Knowledge gaps related to the etiology and pathophysiology of cardiac arrest, and the efficacy and use of existing treatments, impede additional progress in reducing mortality and improving cardiac arrest outcomes (IOM, 2015). A collaborative effort across the resuscitation field and translational research spectrum will be required to overcome persistent knowledge gaps, advance resuscitation science, and ultimately save lives, as described in Recommendations 6 and 7 (see Box 3-1).
Turning Discovery Science into Public Health Impact: Seizing New Opportunities in Cardiac Arrest Research
Gary Gibbons, National Heart, Lung, and Blood Institute, National Institutes of Health
One element of the National Heart, Lung, and Blood Institute’s (NHLBI’s) mission is to support investigator-initiated programs that draw on the collective intelligence of experts across a variety of disciplines in order to advance the prevention and treatment of heart diseases, said Gary Gibbons. To this end, NHLBI’s research portfolio spans the entire translational research spectrum (see Figure 3-1) to ensure that discovery science leads to enhanced prediction, prevention, and treatment of dis-
eases and conditions—which ultimately can improve the health of the nation. Findings at each phase can expand knowledge about the nature of heart disease and sudden cardiac arrest and death, Gibbon indicated.1 For example, discovery science explores the fundamentals of how the
1 As defined in Chapter 1, sudden cardiac arrest is “a severe malfunction or cessation of the electrical and mechanical activity of the heart . . . [which] results in almost instantaneous loss of consciousness and collapse” (IOM, 2015, p. 1). Sudden cardiac death is “defined as death due to a cardiac etiology or cardiac involvement in a noncardiac disorder, in a person
heart and its electrical system function. Translating discovery science into humans (T1) provides insights into the underlying pathobiology and molecular basis for heritable mutations that may predispose a patient to certain cardiac arrhythmias and death. Translating findings at this level into treatment strategies (T2) expands opportunities to more effectively intervene and change the natural history of the disease. The latter phases of the spectrum (T3 and T4) include efforts to establish efficacy of new treatments, noted Gibbons, and to ensure that resuscitation science guides health care practice in real-world settings and communities.
New technologies and tools are expanding opportunities to strengthen researchers’ understanding of the pathophysiology of cardiac disease and arrest, said Gibbons. For example, the ability to sequence an entire human genome, map layers of its proteome and epigenome, and characterize the molecules of the heart and its systems in relatively short time frames has unlocked a wealth of knowledge. Stem cells can now be manipulated to study the electrical system, which could provide a better understanding of the risk factors, triggers, and possible treatments for fatal arrhythmias, Gibbons noted. Furthermore, mobile technologies and sensors—such
as smart phones, watches, and health monitors—are creating new data sources and mechanisms to study the onset and treatment of sudden cardiac arrest and death, prior to arrival in the emergency department. Gibbons suggested that sensor technologies through continuous cardiac monitoring could reveal what happens before cardiac arrest, in addition to connecting individuals trained in cardiopulmonary resuscitation (CPR) to those experiencing a cardiac arrest and to automated external defibrillators. He asked workshop participants to help NHLBI identify the most effective ways to employ mobile health technologies and precision medicine to study cardiac arrest and the subphenotypes associated with resilience and susceptibility.
NHLBI is building on its legacy research portfolio to support initiator− initiated research and research networks that are redefining resuscitation science and how it can influence patient care across health care settings. Gibbons cited a number of National Institutes of Health (NIH) activities that related to the study of cardiac arrest, including the following:
- The Strategies to Innovate EmeRgENcy Care Clinical Trials Network (SIREN) is a new collaborative network among NIH’s Office of Emergency Care Research, the National Institute of Neurological Disorders and Stroke, NHLBI, the Department of Defense (DoD), and others to advance emergency care clinical trials.
- NHLBI’s Trans-omics for Precision Medicine (TOPMed) program uses genome sequencing and -omic and phenotype data in large-scale NHLBI cohort studies (e.g., Women’s Health Initiative, Framingham Heart Study) to explore the underlying pathophysiological causes of disease.
