abbreviations:CDRH (Center for Devices and Radiological Health), CF (cystic fibrosis), CMS (Centers for Medicare & Medicaid Services), EP (electrophysiology), FDA (U.S. Food and Drug Administration), HFC (Heart Failure Collaboratory), HRS (Heart Rhythm Society), HVC (Heart Valve Collaboratory), IDE (investigational device exemption), NHI (National Institutes of Health), NHLBI (National Heart, Lung, and Blood Institute), PCORI (Patient-Centered Outcomes Research Institute), PCORnet (National Patient-Centered Clinical Research Network), PCT (pragmatic clinical trial), PI (primary investigator), QOL (quality of life), RCT (randomized clinical trial)
1. Objectives and goals of this research white paper and the current electrophysiology research landscape
2. Perspectives on challenges and opportunities for future EP research
2.1 HRS members’ perspectives
2.1 a Results from the HRS Member Survey on Barriers to Clinical/Translational Research: Unmet needs
2.1 b HRS members' perspective from the research community at the EP Collaboratory summit
2.2 FDA perspective
Software as a Medical Device (SaMD).
The least burdensome provisions: concept and principles. Guidance for industry and FDA staff.
Guidance for the use of Bayesian statistics in medical device clinical trials.
Electrophysiology Predictable and Sustainable Implementation of National Registries (EP PASSION).
Requests for feedback and meetings for medical device submissions: the Q-Submission Program. Guidance for industry and food and drug administration staff.
2.3 Industry perspective
2.4 Research funding perspective
3. Future opportunities for growth in EP research
3.1 Pragmatic trial designs and evidence generation
|Representative participants||Highly selected participants|
|Considers social determinants of health/environment||Focuses on biology|
|Recruits in usual care, many centers||Recruits using nonusual care screening or recruitment strategies, fewer centers|
|Incorporates settings where results apply||Limits applicability to many settings|
|Interventions “slotted” into usual care||Interventions may need additional resources|
|Flexibility in delivery and adherence||Standardized delivery and highly controlled adherence|
|Follow-up parallels usual care||More intensive follow-up|
|Often multiple primary outcomes that are patient centered||Primary outcome may not be relevant to participants|
|Primary analysis is intention-to-treat||Primary analysis is per protocol|
3.2 Digital health, technology, and social media
- Waring M.E.
- Hills M.T.
- Lessard D.M.
- et al.
|Digital health, technology, and social media||Longitudinal patient assessment.|
Digital health metrics and clinical outcomes.
Heart rhythm disease prediction.
Large-scale population management.
|Regulatory and reimbursement barriers.|
Reliability of data.
Health privacy and ownership of health data.
Institutional inertia to digital adoption.
|Incorporate digital data and tools into clinical trials.|
Create public health and study awareness with patient advocacy groups.
Develop digital tools to engage research participants.
|Diversity and representative populations||Increasing diversity improves health care quality.|
Learning from prior studies with diverse enrollment.
|Lack of diversity and representation in clinical trials.||Diversity working group and diversity champions.|
Diverse research and clinical trial leadership.
|International collaboration||Diverse populations.|
Broad result dissemination.
Large sample size.
Complex, diverse regulatory processes.
|Repositories of regulatory documents.|
International study leads, clinical research organizations, translation services.
|Implementation science||Provider education and training.|
Representative clinical trial populations.
Patient-reported outcomes/quality of life measures.
|Lack of clinical trial data adoption.|
Applied results to clinical practice.
Coverage for new therapies.
|Upstream pragmatic clinical trial designs.|
Incorporate patient input.
Engage regulators, payers.
Research finding and trial result dissemination.
|Translational research||Develop new treatments.|
Transform discoveries to clinical practice.
Determine treatment dosing.
Provide foundation for regulatory approval and clinical trials.
|Difficult replication of the clinical state.|
Costly animal models and translational facilities.
Decline in physician-scientists and protected research time.
