for uniform reporting of SCA. However, to better understand the variation in survival rates, first-response management and patient characteristics should be systematically reviewed. The challenge that will be addressed by PARQ is to establish the network to exchange new knowledge related to SCA management, including regional differences in financial resources. The network will focus on sharing of data related to the effectiveness of text-message and app-based deployment of lay rescuers to understand how new technologies and treatment deployment strategies can enhance effectiveness of bystander response. This requires that consensus is established on best practices for harmonization of application-derived data. In addition, health economics experts in the PARQ Action network will be involved in evaluation of the financial drivers behind the emergency response and treatment procedures established in European countries.
- Overall, improvement of both individual risk prediction and intervention methods are required to achieve the lowest incidence of SCA and the highest chance of survival from SCA. Ultimately, the Action members aim to develop first-response treatment strategies that are as much as possible tailored to an individual (e.g., based on comorbidity, drug use, or medical/genetic background and biomarkers). Traditionally, the research communities that focus on Pillar 1 (typically cardiologist and molecular biologists) do not sufficiently interact with the Pillar 2 research communities (typically emergency medicine and resuscitation scientists), and vice versa. A key challenge addressed by PARQ is to connect these researchers to create a critical mass of participants and to establish education programmes and workshops to foster interdisciplinary training.
The PARQ Action will establish a Europe-wide SCA and resuscitation science network to connect all stakeholders in the field. Whereas SCA cohorts and resuscitation science networks exist, there is no overarching infrastructure or network to facilitate interaction between the different disciplines involved, including cardiology, general practice, resuscitation science, first-responders, healtheconomics, ethics, and data scientists.
Most of the knowledge about predictors and risk factors of SCA is based on isolated studies focusing on single clinical risk factors and genetic risk factors. However, researchers acknowledge that SCA has a complex genetic basis and its manifestation depends on multiple clinical and environmental risk factors. To tackle the complexity of individual risk prediction in SCA, as a starting point, the network will benefit from an established European SCA database that will be available for researchers connecting to the PARQ Action. The database will be expanded to address the challenges as specified in the section above. Thereby, the Action members have defined three innovation focus areas:
- Inclusion of patient data. Since the individual risk to experience SCA depends on a complex interplay of factors, SCA scientists will benefit from large sample sizes that reflect the European population and regional differences. To ensure that additional samples can be added to a joint database, standards for sample collection, handling and data processing should be defined. To achieve this, the PARQ Action will provide a novel platform to an interdisciplinary group of researchers to discuss and outline SOPs for collection, storage and analysis of biological samples. The Action will outline a plan for inclusion of socioeconomic risk factors, including socio-economic status, education, and income. In addition, the PARQ network will aid in development and dissemination of best practice standards enabling harmonization of data handling across Europe.
- Inclusion of personal health records and GP files. Data mining of GP files could indicate whether symptoms and clinical signs that are commonly viewed as nonspecific and irrelevant to an individual’s health may distinguish individuals at risk of impending SCA. This information is lacking in existing SCA research initiatives and cohort studies. A specific barrier for access to patient information is compliance with GDPR and national privacy regulations. PARQ will go beyond the state-of-the-art and facilitate inclusion of these data, through involvement of experts in general practice, data harmonization, ethics and data privacy. The Action members will develop a framework for collection of GP data through workgroup meetings. Short-term scientific meetings will be organized to design best practice standards related to GP data collection and facilitate the exchange of knowledge related to GP data mining.
- Inclusion of first-treatment response data. Existing research networks demonstrated that survival rates greatly vary between European countries. This may be explained by differences in first-response strategies. The consortium can utilize these differences to analyze the relation between treatment and survival rate. Specifically, the PARQ network will facilitate exploration of drivers that have an impact on differences in first-response strategies between different countries, such as financial resources. In addition, the PARQ Action connects leaders of the SCA study cohorts with experts in resuscitation and emergency medicine for the first time on a large scale. This provides the opportunity to develop research projects investigating the interaction between patient characteristics, first-response strategies and outcome. As such, the PARQ Action network will provide the scientific fundaments to update clinical guidelines and tailor these to the opportunities and needs of different regions in Europe (e.g., rural vs. urban regions).
Action in these three focus areas has never been integrated and have never been established on such a broad scale. We will address these challenges in various working groups. Read more below.
Working group 1 aims to coordinate biological and personal data collection to enable future studies into risk prediction and prevention of SCA (WG2), and resuscitation strategies (WG3). Focus points of this workgroup are: the organization and expansion of current SCA population cohort studies; the coordination of the development of best practice guidelines for harmonization of data handling and analysis across Europe; the coordination of collection and integration of personal health records derived from general practitioners (GPs) in cohort studies.
- Identify the European study cohorts relevant to SCA.
- Identify sample collection and analysis procedures in current SCA study cohorts.
- Define common standard operating procedures (SOPs) for collection, processing and storage of biological samples.
- Define SOPs to harmonize genetic data collection, storage, and analysis, including a framework for genetic data imputation and analyses of deep sequencing data.
