The coronavirus disease 2019 (COVID‐19) pandemic has taken an unprecedented toll on the American healthcare system and economy. While numerous COVID‐19 clinical trials have been initiated in hopes of curtailing its impact, most preexisting clinical trials have been forced to suspend or limit activity, which itself can have significant consequences. Missed or postponed trial‐related assessments may hinder data quality, and heterogeneity in data collection both across the country and over time introduces bias. 1 In addition, COVID‐19 may lower specific event rates due to patients avoiding the healthcare system that could result in underpowered outcome analyses, or conversely, some end points (mortality) may be inflated. 2 Nonetheless, while the pandemic has exerted a significant toll on preexisting clinical trials, the increasingly recognized interplay of COVID‐19 with the cardiovascular system has prompted an urgent need for new studies. 3 As such, clinical trials have rapidly commenced to study the impact of COVID‐19 on cardiovascular populations and outcomes, as well as to test the effects of cardiovascular therapies on COVID‐19 disease course (eg, inhibitors of the renin‐angiotensin‐aldosterone system). 4 However, to date, the impact of COVID‐19 on the landscape and scope of preexisting and newly initiated cardiovascular clinical trials has not been systematically studied.
We extracted data from clinicaltrials.gov to describe characteristics of (1) cardiovascular clinical trials before COVID‐19 and (2) COVID‐19 trials with a cardiovascular focus in the United States as of May 13, 2020. All trials were required to be recruiting, enrolling by invitation, active but not recruiting, or suspended. Two reviewers classified all data not populated by the trials database. To define pre–COVID‐19 cardiovascular clinical trials, we used the preferred search term “cardiac disease” (which simultaneously searches synonyms), initially identifying 905 trials. We then excluded trials with a start date after March 16, 2020, when national guidance for social distancing was issued (final n=892). COVID‐19 trials were similarly identified by the preferred search term “COVID‐19.” From these COVID‐19 trials (n=156), we defined cardiovascular COVID‐19 trials by any of the following: a specific cardiovascular patient population (ie, patients with heart failure), a cardiovascular intervention (ie, primary cardiac drug therapy), or cardiovascular outcome (ie, cardiac events or biomarkers) (final n=25). Corresponding coronavirus case load on May 13, 2020, per state was downloaded. 5 Our investigation did not require institutional review board approval because all data were acquired from the public domain.
Among 892 pre–COVID‐19 cardiovascular trials (Table), the most common trial topics are heart failure (29%), electrophysiology (25%), and interventional cardiology (18%). Approximately half (54%) receive industry or federal funding, and trial phases are roughly evenly distributed. Most pre–COVID‐19 trials occur in states with a substantial COVID‐19 case load (New York, California, and Pennsylvania). The median (25th–75th percentile) time until anticipated trial completion is 414 (171–932) days.
Table 1.
Characteristics of Cardiovascular Clinical Trials Initiated Before and During COVID‐19
| Characteristic | Cardiovascular Trials Initiated Before COVID‐19 (n=892) | COVID‐19 Trials With a Cardiovascular Focus (n=25) | P Value* |
|---|---|---|---|
| Phase of trial, n (%) | 0.005 | ||
| I | 51 (5.7) | 2 (8.0) | |
| II | 102 (11.4) | 14 (56.0) | |
| III | 103 (11.5) | 4 (16.0) | |
| IV | 85 (9.5) | 1 (4.0) | |
| Not available | 551 (61.8) | 4 (16.0) | |
| Target enrollment (median, 25th–75th percentile) | 100 (40–359) | 200 (70–626) | 0.15 |
| Time from trial initiation (median, 25th–75th percentile) | 846 (441–1563) | 27 (18–34) | <0.001 |
| Anticipated time until trial completion (median, 25th–75th percentile) | 414 (171–932] | 232 (180–323) | 0.014 |
| Source of funding, n (%) | 0.002 | ||
| Industry | 330 (37.0) | 2 (8.0) | |
| Federal | 141 (15.8) | 2 (8.0) | |
| Both | 13 (1.5) | 0 (0.0) | |
| Other† | 408 (45.7) | 21 (84.0) | |
| States with the highest number of trials (COVID‐19 cases per state) | |||
| State 1 | California: 293 (73 218) | New York: 6 (345 828) | |
| State 2 | New York: 263 (345 828) | California: 5 (73 218) | |
| State 3 | Pennsylvania: 245 (62 194) | North Carolina: 3 (15 850) | |
| Cardiovascular trial field(s), n (%)‡ | |||
| Heart failure | 260 (29.1%) | … | |
| Electrophysiology | 223 (25.0%) | … | |
| Interventional | 160 (17.9%) | … | |
| Pediatric or congenital | 81 (9.1 %) | … | |
| General | 67 (7.5 %) | … | |
| COVID‐19 trial with cardiovascular patient population, n (%) | … | 7 (28.0%) | |
| COVID‐19 trial with any cardiovascular intervention, n (%) | … | 13 (52.0%) | |
| COVID‐19 trial with RAAS active agent, n (%) | … | 6 (24.0%) | |
| COVID‐19 trial with any cardiovascular outcome, n (%) | … | 16 (64.0%) | |
| COVID‐19 trial with biomarker outcome, n (%) | … | 8 (32.0%) | |
Data are in reference to May 13, 2020. COVID‐19 indicates coronavirus disease 2019; RAAS, renin‐angiotensin‐aldosterone system.
