Characteristics of clinical trials evaluating cardiovascular therapies for Coronavirus Disease 2019 Registered on ClinicalTrials.gov: a cross sectional analysis

Abstract

Background Morbidity and mortality associated with COVID-19 has increased exponentially , and patients with cardiovascular (CV) disease are at risk for poor outcomes. Several lines of evidence suggest a potential role for CV therapies in COVID-19 treatment. Characteristics of clinical trials of CV therapies related to COVID-19 registered on ClinicalTrials.gov have not been described. Methods ClinicalTrials.gov was queried on August 7, 2020 for COVID-19 related trials. Studies evaluating established CV drugs, other fibrinolytics (defibrotide), and extracorporeal membrane oxygenation were included. Studies evaluating anti-microbial, convalescent plasma, non-colchicine anti-inflammatory, and other therapies were excluded. Trial characteristics were tabulated from study-specific entries. Results A total of 2,935 studies related to COVID-19 were registered as of August 7, 2020. Of these, 1,645 were interventional studies, and the final analytic cohort consisted of 114 studies evaluating 10 CV therapeutic categories. Antithrombotics (32.5%; n=37) were most commonly evaluated, followed by pulmonary vasodilators (14.0%; n=16), renin-angiotensin-aldosterone system-related therapies (12.3%; n=14), and colchicine (8.8%; n=10). Trials evaluating multiple CV therapy categories and CV therapies in combination with non-CV therapies encompassed 4.4% (n=5) and 9.6% (n=11) of studies, respectively. Most studies were designed for randomized allocation (87.7%; n=100), enrollment of less than 1000 participants (86.8%; n=99), single site implementation (55.3%; n=63), and had a primary outcome of mortality or a composite including mortality (56.1%; n=64). Most study populations consisted of patients hospitalized with COVID-19 (81.6%; n=93). At the time of database query, 28.9% (n=33) of studies were not yet recruiting and the majority were estimated to be completed after December 2020 (67.8%; n=78). Most lead sponsors were located in North America (43.9%; n=50) or Europe (36.0%; n=41). Conclusions A minority (7%) of clinical trials related to COVID-19 registered on ClinicalTrials.gov plan to evaluate CV therapies. Of CV therapy studies, most were planned to be single center, enroll less than 1000 inpatients, sponsored by European or North American academic institutions, and estimated to complete after December 2020. Collectively, these findings underscore the need for a network of sites with a platform protocol for rapid evaluation of multiple therapies and generalizability to inform clinical care and health policy for COVID-19 moving forward.

Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19

“…Notwithstanding the good will of investigators, the constant pressure to provide a rapid pandemic response may pose challenges as well. In some cases, multiple small single-center RCTs underpowered for their clinical points or using surrogate endpoints with short follow-up have been designed ( 74 , 82 ) and may compete against larger multicenter, and potentially more definitive, studies. The large numbers of these trials alone, in addition to the intense pressure to present broadly and publish these findings, suggests at least some potential for type I error with amplification of these results through rapid dissemination of the results.…”

“…Additional methodological aspects deserve attention. Interpretation of these trial results may be limited by underutilization of placebo (perhaps except for the outcome of mortality) ( 57 , 82 ). Some experts consider that the pressures of working during a global pandemic make the use of placebo more aspirational than realistic.…”

Hospital mortality in COVID-19 patients in Belgium treated with statins, ACE inhibitors and/or ARBs

“…The sample size (959 patients) was small; our findings will need to be replicated in larger studies. We could not evaluate separately the effects of ACEI and ARB treatment, although investigators have reported greater effectiveness for ACEI compared with ARB treatment [94]. We did not correct for immortal time bias.…”

Antithrombotic Therapy in COVID-19: Systematic Summary of Ongoing or Completed Randomized Trials

“…Notwithstanding the good will of investigators, the constant pressure to provide rapid pandemic response may pose challenges, as well. In some cases, multiple small single-center RCTs underpowered for their clinical points or using surrogate endpoints with short follow-up have been designed (71, 79) and may compete against larger multicenter, and potentially more definitive, studies. The large numbers of these trials alone, in addition to the intense pressure to present broadly and publish these findings suggests at least some potential for Type I error with amplification of these results through rapid dissemination of the results.…”

“…Additional methodological aspects deserve attention. Interpretation of these trial results may be limited by underutilization of placebo (perhaps except for the outcome of mortality) (54, 79). Some experts consider that the pressures of working during a global pandemic makes the use of placebo more aspirational than realistic.…”