- NIH’s new Precision Medicine Initiative® Cohort Program,2 which aims to enroll more than 1 million participants in a process that generates data, develops data standards and interoperability, leverages electronic health records (EHRs), and uses mobile and sensor technologies to better predict and prevent disease.
In the spirit of collaboration and information exchange, Gibbons urged workshop participants to consider the most important scientific questions to ask in preclinical models and clinical trials in order to reduce cardiac arrest mortality. Gibbons noted that NHLBI is in the final stages of its strategic visioning process, which used crowdsourcing to establish an agenda for the next 5 to 10 years. One identified objective was to “develop and optimize novel diagnostic and therapeutic strategies to prevent, treat,
2 On October 12, 2016, NIH announced that the Precision Medicine Initiative® Cohort Program had been renamed as the All of Us™ Research Program.
and cure HLBS [heart, lung, blood, and sleep] diseases,” (NHLBI, 2016, p. 9), including sudden cardiac arrest and death.
In response to an audience question, Gibbons noted that the ultimate goal of improving outcomes for patients is shared across all potential stakeholders and numerous mechanisms to collaborate and advance specific goals (e.g., data sharing or precision medicine). In closing, he encouraged the participants to think about strategies that can be used to leverage existing systems and datasets to transcend silos and work toward wide-scale adoption of effective treatments for cardiac arrest.
Creating a Research Network to Build Solutions
Natasha Bonhomme, Genetic Alliance
Genetic Alliance is a health advocacy organization that was formed 30 years ago as a resource for support groups and individuals who were interested in starting foundations, contributing to research, or getting involved with a particular health condition. Today, Genetic Alliance has a network of more than 10,000 organizations, individuals, and agencies that are involved in policy, advocacy, education, and research, said Natasha Bonhomme. As part of Genetic Alliance, these organizations are committed to individuals, families, and communities and to ensuring that people are at the center of research efforts.
In collaboration with its stakeholders and communities, the Genetic Alliance has created a highly customizable registry platform called the Platform for Engaging Everyone Responsibly (PEER). PEER was designed to collect privacy-assured health information, and at its core is meant to be engaging, consumer centric, collaborative, and dynamic—connecting participants with research in a meaningful way. Currently 40 different communities are using PEER. These communities range from disease-specific advocacy organizations to a town in Pennsylvania that wanted to follow the potential health implications of local fracking.
A cornerstone of PEER is creating an environment of trust, said Bonhomme. Trust is garnered, in part, by allowing organizations to brand the platform as their own and fully integrate it into their website. This gives individuals a sense of familiarity and trust when they decide to participate and register. Trust is also fostered through privacy layers and by empowering participants to make decisions about how their personal information is used. Because of varying privacy concerns and preferences, the platform allows individuals to customize their own privacy and health data–sharing settings, thus determining exactly what information is included and shared and under what circumstances. Some individuals may be willing to share everything, while others may be more conser-
vative and only willing to share information when they are asked. The ability to make these decisions and knowing that their information is protected solidifies participants’ trust in the system. When more than 12,000 users were asked about their level of trust in PEER, 90 percent reported being extremely confident and having complete trust in the system.
Genetic Alliance has also launched a program called Community Engaged Network for All (CENA), which is supported by the Patient-Centered Outcomes Research Institute (PCORI) and uses PEER. Currently in the second phase of funding, CENA is actively engaging 12 disease-specific advocacy organizations that represent 32 health conditions. The goal is to put patients at the center of the research paradigm by developing community- and participant-driven studies. Patients, clinicians, researchers, and other stakeholders are actively working together to identify feasible patient-centered research questions and to design studies with patient-centered protocols. CENA is using PEER and another registry platform called Mosaic to build cohorts of participants for the studies.