P values shown for chi‐square and Wilcoxon rank‐sum tests, as appropriate.
Other funders include individuals, universities, and community‐based organizations.
The 5 most frequent fields classified by investigators are listed (remaining categories include critical care, genetics, imaging, cardio‐oncology, pulmonary hypertension, prevention, cardiac surgery, and other). Each clinical trial was categorized in up to 2 fields.
Among 25 cardiovascular COVID‐19 trials (Table), 7 (28%) specifically enroll a cardiovascular population, and 13 (52)% employ a cardiovascular intervention (with renin‐angiotensin‐aldosterone system–based interventions occurring in 6 [24%]). Sixteen trials (64%) assess a cardiovascular outcome, and 8 (32%) specifically study a biomarker outcome (7 prespecified troponin and 5 prespecified natriuretic peptides). The most frequent trial sites are located in New York, California, and North Carolina. Fourteen studies are in phase II, and 4 receive industry or federal funding. The median (25th–75th percentile) time until anticipated trial completion is 232 (180–323) days.
Here, we describe the characteristics of active cardiovascular clinical trials initiated before COVID‐19 as well as recently initiated COVID‐19 trials with a cardiovascular focus. Of the 892 pre–COVID‐19 clinical trials, many enroll in states with substantial COVID‐19 burden that are likely suspended or limited in activity. Further, more than a quarter were anticipated to complete within 6 months. Heart failure, electrophysiology, and interventional cardiology trials are the most frequent ongoing trials. In the COVID‐19 era, a modest number of studies (25) include a cardiovascular patient population, intervention, or outcome. These trials, mostly in phase II, reflect the substantial interest in renin‐angiotensin‐aldosterone system–based therapies, principally use biomarker outcomes, and are largely anticipated to report in 2021. 3 , 4
While systematically searched, our data are limited to documented fields, and are thus predicated on accurately entered and updated information. In addition, these data will continue to evolve as further research is stimulated during the pandemic.
In conclusion, we present the landscape of ongoing cardiovascular clinical trials that were initiated before COVID‐19, as well as the characteristics of recently initiated COVID‐19 clinical trials with a cardiovascular focus. Such data underscore the magnitude of the toll COVID‐19 has taken on the clinical trial community and provide insight into new directions of cardiac‐focused COVID‐19 research.
Sources of Funding
None.
Disclosures
Dr Selvaraj receives research support from the National Institutes of Health (Training Grant 5‐T32HL007843‐23), the Doris Duke Charitable Foundation (Physician Scientist Fellowship Award 2020061), the Measey Foundation, Institute for Translational Medicine and Therapeutics (Junior Investigator Preliminary/Feasibility Grant Program award), and the American Society of Nuclear Cardiology (Institute for the Advancement of Nuclear Cardiology award). Dr Khatana is supported by the National Institutes of Health (Training Grant 5‐T32HL007843‐23). Dr Greene has received a Heart Failure Society of America/Emergency Medicine Foundation Acute Heart Failure Young Investigator Award funded by Novartis; has received research support from Amgen, AztraZeneca, Bristol‐Myers Squibb, Merck, and Novartis; serves on advisory boards for Amgen and Cytokinetics; and serves as a consultant for Amgen and Merck. Dr. Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lone Star Heart, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, Respicardia, Sanofi Pasteur, Theracos, and has consulted for Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi‐Sankyo, Gilead, GSK, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Tenaya, Sanofi‐Pasteur, Dinaqor, Tremeau, CellProThera, Moderna. Dr Bhatt discloses the following relationships—Advisory Board: Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, PhaseBio, PLx Pharma, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the CENTERA THV System in Intermediate Risk Patients Who Have Symptomatic, Severe, Calcific, Aortic Stenosis Requiring Aortic Valve Replacement [ExCEED] trial, funded by Edwards), Contego Medical (Chair, Protection Against Emboli During Carotid Artery Stenting Using the Neuroguard IEP System [PERFORMANCE‐II]), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the Edoxaban Compared to Standard Care After Heart Valve Replacement Using a Catheter in Patients With Atrial Fibrillation [ENVISAGE] trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice‐Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting [REDUAL‐PCI] clinical trial steering committee funded by Boehringer Ingelheim; AEGIS‐II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease [PRONOUNCE], funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Medtelligence/ReachMD (CME steering committees), Level Ex, MJH Life Sciences, Population Health Research Institute (for the Cardiovascular Outcomes for People Using Anticoagulation Strategies [COMPASS] operations committee, publications committee, steering committee, and USA national co‐leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), National Cardiovascular Data Registry (NCDR)‐ACTION Registry Steering Committee (Chair), Veterans Affairs Clinical Assessment, Reporting, and Tracking (VA CART) Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co‐Investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, Takeda. The remaining authors have no disclosures to report.
(J Am Heart Assoc. 2020;9:e018274 DOI: 10.1161/JAHA.120.018274.)
For Sources of Funding and Disclosures, see page 3.
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