COVID-19 and the cardiovascular system: a systematic review of the clinical trial landscape
Original Article

COVID-19 and the cardiovascular system: a systematic review of the clinical trial landscape

Hendre Fichardt1, Gail Fernandes2, Anand Prasad3

1Department of Internal Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; 2University of Notre Dame, Notre Dame, IN, USA; 3Department of Medicine, Division of Cardiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

Contributions: (I) Conception and design: All authors; (II) Administrative support: All authors; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: H Fichardt, G Fernandes; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Hendre Fichardt, MD. Resident physician at the Department of Internal Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. Email: hendredt@gmail.com.

Background: At the end of 2019, a novel coronavirus was identified as the cause of a cluster of pneumonia cases in Wuhan, China. Due to its high rate of interpersonal transmission the disease rapidly spread in China resulting in an epidemic and subsequently a pandemic with severe impact on social, economic and medical systems globally. Our understanding of the SARS-CoV-2 virus and its effects on the human body continues to evolve as new information becomes available. This paper is an overview of ongoing clinical trials registered with ClinicalTrials.gov on August 3, 2020 to guide future research and clinical practice. Our objective is to do a systematic review of the existing trials registered with ClinicalTrials.gov related to COVID-19 and the cardiovascular (CV) system. The aim of this is to describe the ongoing research in order to guide future practice and evaluate areas of deficiencies.

Methods: We conducted our search on ClinicalTrials.gov (https://clinicaltrials.gov/) on August 3, 2020 and used the key terms “COVID-19” and “cardiovascular. An independent two-person review was carried out for exclusion criteria. Exclusion criteria was defined as studies that were terminated, withdrawn, suspended, of unknown status, or had no connection to the CV system. Three duplicate studies were removed; 141 studies were removed after an independent two person review determined that it did not hold any relevant connection to the CV system and two studies were removed from the data as they were withdrawn and suspended respectively. There were no conflicting opinions between the two researchers regarding the 141 clinical trials excluded. The remaining 122 studies included were then grouped together based on their primary and secondary objectives. The trial was conducted in accordance with the Declaration of Helsinki. No experiments involving humans were done by the researchers and therefore ethical approval was not required.

Results: We found 122 studies applicable to our search criteria and then grouped them together based on topics of investigation as identified by primary and secondary objectives. The identified studies varied from observational, registry based and interventional with most of them falling into the first two categories. The studies were ongoing at that point and did not have results to report or analyze.

Conclusions: Our search on ClinicalTrials.gov produced a variety of studies that investigate relationships between COVID-19 and the CV system. Our search identified the main areas with ongoing research that has the ability to resolve controversies regarding current management of patients with COVID-19 including the ideal thromboprophylaxis regimen; arrhythmogenic potential of patients with COVID-19 and appropriate monitoring of these patients and long term morbidity related to COVID-19 and the CV system. The key finding of our analysis is that the majority of the ongoing studies are observational in nature and not randomized controlled trials. Review of these ongoing studies can aid medical professionals and researchers in outlining current areas of clinical equipoise and help with planning prospective research study topics and design.

Keywords: COVID-19; cardiovascular (CV); cardiology; clinicaltrials.gov; SARS-Cov-2


Received: 12 November 2020; Accepted: 22 December 2020; Published: 30 March 2021.

doi: 10.21037/jxym-20-110


Introduction

The spread of the disease known as COVID-19 caused by the novel SARS-CoV-2 viral strain has resulted in a global pandemic. The virus impacts multiple organ systems resulting in a wide variety of clinical presentations. Data on cardiovascular (CV) involvement has been emerging steadily in the literature (1). Specific aspects of interest include risk and benefits of CV specific medications, myocardial injury, ventricular dysfunction, arrhythmias, vascular thrombosis and even the psychological impact of the pandemic on CV health. Multiple clinical trials are underway to study and characterize these areas of interest, and in this paper, we classify these ongoing studies utilizing the ClinicalTrials.gov database. We present the following article in accordance with the PRISMA reporting checklist (available at http://dx.doi.org/10.21037/jxym-20-110).


Methods

We conducted our search on ClinicalTrials.gov (https://clinicaltrials.gov/) on August 3, 2020 and used the key terms “COVID-19” and “cardiovascular. No filters were applied in order to include all studies registered with the database filtered by the search phrases, regardless of the clinical trial phase or type of clinical trial. An independent two-person review was carried out for exclusion criteria. Exclusion criteria was defined as studies that were terminated, withdrawn, suspended, of unknown status, or had no connection to the CV system. Three duplicate studies were removed; 141 studies were removed after an independent two person review determined that it did not hold any relevant connection to the CV system and two studies were removed from the data as they were withdrawn and suspended respectively. There were no conflicting opinions between the two researchers regarding the 141 clinical trials excluded. The remaining 122 studies included were then grouped together based on their primary and secondary objectives and summarized in Table S1. The trial was conducted in accordance with the Declaration of Helsinki. No experiments involving humans were done by the researchers and therefore ethical approval was not required.