Bonhomme said the notion of merging data collection efforts to further research is a powerful one. When there are too many registries or datasets to populate, the users see the process as a burden and become disinterested. However, when you combine efforts, as Genetic Alliance did with PEER, disparate groups that thought they had nothing in common came to realize that there is often a lot of overlap in both the experiences they share and their data needs. Bonhomme suggested starting with a shared infrastructure for collecting common data points that can then be tailored and expanded, as needed, to collect data points that are unique to cardiac arrest.
Challenges and Opportunities
Bonhomme noted that there are still many challenges in getting interested individuals fully integrated into research and determining where consumers and caregivers fit into research efforts. Regardless of their role in research, building trust and trustworthiness among participants and researchers will be critical to success. Current research infrastructures are designed for making transactions, not always building trust and relationships. Participants should feel like they are playing an active role in research, not just a one-sided interaction in which they supply data to researchers without further interaction. Bonhomme emphasized the importance of patient engagement in the research process and highlighted PCORI and the NIH Personalized Medicine Initiative. This type of engagement can humanize data and connect stories and faces to data points. In this vein, Bonhomme called for more real-life models of patients and families being truly involved in the research process. Valuable lessons
can be learned from these experiences and applied to future efforts to actively involve patients in the research enterprise.
Public−Private Partnerships as Driving Forces for Innovative Treatments and Research Policies
Nigel Hughes, Janssen Research and Development
A number of public−private partnerships in the European Union (EU) could serve as exemplars for advancing cardiac arrest research and surveillance in the United States, said Nigel Hughes. For example, the Innovative Medicine Initiative (IMI) (IMI, 2016), which was established in 2008 across 28 European countries, has the overarching goal of accelerating access to innovative medical therapies for EU citizens. The initiative supports programs across all diseases and health conditions and also across the spectrum of care from diagnostics to therapeutics. Perhaps one of the largest public−private partnerships in the world, Hughes noted that the budget for the first iteration of the initiative was €3 billion, which was split between the European Federation of Pharmaceutical Industries and Associations and the EU. As partners, the pharmaceutical industry agreed to match the resources provided through in-kind services and resources, such as technology, expertise, time, and other types of support. The second iteration of IMI was launched in 2014 with a slightly larger budget and is already supporting various programs throughout the EU.
One of the ongoing, IMI-supported public−private partnership programs is the European Medical Information Framework (EMIF) (EMIF, 2016). This 5-year initiative, which started in 2013, has a budget of €56 million and engages 58 partners from 14 EU countries. Hughes indicated that EMIF is developing a governance and technology platform, which will allow researchers to identify, access, assess, and use a variety of data sources, such as EHRs, cohort datasets, registries, and payer datasets. Within the initiative, two subgroups are working to identify early biomarkers using the EMIF platform and processes—metabolic diseases, such as obesity and diabetes, and Alzheimer’s disease. The research efforts are driven by cohort and population and have already resulted in a number of publications describing outcomes. At the end of the 5-year initiative, the goal is to have a fully sustainable platform, along with streamlined processes (e.g., contracting, ethics committees) that can be used in other disease areas.
The Electronic Health Record for Clinical Research (EHR4CR) was an IMI-supported project that is now transitioning to the sustainable, scalable part of its life cycle, said Hughes (EHR4CR, 2016). With eight partners involved, it is being supported by a number of pharmaceutical
companies in collaboration with hospital networks across the EU. The purpose of this program was to establish a data exchange infrastructure or the digital plumbing that, as Hughes described it, would allow hospitals and medical systems across Europe to share data under the appropriate set of conditions and criteria (e.g., legal, ethical). In turn, the data shared across systems could then be used to promote clinical research. For example, if a researcher wanted to assess a clinical trial protocol, the researcher could access the hospital network platform and compare existing patient populations against the exclusion and inclusion criteria in the protocol. This assessment, said Hughes, would hopefully accelerate the time required to get to the testing phase and eliminate some of the uncertainties about enrollment.