Establish core resources and core expertise.
Identify unmet needs/knowledge gaps.
Translational research curriculum/mentorship.
3.3 Maximizing diversity and representative populations
- •Collaborative community infrastructure. The organization of a Collaboratory will include diversity champions to ensure diversity and representation of the enrolled populations. In addition, the inclusion of a diverse stakeholder group may further cultivate potential solutions.
- •Diversity working group. The goal of a dedicated diversity working group would be to work in collaboration with various stakeholders (eg, funding agencies and industry) to identify key priority areas and deliverables, specifically defining diversity benchmarks, best practices, and mechanisms for accountability. For example, this group could establish enrollment targets for sex, racial, or ethnic groups based on specific disease prevalence as well as diversity targets for leadership positions in trials and measures of accountability.
- •Lessons learned from the past. There are several notable examples of cardiovascular clinical trials that have exclusively focused on enrolling underrepresented populations.28,29,30Establishing a mechanism to learn from prior studies that were successful at enrolling diverse patients will be important. The follow-through would be to have a platform where successful strategies could be summarized and shared. This may help inform the design of future studies that could formally test those strategies.
- •Protocol to practice. A strong research system would ideally be examined to determine ways for improving the representation of diverse populations. Examples include (1) review of eligibility criteria that would promote diverse enrollment, (2) use of technologies such as electronic health records for screening, (3) identification of sites with diverse populations, (4) providing local investigators with a tool kit to help maximize diversity, and (5) ensuring educational material is tailored to diverse populations.
- •Building capacity. Prior studies have shown that diverse research leadership results in more diverse patient enrollment. This begins by developing initiatives that increase diversity at all levels of the medical workforce.31Identifying and training diverse research team members (local PI, national PI, steering committee, and executive committee), particularly in leadership positions, may maximize the recruitment of representative populations.
3.4 International collaborative research
3.5 Implementation science
- Chan W.V.
- Pearson T.A.
- Bennett G.C.
- et al.
3.6 Translational research
4. Potential blueprints for addressing the challenges to growth in EP research
4.1 Patient-centered foundation’s clinical trial ecosystem
Annual reports and financials.
4.2 Federal funding initiatives
- National Heart Lung
Clinical trial development continuum.
4.3 Role of the FDA
Collaborative communities: addressing health care challenges together.
4.4 Collaboratory experience in the cardiac space: Genesis, design, and activities of the Heart Valve and Heart Failure Collaboratories
4.5 An EP Collaboratory
5. Governance and structure of an EP Collaboratory: Role of HRS
- Supplementary matirial
|Ownership/partnership/principal/majority stockholder||Stock or stock options||Intellectual property/royalties||Other|
|Duy T. Nguyen, MA, MD, FHRS||Stanford University, Stanford, California||None||None||None||None||None||None||None||None|
|Kenneth C. Bilchick, MD, MS, FHRS||University of Virginia Health System, Charlottesville, Virginia||None||None||3: Siemens; 4: University of Virginia; 5: AHA; 5: NIH/NHLBI||None||None||None||None||None|