Results

The study search results are shown in Figure 1. Based on these search criteria, we identified 268 ongoing clinical trials in the database. We removed 3 duplicate studies and 265 studies remained. After exclusion criteria, 141 studies were subsequently excluded. The specific studies and details of the remaining 122 studies are shown in Table S1. The overview of the studies according to subject area is shown in Figure 2. The vast majority of studies focused on anticoagulation or cardiac injury in COVID-19 patients. Observational protocols or registries were the predominant studies.

Figure 1 PRISMA flow diagram.
Figure 2 Chart representing the number of studies within each category.

Discussion

Clinical trials related to the Renin Angiotensin Aldosterone System (RAAS)

Angiotensin converting enzyme inhibitors (ACEi) and Angiotensin Receptor blockers (ARB) are members of a class of widely used medications for hypertension and are favored for their renoprotective effects and impact on CV outcomes. It has been discovered that the SARS-CoV-2 virus enters the lungs through the ACE2 receptor. In animal models, the use of ACEi and ARB led to an increased expression of ACE2 membrane bound aminopeptidase in the pulmonary, CV and renal systems (2,3). Thus, some healthcare providers and media sources have questioned the continued use of ACE inhibitors and ARBs due to concerns that patients could experience an augmentation of SARS-CoV-2 infection and severity due to these drugs (4). In contrast, emerging research suggests that the use of these drugs is likely safe in COVID-19 (5). Some research even suggests that RAAS blockade has potential benefits in the prevention and treatment of lung injury caused by COVID-19 (6,7). The current recommendation from the European Society of Hypertension, the European Society of Cardiology, the American Heart Association, the Heart Failure Society of America, and the American College of Cardiology is not to withhold RAAS blockers as a standard of therapy (8,9). Much of the currently published data consists of animal studies or expert opinions and therefore high quality research is needed to better understand the interaction of COVID-19 and RAAS.

In our search of ClinicalTrials.gov, we found 11 studies investigating the correlation between RAAS and COVID-19 disease course, 3 of which are interventional randomized controlled clinical trials (RCTs) while the remaining are large volume observational studies (Table S1, studies 1–11). Combined, the observational studies are targeting 11,155 participants with the largest observational study having 7,000 recruits. This latter study (Mach et al., study #8 in Table S1) is a single center observational study at the Geneva University Hospital whose primary aim is to gather data comparing clinical outcomes in COVID-19 hospitalized patients with and without CVD. Furthermore, the investigators will study prognosis and outcomes according to the use of RAAS blockade. Other studies in this category compare time to clinical improvement, severity of disease, and mortality in patients using versus not using RAAS blockade. The 3 interventional studies (Montalescot et al., study #4, Lopes et al., study #5, and University of Pennsylvania, study #7 in Table S1) all test continuation versus discontinuation of RAAS blockers in patients admitted with COVID-19 infection previously using these medications, and will enroll a total of 1,406 participants. Primary objectives of these studies include (I) time to clinical improvement, (II) number of days alive in and out of the hospital, and (III) composite endpoint including time to death, number of days requiring mechanical ventilation or extra-corporeal membrane oxygenation (ECMO), number of days requiring renal replacement therapy or vasopressor use, and Sequential Organ Failure Assessment (SOFA) scores.