In the United States, NIH’s Accelerating Medicines Partnership is a 5-year public−private partnership program launched in 2014 that is developing knowledge portals (NIH, 2016). These portals will be used to collect and assemble genotypic and phenotypic data for translational research purposes. Similar to EMIF, this partnership is currently focused on three disease areas: Alzheimer’s disease, type 2 diabetes, and autoimmune disorders, including lupus and rheumatoid arthritis. This provides a model of collaboration, bringing together partners from all over academia, clinical settings, and industry, said Hughes.
Lessons Learned and Successes
In response to a comment, Hughes agreed that in order to advance research, the resuscitation field needs a large-scale data source that can be used to follow patients over decades, not just years or 30 days. Hughes noted that differing views of confidentiality and privacy in Europe provide linked data opportunities that are not currently possible in the United States. Some countries have been able to link health data, social data, census data, and other types of data, offering a complete picture, valuable context, and the ability to follow individuals longitudinally over the course of their lives. Hughes urged a reconsideration of data collection and privacy in the United States. In most countries, organ donation is managed using an opt-in or opt-out system. Hughes said the research community should consider developing a similar system for altruistic data donation and sharing that could be used to benefit health research. However, there is some degree of persistent reticence about data sharing, linkages, and privacy—even among health care providers and researchers—that prevent this from happening, said Hughes.
Data from industry-funded clinical trials are limited to the clinic-based, observational data that cannot always provide context and background. Public−private partnerships could expand the availability of data
to encompass cohorts, allowing researchers to better understand the natural history of the disease and what outcomes are possible. This broader view could lead to more translational research and the development of new biomarkers. Although most people only think about the funding aspects of public−private partnerships, there are many other benefits for all collaborators. For example, industry can also share goals, expertise, skills, technologies, and research outputs with the public side of the partnership. Hughes said the more productive approach to public−private partnerships goes beyond funding and requires the development of long-term, longitudinal partnerships that would engage clinicians, academics, industry, and patient groups.
Hughes stated that, through all of these partnership efforts, the most important lesson is that “it’s not about data, it’s not really about the technology—it’s all about the people.” Another element for success is optimal project management of large-scale programs. To effectively align disparate agendas, he said, the needs of the stakeholders must be considered in the planning phases, and leaders need to understand what the individual agendas are before trying to merge and align those agendas. Hughes described the need for harmonized data sources to ensure efficient access, saying that “there are only two types of data to worry about—data you own and data you don’t own—and it’s the data you don’t own that [present] the challenge.” He also urged stakeholders not to underestimate the time required to develop real-world data programs. In closing, Hughes reflected on successes across recent public–private partnership efforts. He highlighted that today there is a much larger precompetitive collaboration of industry partners, better alignment between industry and academic research and development, and improved harmonization of data sources and information portals. Overall, industry and academia are open to more collaborative models of research and agree that therapeutic research efforts can no longer be pursued in isolation.
Environments and Conditions That Facilitate Cardiac Arrest Research Through Better Coordination, Oversight, and Strategy
Demetris Yannopoulos, University of Minnesota
The complexity of cardiac arrest at the pathophysiological level has resulted in many unanswered scientific questions, began Demetris Yannopoulos. For example, the physiology of low and no blood flow situations that lead to generalized tissue hypoxia or anoxia followed by reperfusion is not well understood, especially given the multisystem involvement of this process (e.g., heart, brain, lungs, kidneys). These complex challenges surpass the singular expertise of any of the traditional
scientific fields and may require a large national strategic effort—similar to the Human Genome Project or the BRAIN (Brain Research through Advancing Innovative Nanotechnologies) Initiative—with congressional support in order to make progress. A national fund dedicated to cardiac arrest science and resuscitation could be established by pooling resources from major funding agencies (e.g., NIH, DoD, PCORI), organizations (e.g., National Science Foundation, American Heart Association), and corporate foundations, suggested Yannopoulos. The resources from this national fund could then be allocated strategically for projects with a clear purpose. Yannopoulos emphasized that no progress can be made or improvements achieved without adequate resources.