|Sanjiv M. Narayan, MD, PhD, FHRS||Stanford University, Stanford, California||1: TDK Inc; 1: UpToDate; 2: LifeSignals; 3: Abbott||None||5: NIH||None||None||None||2: University of California Regents||None|
|Mina K. Chung, MD, FHRS||Cleveland Clinic, Department of Cardiovascular Medicine, Heart, Vascular & Thoracic Institute, and Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland, Ohio||1: Columbia University School of Medicine; 1: Kansas City Heart Rhythm Society; 1: Geisinger Health Systems; 1: Arrhythmia Education, Inc; 1: Cleveland Clinic; 1: France ANR; 2: ABIM||None||5: NIH; 5: AHA||None||None||None||1: Elsevier; 1: UpToDate||3: AHA|
|Kevin Thomas, MD, FHRS||Duke University Medical Center, Durham, North Carolina||1: Biosense Webster, Inc; 1: Janssen Pharmaceuticals||None||2: NIH/NHLBI||None||None||None||None||None|
|Kenneth R. Laurita, PhD||Case Western Reserve University, Cleveland, Ohio||None||None||0: NIH||None||None||None||None||None|
|Marmar Vaseghi, MD, MS, PhD, FHRS||University of California, Los Angeles Cardiac Arrhythmia Center, Los Angeles, California||1: Biosense Webster, Inc; 1: Medtronic, Inc||None||None||None||None||0: NeuCures||None||None|
|Roopinder Sandhu, MD, MPH, FHRS||Cedars-Sinai Medical Center, Los Angeles, California||None||None||3: BMS-Pfizer Alliance; 5: Servier||None||None||None||None||None|
|Mihail G. Chelu, MD, PhD, FHRS||Baylor College of Medicine, Houston, Texas||1: Medtronic; 1: Impulse Dynamics USA||None||0: Abbott; 0: Impulse Dynamics USA||None||None||None||None||1: Biosense Webster, Inc|
|Prince J. Kannankeril, MD, MSci, FHRS, CEPS-P||Vanderbilt University Medical Center, Nashville, Tennessee||None||None||5: NIH||None||None||None||None||0: PACES|
|Douglas L. Packer, MD, FHRS||Mayo Clinic-St. Mary’s Hospital, Rochester, Minnesota||0: Johnson & Johnson; 0: Atrifix, Inc; 0: Medlumics; 0: Centrix; 0: NeuCures; 0: Xenter, Inc; 0: Biosense Webster, Inc; 0: CardioFocus, Inc; 0: St. Jude Medical; 0: Sig.num Pre-emptive Healthcare, Inc; 0: Thermedical; 0: Spectrum Dynamics; 0: Medtronic; 0: Abbott; 1: Mediasphere Medical||None||0: Abbott; 0: Siemens; 0: Robertson Foundation; 0: Medtronic; 1: University of Utah; 2: Boston Scientific; 3: Biosense Webster, Inc; 3: Mayo Clinic Heart Rhythm Development; 4: Thermedical; 4: Goldsmith Foundation; 5: NIH; 5: St. Jude Medical||None||None||None||0: AHA; 4: Wiley-Blackwell; 4: St. Jude Medical||1: Abbott; 1: Medtronic; 1: Thermedical; 1: Cordis–Johnson & Johnson|
|David D. McManus, MD, MSci, FHRS||University of Massachusetts Medical School, Worcester, Massachusetts||0: Mobile Sense; 1: Samsung; 1: Rose Consulting; 1: FLEXcon; 1: Philips; 1: Avania; 2: Fitbit; 2: BMS; 2: Pfizer, Inc; 3: Heart Rhythm Society||None||0: Samsung; 0: Apple Inc; 0: Care Evolution; 0: Fitbit; 4: Otsuka Pharmaceuticals; 4: Sanofi; 4: FLEXcon; 5: Biotronik; 5: Pfizer, Inc; 5: BMS; 5: Boehringer Ingelheim; 5: Philips||None||None||None||None||2: Boston Biomedical Associates|
|Atul Verma, MD, FRCPC, FHRS||Southlake Regional Health Center, Newmarket, Ontario, Canada||1: Kardium; 1: Galaxy Medical, Inc; 1: Bayer HealthCare Pharmaceuticals; 1: Thermedical; 2: Biosense Webster, Inc; 2: Medtronic||None||2: Adagio Medical||None||None||None||None||None|
|Matthew Singleton, MD, MHS, MSci||WellSpan Health, York, Pennsylvania||1: Biosense Webster, Inc||None||None||None||None||None||None||None|
|Khaldoun Tarakji, MD, MPH, FHRS||Cleveland Clinic, Cleveland, Ohio||1: Medtronic; 1: Janssen Pharmaceuticals; 2: AliveCor||None||None||None||None||None||None||None|
|Sana M. Al-Khatib, MD, MHS, FHRS, CCDS||Duke University Medical Center, Durham, North Carolina||None||None||1: Medtronic; 1: Abbott; 1: Boston Scientific||None||None||None||None||3: AHA|
