Placing the safety and well-being of heart failure trial participants and research team members first has become of the utmost importance, since the beginning of the COVID-19 pandemic. As a consequence of restrictions placed on clinical trials to meet this goal, the pandemic has disrupted every aspect of heart failure clinical trial activity, creating substantial challenges to site activation, study enrollment, patent follow-up, endpoint and event ascertainment, and site monitoring and source document verification. In addition, the pandemic has had a real effect on event rates, causing an approximate 50% reduction in heart failure hospitalizations during the peak of the first global COVID-19 wave.¹ While the cause of this reduction in heart failure hospitalizations is uncertain, it is likely due to public health warnings for at-risk patients to avoid contact with the hospital environment and the fear that such warnings has created within the heart failure patient community. In this context, COVID-19-related social distancing has resulted in many heart failure patients sheltering in place with little activity and even less social contact outside of the home. The effects of this increase in patient isolation on quality of life, particularly on social functioning, and on their propensity toward anxiety and depression has yet to be fully understood. Together, these observations create specific challenges for the execution, analysis, and interpretation of heart failure clinical trials data.

Fortunately, the implementation of multiple adaptations has allowed the heart failure clinical trials ecosystem to continue to function, albeit at a slowed pace, during the COVID-19 pandemic. While the protection of heart failure trial participants and research team members remains a primary goal of such strategies, preserving the integrity of heart failure clinical trials activity is also a major goal. Over the past year, a number of regulatory guidance documents have addressed the conduct of clinical trials in general during the COVID-19 pandemic,^2-4 and several statements from various professional societies and organizations in the cardiovascular medicine/heart failure space have focused on the conduct of heart failure clinical trials during the pandemic, in particular.^5-8 Taken together, these documents provide a reasonable roadmap, and following a year of experience with various recommended clinical trial modifications, the most successful of these strategies can be identified and suggested for ongoing use.

Telehealth and remote study assessments remain among the best means for safely continuing heart failure clinical trials activities during the COVID-19 pandemic. In addition to minimizing patient and research team member exposure to COVID-19, these adaptations minimize out-of-window study follow-up visits and missing study data. Of course, there are inherent challenges to converting in-person study visits and assessments to virtual ones. Some study assessments are difficult, if not impossible, to perform remotely. Validated assessments of exercise ability, such as the 6-minute hall walk test and the metabolic exercise test, blood sampling, and cardiac imaging studies (e.g., echocardiography) are a few examples of study assessments generally requiring in-person visits to a clinic or hospital-based facility. Fortunately, many measures can be reliably ascertained remotely including adverse events, mortality, morbidity (e.g., LVAD implantation, transplantation, hospitalization, and emergency department visits), medications and medication changes, clinician-determined functional status measures (e.g., the New York Heart Association Class Ranking),⁹ and many patient-reported outcomes such as the Kansas City Cardiomyopathy Questionnaire¹⁰ and the Minnesota Living with Heart Failure Questionnaire.¹¹ The approach to and validity of these remote patient assessments is extensively discussed elsewhere,⁷ and the remote assessment of various physiological parameters, such as heart rate, blood pressure, and pulse oximetry, during COVID-19 is addressed in a US Food and Drug Administration (FDA) guidance document.¹²

In cases where certain measures cannot be remotely assessed or an in-person study visit is required for reasons central to the execution of a trial, such as in the case of implantable heart failure device studies, study procedures or interventions may need to be delayed. Such delays increase the risk of out-of-window study visits and procedures and the likelihood of missing data. These risks must be taken into account in a revised statistical analysis plan. In this context, the general principle that "some data is better than no data" has been applied to heart failure clinical trials during the COVID-19 pandemic, so continued attempts to obtain such information, even if late, should be made.

Remote and/or risk-based clinical trial monitoring are generally effective approaches to increasing research team safety during the COVID-19 pandemic and have been endorsed by the FDA.^2,13 These approaches minimize or eliminate the need for on-site clinical trial monitoring, thus distancing study monitors from site study personnel. Purpose-built systems that support remote clinical trial monitoring in a secure, HIPAA-compliant manner are available and have seen broader use during the COVID-19 pandemic. However, the use of such systems may require certain special considerations in regions with very strict patient privacy and data protection laws.

Virtual rather than in-person investigator and coordinator meetings and meetings of various trial committees including executive and steering committees, clinical event adjudication committees, and data and safety monitoring boards have been successfully implemented as another means of social distancing during the COVID-19 pandemic. The conduct of clinical events adjudication requires special comment, due to the potential confounding effects of COVID-19 on clinical endpoints. Adjudication definitions should be adjusted to take into account the potential relatedness of events to COVID-19, for example, in the setting of acute COVID-19 infection, whether hospitalization for worsening heart failure is related or unrelated to COVID-19 and which event represents the primary cause of hospitalization. Such issues should be addressed prospectively in a revised clinical events committee manual of operation. In this context, ascertainment of COVID-19 exposure status through acute and convalescent antigen, PCR, and antibody testing, as well as the patient's vaccination status, should be recorded for each study participant. Knowledge of study participant COVID-19 exposure and vaccination status may aid in the development of COVID-19 adjusted statistical analyses. A recently concluded studied showed how even a crude COVID-19 adjustment excluding events accrued since the onset of the pandemic changed the results of a randomized controlled trial from negative to positive.¹⁴ General principles for statistical analysis of heart failure clinical trials conducted during the COVID-19 pandemic are further discussed in the professional society expert consensus statements.^7,8