- Investigate ethical concerns related to big data analysis
- Define SOPs on obtaining the necessary patient information such as clinical data, family history, environmental factors, and resuscitation factors (Utstein template).
- Develop SOPs to obtain health records of SCA patients from GPs.
- Develop standards for data digitalization and handling in compliance with EU’s General Data Protection Regulation (GDPR).
- Manage established SCA research networks and establish a taskforce for development of research projects to identify biomarkers for risk prediction.
- Develop and disseminate publications on SOPs, including practical issues and solutions for collection and storage of biological samples and data.
These tasks will be accomplished through video conferences (Task 1-7), work group meetings (Task 1-7), short-term scientific missions (Task 3-5), international symposium (Task 8), development of dissemination material and scientific publications (Task 9-10).
- M1.1 WG Meetings (first quarter of each year) which will be based on the progress made in WG-3 followed by the respective reports (months 12, 24, 36, 48).
- M1.2 Calls for STSMs (2nd and 4th quarter of each year) for training of young scientists on the technologies developed in WG-4 (months 12, 24, 36, 48)
Working group 2 aims to coordinate genome-wide association analysis, identification of risk factors and development of prediction models. Focus points of this workgroup are: coordination of the inclusion of European samples in genome-wide association analysis; coordination of the identification of risk factors in multiple cohort studies; the facilitation of the development of prediction models.
- Identify the European study cohorts relevant to genome-wide association studies.
- Establish a scientific network for coordination of risk prediction research.
- Coordinate identification of inherited and acquired risk factors between Action members.
- Coordinate definition of risk scores to develop a common risk prediction model.
- Design research projects for risk score validation studies in different European regions.
These tasks will be accomplished through video conferences (Task 1-5), work group meetings (Task 1-5), short-term scientific missions (Task 2-4), Development of scientific publications (2-5).
- M2.1 WG Meetings (first quarter of each year) which will be based on the progress made in WG-3 followed by the respective reports (months 12, 24, 36, 48).
- M2.2 Calls for STSMs (2nd and 4th quarter of each year) for training of young scientists on the technologies developed in WG-4 (months 12, 24, 36, 48).
This workgroup will identify the regional and national differences in emergency response and treatment procedures for out-of-hospital SCA between network members. This is envisioned as a continuously expanding process since the network will keep growing with new members from other countries.
- Coordinate identification of technical drivers behind the emergency response and treatment procedures established in European countries.
- Coordinate identification of financial drivers behind the emergency response and treatment procedures established in European countries.
- Compile all procedural variations of first-treatment response to SCA and SCA management in a publication.
- Evaluate the strengths and weaknesses of different first response treatment procedures.
- To integrate proposals, and identified solutions for SCA treatment into a best practice guideline
- To develop a whitepaper for the best practice SCA first-response treatment in different regions.
- To set up a network of scientists responsible for dissemination of best-practice guidelines in different countries.
These tasks will be accomplished through video conferences, work group meetings, short-term scientific missions, a symposium, development of dissemination material and scientific publications.
- M3.1 WG Meetings (first quarter of each year) which will be based on the progress made in WG-1 followed by the respective reports (months 12, 24, 36, 48).
- M3.2 Calls for STSMs (2nd and 4th quarter of each year) for training of young scientists on the technologies developed in WG-4 (months 12, 24, 36, 48).
- M3.3 Publication of best practice whitepaper on first-response treatment strategies and their impact in Europe
Working group 4 aims to expand the PARQ network through communication and dissemination activities. This will strengthen the interactions between experts in SCA risk prediction and resuscitation science to establish research collaborations in these areas.
- To design a website and expand the PARQ network. A website for PARQ will be created with sections on project objectives, member information, education curriculum, how to join, publications, stakeholders, a password-protected user section, section for the general public, and an agenda with PARQ activities. In addition, to extend the network, recruitment material in the form of a flyer, LinkedIn page, Facebook account, and Twitter account will be created and actively used to expand the network during the first 6 months of the COST Action.
- To recruit new network members.
- To disseminate the PARQ results, including the whitepapers for best practices outside of the COST network through ‘classic’ dissemination channels as explained in section 2.2.2. Dissemination and/or Exploitation Plan.
- To implement new knowledge and SOPs by education in the training program, aligned with European summer schools. The education curriculum will consist of yearly training schools, workshops and STSMs. The education curriculum will combine parts of existing curricula to both ensure attainability and quality. This education curriculum will have a dedicated part on the PARQ website.
- Establish a network that will be responsible for dissemination of project results to governments, regulatory bodies, organizations that offer emergency medical services, and the general public.
- Create training modules for professionals involved in first-response treatment, such as police and firefighters.
- Develop a dissemination strategy tailored to individual countries for increasing awareness of SCA risk factors and first-response strategies among the general public.
These tasks will be accomplished through video conferences (Task 1-7), work group meetings (Task 1-7), development of dissemination material and scientific publications (Task 1,3).
- M4.1 WG Meetings (first quarter of each year) which will be based on the progress made in WG-5 followed by the respective reports (months 12, 24, 36, 48).