Across cardiac arrest clinical trials, Yannopoulos highlighted a persistent challenge with demonstrating statistical power, p values, and the magnitude of effect, which impact how study findings are interpreted and judged. When therapies benefit patients but fail to reach the desired p value (≤ 0.05), the findings are often discarded, and the field remains stagnant. For example, a recent study by Moler and colleagues (2015) tested the use of therapeutic hypothermia following cardiac arrest in a population of 260 children. The p value was 0.14, indicating that the therapeutic hypothermia was not effective. However, 20 percent of children who received the hypothermic treatment survived, whereas the survival rate without the treatment was only 12 percent. Yannopoulos asked researchers to consider exactly what a successful outcome in resuscitation science looks like if a 66 percent higher chance for survival in children is dismissed based on a study that overestimated the effect of the treatment. Referring to a statement from Andrew Gelman, a statistician, Yannopoulos noted that, although physicians and scientists want certainty, that is not always a possibility. He also warned of the overreliance on the significance of p values and pointed out that the American Statistical Association recently released a statement on the inappropriate use of p values in research, which also included guidelines on the appropriate application of p values (ASA, 2016; Baker, 2016).
Accounting for confounders, such as nearly uncontrollable variation (e.g., quality of manual CPR) and the presence of unknown variables (e.g., coronary artery stenosis), poses sizable design challenges to cardiac arrest studies. Confounders can significantly affect study findings and the subsequent interpretation of those findings. As noted by Yannopoulos and colleagues (2015), the quality of CPR represents a significant effect modifier of outcomes—good-quality CPR is beneficial, whereas low-quality CPR is harmful, and its interactions with proposed interventions can be difficult to model or predict. Because the quality of manual CPR is difficult to effectively govern, Yannopoulos indicated that standard, manual CPR techniques are an unreliable control for studies testing alternate
CPR techniques, such as the impedance threshold devices developed by researchers from the Resuscitation Outcomes Collaborative.
Existence of underlying coronary artery stenosis also represents a notable challenge to cardiac arrest studies. The degree of blockage is directly related to the ability of achieving return of spontaneous circulation following a cardiac arrest. Therefore, the uneven distribution of patients with stenosis could mask the effect of a therapeutic prehospital intervention being tested when survival rates are used as the outcome measure. Yannopoulos said that having, arguably, one of the most important contributors to survival be an unknown, the untreated variable is a problem that may not be solved by randomization and that will ultimately affect the evaluation of the study results. Yannopoulos and colleagues (2016) tested an intervention that involved getting eligible patients to a catheterization laboratory for identification and appropriate treatment for stenosis (e.g., extracorporeal membrane oxygenation [ECMO]) and percutaneous coronary intervention [PCI]) within 2 hours of cardiac arrest. The researchers found a significant increase in survival and positive outcomes when this alternate approach to advanced cardiac life support was used—55 percent survival to hospital discharge and 50 percent with good neurological outcomes compared with less than 9 percent of controls following the current guidelines (Yannopoulos et al., 2016). Yannopoulos argued that, unless the scientific community tries to identify and treat the underlying cause of arrest, prehospital interventions might not reliably demonstrate an impact on survival rates when studied.
Opportunities for Advancing Cardiac Arrest Research
Advancing cardiac arrest research will require funding and new approaches to study design, said Yannopoulos. First, the scientific community and the nation must come together and “declare war on cardiac arrest.” He added that a united front will also be needed to establish a national initiative that combines resources from funding agencies, organizations, and industry. The funding should be used to review, evaluate, and fund basic, translational, and clinical research in the resuscitation field, commented Yannopoulos. In terms of study design, confounders and underlying determinants of cardiac arrest outcomes need to be considered and factored into the study design, said Yannopoulos, noting that clinicians and statisticians need to be part of the discussion and decisions regarding what level of significance, chance, and certainty are acceptable when considering the possible benefit to patients. Finally, said Yannopoulos, the nihilism related to resuscitation practice needs to be decreased—moving away from the mandated 0.05 p value.