|Jonathan R. Kaltman, MD||Children’s National Hospital, Washington, District of Columbia||None||None||None||None||None||None||None||None|
|Ravi C. Balijepalli, PhD||NHLBI, NIH, Bethesda, Maryland||None||None||None||None||None||None||None||None|
|George F. Van Hare, MD, FHRS, CEPS-P||Office of Cardiovascular Devices, Center for Devices and Radiological Health, U.S. Food and Drug Administration, Silver Spring, Maryland||None||None||None||None||None||None||None||0: International Board of Heart Rhythm Examiners|
|Jodie L. Hurwitz, MD, FHRS||North Texas Heart Center, Dallas, Texas||None||None||None||None||None||None||None||None|
|Andrea M. Russo, MD, FHRS||Cooper University Hospital, Camden, New Jersey||1: Biosense Webster, Inc; 1:|
PaceMate; 1: Biotronik;
1: BMS-Pfizer Alliance
|None||1: MediLynx; 1: Kestra, Inc; 2: Boston Scientific||None||None||None||1: Up to Date||1: Medtronic; 1: ABIM; 1: Boston Scientific|
|Fred M. Kusumoto, MD, FHRS||Mayo Clinic Jacksonville, EP and Pacing Services, Jacksonville, Florida||None||None||None||None||None||None||None||None|
|Christine M. Albert, MD, MPH, FHRS||Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California||None||None||5: Abbott; 5: Roche Diagnostics; 5: St. Jude Medical; 5: NIH||None||None||None||None||None|
|Ownership/partnership/principal/majority stockholder||Stock or stock options||Intellectual property/royalties||Other|
|Kristen B. Campbell, PharmD||Duke University Hospital, Durham, North Carolina||None||None||None||None||None||None||None||None|
|Nassir F. Marrouche, MD, FHRS||Tulane University School of Medicine, New Orleans, Louisiana||0: Sanofi; 1: Biotronik; 1: Biosense Webster, Inc; 1: Bristol Myers Squibb; 1: AtriCure, Inc||None||0: Abbott; 0: Boston Scientific; 1: Janssen Pharmaceuticals||None||0: Cardiac Design||None||None||None|
|Daniel P. Morin, MD, MPH, FHRS||Ochsner Clinic, New Orleans, Louisiana||1: Abbott||1: Boston Scientific; 2: Zoll Medical Corporation||None||None||None||None||None||None|
|Jayasree Pillarisetti, MD, FHRS||UT Health San Antonio, San Antonio, Texas||None||None||None||None||None||None||None||None|
- Frequency of cardiac rhythm abnormalities in a half million adults.Circ Arrhythm Electrophysiol. 2018; 11e006273
- Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study.Circulation. 2014; 129: 837-847
- The spectrum of epidemiology underlying sudden cardiac death.Circ Res. 2015; 116: 1887-1906
- Atrial fibrillation: epidemiology, pathophysiology, and clinical outcomes.Circ Res. 2017; 120: 1501-1517
- Software as a Medical Device (SaMD).https://www.fda.gov/medical-devices/digital-health-center-excellence/software-medical-device-samdDate accessed: July 30, 2022
- strategic priorities.
- The least burdensome provisions: concept and principles. Guidance for industry and FDA staff.https://www.fda.gov/regulatory-information/search-fda-guidance-documents/least-burdensome-provisions-concept-and-principlesDate accessed: July 30, 2022
- Guidance for the use of Bayesian statistics in medical device clinical trials.https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-use-bayesian-statistics-medical-device-clinical-trialsDate accessed: July 30, 2022
- Electrophysiology Predictable and Sustainable Implementation of National Registries (EP PASSION).https://nestcc.org/portfolio-item/electrophysiology-predictable-and-sustainable-implementation-of-national-registries-ep-passion/Date accessed: July 30, 2022
- Leveraging existing clinical data for extrapolation to pediatric uses of medical devices. Guidance for industry and food and drug administration staff.