An example of successful heart failure clinical trial adaptation using these strategies is the NIH-sponsored LOFT-HF (The Impact of Low Flow Nocturnal Oxygen Therapy on Hospital Admissions and Mortality in Patients With Heart Failure and Central Sleep Apnea) trial.¹⁵ Early in the pandemic, LOFT-HF transitioned to a fully virtual clinical trial requiring no in-person visits for site assessment, activation, and training; patient enrollment using eConsent and telehealth visits for baseline assessment and in-home sleep studies; touch-free delivery of oxygen concentrators to the patient's home; remote study follow-up visits; remote site monitoring; and virtual meetings of key trial committees, including the clinical events adjudication committee.

In conclusion, while the COVID-19 pandemic has posed substantial challenges to the conduct of heart failure clinical trials, solutions have been implemented to overcome many of these challenges. Many of these solutions have streamlined the conduct of heart failure clinical trials and may represent long-term strategies for trial implementation and conduct long after the end of the pandemic.

References

1. Cox ZL, Lai P, Lindenfeld J. Decreases in acute heart failure hospitalizations during COVID-19. Eur J Heart Fail 2020;22:1045-46.
2. Conduct of Clinical Trials of Medical Products During COVID-19 Public Health Emergency: Guidance for Industry, Investigators, and Institutional Review Boards (FDA website). 2021. Available at: https://www.fda.gov/media/136238/download. Accessed 03/31/2021.
3. Guidance for NIH-funded Clinical Trials and Human Subjects Studies Affected by COVID-19 (NIH website). 2020. Available at: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-20-087.html . Accessed 03/31/2021.
4. Guidance on the Management of Clinical Trials During the COVID-19 (Coronavirus) Pandemic (European Medicines Agency website). 2021. Available at: https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/guidanceclinicaltrials_covid19_en.pdf. Accessed 03/31/2021.
5. Abraham WT, Fiuzat M, Psotka MA, O'Connor CM. Heart Failure Collaboratory statement on clinical trials in the landscape of COVID-19. JACC Heart Fail 2020;8:423-25.
6. Abraham WT, Fiuzat M, Psotka MA, O'Connor CM. Heart Failure Collaboratory statement on remote monitoring and social distancing in the landscape of COVID-19. JACC Heart Fail 2020;8:692-94.
7. Psotka MA, Abraham WT, Fiuzat M, et al. Conduct of clinical trials in the era of COVID-19: JACC Scientific Expert Panel. J Am Coll Cardiol 2020;76:2368-78.
8. Anker SD, Butler J, Khan MS, et al. Conducting clinical trials in heart failure during (and after) the COVID-19 pandemic: an Expert Consensus Position Paper from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur Heart J 2020;41:2109-17.
9. Criteria Committee, New York Heart Association, Inc. Diseases of the Heart and Blood Vessels: Nomenclature and Criteria for Diagnosis. 6th ed. Boston, MA. Little, Brown and Co;1964:114.
10. Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart failure. J Am Coll Cardiol 2000;35:1245-55.
11. Rector TS, Cohn JN. Assessment of patient outcome with the Minnesota Living with Heart Failure questionnaire: reliability and validity during a randomized, double-blind, placebo-controlled trial of pimobendan. Pimobendan Multicenter Research Group. Am Heart J 1992;124:1017-25.
12. Enforcement policy for non-invasive remote monitoring devices used to support patient monitoring during the coronavirus disease-2019 (COVID-19) public health emergency: guidance for industry and food and drug administration staff (FDA website). 2020. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/enforcement-policy-non-invasive-remote-monitoring-devices-used-support-patient-monitoring-during . Accessed 03/21/2021.
13. Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring (FDA website). 2013. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/oversight-clinical-investigations-risk-based-approach-monitoring . Accessed 03/31/2021.
14. Ponikowski P, Kirwan BA, Anker SD, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. Lancet 2020;396:1895-1904.
15. The Impact of Low Flow Nocturnal Oxygen Therapy on Hospital Admissions and Mortality in Patients with Heart Failure and Central Sleep Apnea (ClinicalTrials.gov). 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT03745898. Accessed 03/31/2021.

Clinical Topics: Cardiovascular Care Team, COVID-19 Hub, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Prevention, Acute Heart Failure, Echocardiography/Ultrasound

Keywords: Heart Failure, COVID-19, Quality of Life, Health Insurance Portability and Accountability Act, Pandemics, Clinical Trials Data Monitoring Committees, Exercise Test, Heart Rate, Blood Pressure, Patient Isolation, United States Food and Drug Administration, Public Health, Interpersonal Relations, Hospitalization, Echocardiography, Telemedicine, Cardiomyopathies, Morbidity, Oximetry, Emergency Service, Hospital, Hospitals, Vaccination, Polymerase Chain Reaction

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