Jeremy Brown and Arthur Sanders, Planning Committee Members3
Jeremy Brown and Arthur Sanders facilitated the two breakout sessions that discussed accelerating research and translation in response to Recommendations 6 and 7 in the Institute of Medicine’s report (see Appendix A). The two groups considered barriers and methodological challenges to overcome, partners to engage, and possible funding strategies to fulfill the vision of advancing resuscitation research and translating that research into high-quality cardiac arrest care. Some members of the breakout sessions identified a number of alternative research methods that could be used to respond to methodological limitations and improve resuscitation research. For example, the resuscitation field could support the broader use of adaptive trials, stratified patient groups, and individualized protocols that are tied to the principles of patient-centered research. Sanders echoed the call for the development and application of standardized definitions to guide cardiac arrest research and surveillance.
Brown and Sanders both encouraged greater focus on implementation science to ensure that research findings are reaching patients and being used to improve outcomes across the United States. Implementation science can also be used to identify practice gaps, said Sanders, and determine how disparities—including regional variation—can be remedied. The resuscitation field needs a better understanding of why some communities, hospitals, and emergency medical services systems demonstrate significantly better outcomes when compared with others and what strategies can be easily transferred from those benchmark communities and systems, he said. Sanders said the goal should be to identify and promote the adoption of effective, evidence-based practices nationwide.
As with surveillance initiatives, funding is a serious stumbling block for advancing research, Brown noted. Some members of Brown’s breakout group highlighted a number of areas where a lack of funding is particularly problematic. For example, a lack of funding limits opportunities for targeting funding toward specific areas of research, implementing evidence-based findings, investing in the next generation of cardiac arrest researchers, and exploring new research methodologies. In line with the national funding initiative that Yannopoulos described, some members of the breakout sessions suggested further exploration of a bundled fund-
3 Breakout session presenters were asked to summarize the major ideas and opinions proposed by individual participants during their respective breakout sessions. Individual statements described below are not necessarily the position of the presenter and should not be interpreted as consensus statements from the breakout group as a whole or of the National Academies of Sciences, Engineering, and Medicine.
ing mechanism that would allow funds to be allocated to agreed-upon research goals. The allocation of funds could evolve as the research needs and priorities shift, noted some individuals.
Given current and projected budget limitations, especially at NIH, Brown’s group discussed alternate strategies to gain further financial support for research. He suggested to start with how branding and marketing could be used to expand public awareness—separating cardiac arrest from heart diseases overall. Increased public awareness could, in turn, lead to greater advocacy for cardiac arrest and advocacy for additional funding for research. Brown said that, although many people know someone who has experienced a cardiac arrest, most people do not identify cardiac arrest as a top-10 health concern in the United States—signaling a lack of awareness. A few members of Brown’s breakout group also considered other fundraising strategies, such as building public−private partnerships with health-oriented funding foundations (e.g., the Bill & Melinda Gates Foundation, the Ford Foundation, Kellogg Foundation) and other partners. Brown and Sanders each offered a list of potential partners that could be engaged to overcome barriers and advance research efforts in the resuscitation field (see Box 3-2).
Cardiac arrest could leverage existing resources, infrastructure, and partnerships through a number of existing research programs across the federal government, said Brown. The Centers for Medicare & Medicaid Services’ Million Hearts Initiative is just one example. Brown also suggested that the resuscitation field should consider uniting with stroke and trauma to establish an NIH task force. Although improvements are possible using existing resources, true progress will require new and creative strategies, collaboration, and leadership, Brown emphasized, further proposing that the resuscitation field will need to identify a single convener in order to build the public−private partnerships required to stimulate growth across research and translation. It will be important to have a single, collaborative voice as the field moves forward together, concluded Brown.
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