- Requests for feedback and meetings for medical device submissions: the Q-Submission Program. Guidance for industry and food and drug administration staff.https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-meetings-medical-device-submissions-q-submission-programDate accessed: July 30, 2022
- National Heart, Lung, and Blood Institute cardiovascular clinical trial perspective.Am Heart J. 2020; 224: 25-34
- What are pragmatic trials?.BMJ. 1998; 316: 285
- Cluster randomized controlled trials.J Eval Clin Pract. 2005; 11: 479-483
- Pragmatic trials.N Engl J Med. 2016; 375: 454-463
- The PRECIS-2 tool: designing trials that are fit for purpose.BMJ. 2015; 350: h2147
- Pragmatic clinical trials embedded in healthcare systems: generalizable lessons from the NIH Collaboratory.BMC Med Res Methodol. 2017; 17: 144
- A digital health industry cohort across the health continuum.NPJ Digit Med. 2020; 3: 68
- Mobile health advances in physical activity, fitness, and atrial fibrillation: moving hearts.J Am Coll Cardiol. 2018; 71: 2691-2701
- Emerging technologies for identifying atrial fibrillation.Circ Res. 2020; 127: 128-142
- Survey of current perspectives on consumer-available digital health devices for detecting atrial fibrillation.Cardiovasc Digit Health J. 2020; 1: 21-29
- Patient-reported triggers of paroxysmal atrial fibrillation.Heart Rhythm. 2019; 16: 996-1002
- Atrial fibrillation future clinic: novel platform to integrate smart device electrocardiogram into clinical practice.Cardiovasc Digit Health J. 2021; 2: 92-100
StopAfib.org. Accessed July 30, 2022.
- Characteristics associated with Facebook use and interest in digital disease support among older adults with atrial fibrillation: cross-sectional analysis of baseline data from the Systematic Assessment of Geriatric Elements in Atrial Fibrillation (SAGE-AF) cohort.JMIR Cardio. 2019; 3e15320
- Diversity improves performance and outcomes.J Natl Med Assoc. 2019; 111: 383-392
- Overcoming lack of diversity in cardiovascular clinical trials: a new challenge and strategies for success.Circulation. 2019; 140: 1690-1692
- A trial of blood-pressure reduction in black barbershops.N Engl J Med. 2018; 379: 200-201
- Combination of isosorbide dinitrate and hydralazine in blacks with heart failure.N Engl J Med. 2004; 351: 2049-2057
- Outcomes in women and minorities compared with white men 1 year after everolimus-eluting stent implantation: insights and results from the PLATINUM Diversity and PROMUS Element Plus Post-Approval Study pooled analysis.JAMA Cardiol. 2017; 2: 1303-1313
- The urgent and ongoing need for diversity, inclusion, and equity in the cardiology workforce in the United States.J Am Heart Assoc. 2021; 10e018893
- Avoiding pitfalls with implementation of randomized controlled multicenter trials: strategies to achieve milestones.J Am Heart Assoc. 2016; 5e004432
- Effective strategies for implementing a multicenter international clinical trial.J Nurs Scholarsh. 2008; 40: 101-108
- Provider education to promote implementation of clinical practice guidelines.Chest. 2000; 118: 33S-39S
- ACC/AHA special report: clinical practice guideline implementation strategies: a summary of systematic reviews by the NHLBI Implementation Science Work Group: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.J Am Coll Cardiol. 2017; 69: 1076-1092
- Generalizability of clinical trials supporting the 2017 American College of Cardiology/American Heart Association Blood Pressure Guideline.JAMA Intern Med. 2020; 180: 795-797
- Generalizability of the REDUCE-IT trial in patients with stable coronary artery disease.J Am Coll Cardiol. 2019; 73: 1362-1364
- Under-reporting and under-representation of racial/ethnic minorities in major atrial fibrillation clinical trials.JACC Clin Electrophysiol. 2020; 6: 739-741
- Participation of women in clinical trials: not yet time to rest on our laurels.J Am Coll Cardiol. 2018; 71: 1970-1972
- Atrial fibrillation ablation in practice: assessing CABANA generalizability.Eur Heart J. 2019; 40: 1257-1264
- Generalizability of the CASTLE-AF trial: catheter ablation for patients with atrial fibrillation and heart failure in routine practice.Heart Rhythm. 2020; 17: 1057-1065
- Gaps in patient-reported outcome measures in randomized clinical trials of cardiac catheter ablation: a systematic review.Eur Heart J Qual Care Clin Outcomes. 2020; 6: 234-242
- Preclinical research: make mouse studies work.Nature. 2014; 507: 423-425
- Translation of research evidence from animals to humans.JAMA. 2006; 296: 1731-1732
- Translational models of arrhythmia mechanisms and susceptibility: success and challenges of modeling human disease.Front Cardiovasc Med. 2019; 6: 135
- Why translation from basic discoveries to clinical applications is so difficult for atrial fibrillation and possible approaches to improving it.Cardiovasc Res. 2021; 117: 1616-1631
- Methodological rigor in preclinical cardiovascular research: contemporary performance of AHA scientific publications.Circ Res. 2021; 129: 887-889
- Translational applications of computational modelling for patients with cardiac arrhythmias.Heart. 2020; 107: 456-461
- NIH research funding and early career physician scientists: continuing challenges in the 21st century.FASEB J. 2014; 28: 1049-1058
- Annual reports and financials.https://www.cff.org/about-us/reports-and-financials/annual-reports-and-financials/Date accessed: July 30, 2022
- Patient registry.
- Cystic fibrosis.Lancet. 2009; 373: 1891-1904
- Publication of trials funded by the National Heart, Lung, and Blood Institute.N Engl J Med. 2013; 369: 1926-1934
- Clinical trial development continuum.https://www.nhlbi.nih.gov/grants-and-training/clinical-trial-development-continuumDate accessed: July 30, 2022
- Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: the CABANA randomized clinical trial.JAMA. 2019; 321: 1261-1274
- The ADAPTABLE trial and PCORnet: shining light on a new research paradigm.Ann Intern Med. 2015; 163: 635-636
- Collaborative communities: addressing health care challenges together.https://www.fda.gov/about-fda/cdrh-strategic-priorities-and-updates/collaborative-communities-addressing-health-care-challenges-togetherDate accessed: July 30, 2022
- Consensus document on non-suitability for transcatheter mitral valve repair by edge-to-edge therapy.Struct Heart. 2021; 5: 227-233
- Design of a “lean” case report form for heart failure therapeutic development.JACC Heart Fail. 2019; 7: 913-921
- Heart failure end points in cardiovascular outcome trials of sodium glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus: a critical evaluation of clinical and regulatory issues.Circulation. 2019; 140: 2108-2118
- Standardized definitions for evaluation of heart failure therapies: scientific expert panel from the Heart Failure Collaboratory and Academic Research Consortium.JACC Heart Fail. 2020; 8: 961-972
Funding Sources: Heart Rhythm Society.
Disclosures: The authors have no conflicts of interest to disclose.
The views expressed in this manuscript are those of the authors. This manuscript does not necessarily represent the views, practices, policies, requirements, or recommendations of the National Heart, Lung, and Blood Institute; the National Institutes of Health; the U.S. Department of Health and Human Services; the U.S. Food and Drug Administration; or the Heart Rhythm Society.