Anticoagulation and prothrombotic state in COVID-19 patients

Evidence of abnormal coagulation parameters associated with COVID-19 appeared in early reports from China and Japan (10). A prominent increase in D-dimer levels as a predictor of adverse outcomes is persistently seen in COVID-19 infection suggesting an underlying coagulopathy (11). Based on this observation, ongoing studies aim to understand the prevalence and characteristics of coagulation abnormalities in these patients while others investigate therapeutic options. Our search revealed a total of 38 studies that investigate the relationship between anticoagulation and COVID-19 (Table S1, Studies 12–49). Twenty-two of these studies are observational in nature, while 16 test an intervention. Many of the studies aim to determine which anticoagulation regimen is beneficial and safe, while others aim to describe the incidence of thromboembolic complications in COVID-19. The studies are separated into two main objectives: to define the abnormal coagulation parameters identified in COVID-19 patients by means of laboratory testing or to identify the number of thrombotic related complications including deep venous thrombi (DVT), pulmonary emboli (PE), and arterial thrombi. Thirteen of the interventional studies compare the standard of care thromboprophylaxis to an intervention for prevention of thrombotic events. These latter studies assessed the outcomes for efficiency of the intervention at preventing thrombotic complications and the safety in terms of bleeding risk. The interventional drugs include therapeutic anticoagulation with low molecular weight heparin (LMWH), unfractionated heparin, direct oral anticoagulants (DOACs), and adjusted dose prophylaxis with LMWH. One interventional trial investigates whether infusion of an Angiotensin 1–7 related peptide is effective at normalizing the hypercoagulable state (Owen et al., study #39 in Table S1). The authors hypothesize that the coagulopathy associated with COVID-19 is driven by overactivation of the RAAS system causing a relative deficiency of Angiotensin 1–7 peptide (12).

Arrhythmias

A heightened concern for increased arrhythmic burden (atrial and ventricular) has been present in patients with COVID-19. Recently, a meta-analysis stated that 19% of hospitalized patients and 48% of patients in the Intensive Care Unit with COVID-19 and poor outcomes had cardiac arrhythmias (13). Cardiac arrhythmias, hypotension and sudden cardiac death are each associated with COVID-19 (14). Cardiac injury by biomarker detection or frank ventricular dysfunction in these patients is also associated with the development of arrhythmias. Our search revealed 4 studies concerning COVID-19 and cardiac arrhythmias (Table S1, studies 50–53). Out of these 4 studies, 1 was an interventional clinical trial and 3 were observational. Although only 4 studies were identified, the observational studies combined include 21,000 targeted recruits. The COVIDAR Registry (Arbelo et al., study #52 in Table S1) is an international longitudinal multicenter observational study which aims to assess the incidence, type, and risk factors of arrhythmias in the context of SARS-CoV-2 infection, while also providing relevant information on events and major CV outcomes. The primary objective is to describe the time from the onset of first arrhythmia to 12 months post admission or death. All 3 of the observational studies aim to characterize the arrhythmia burden in COVID-19 patients. Improved characterization of arrhythmia burden and mechanism of death is critical in guiding the need for developing treatment strategies as some of the current pharmacological therapies (hydroxychloroquine, azithromycin) have arrhythmogenic potential (15). To this end, one specific trial (Reddy et al., study #53 in Table S1) is studying remote cardiac monitoring with a VitalConnect Vital Sign Patch (VitalConnect, San Jose, CA) for patients with COVID-19 managed in the outpatient setting to characterize arrhythmia burden.

The effect of CV comorbidities on COVID-19 infection

Observations from early in the pandemic demonstrated that patients with baseline cardiometabolic comorbidities were at a higher risk of suffering a severe form of COVID-19 infection. A study of 44,672 patients with COVID-19 found that a history of CVD was associated with a nearly five-fold increase in the case fatality rate when compared to patients without CVD (10.5% vs. 2.3%) (16). In addition, multiple publications now have linked CVD risk factors such as age, diabetes, obesity and hypertension with poor outcomes in COVID-19 (17,18). The present search identified 17 clinical trials investigating the association between COVID-19 infection and the severity of disease based on the presence of CV comorbid conditions (Table S1, studies 54–70). All the trials are observational by design. They investigate whether comorbid CV conditions translate into a higher risk of severe infection, higher mortality rates, and increased morbidity post recovery at certain time intervals. Combined, these trials have 52,907 recruits. The largest of the observational trials is a Swedish nationwide registry based case control study (Karolinska Institute, study #66 in Table S1) that has an estimated enrollment of 22,784 participants with an aim to study risk factors and the effect they have on outcomes for severe COVID-19, with a focus on CVD, different treatments, and socioeconomic factors. Similarly, another study in France (Weizman et al., study #63 in Table S1) with 2,878 participants aims to identify early predictors of clinical worsening in patients hospitalized for COVID-19. Clinical data relating to history, comorbidities, risk factors, treatments, clinical parameters, biological and cardiological data, procedures and events during hospitalization will be recorded. A Spanish study (Torres et al., study #62 in Table S1) aims to characterize the effect that comorbid CV conditions have on long term (one year) outcomes of patients admitted to the hospital with severe COVID-19. One study (Parati et al., study #68 in Table S1) uses artificial intelligence to create a risk scoring system taking into account various clinical and laboratory findings to predict in-hospital outcomes. Lastly, a global observational study from the World Heart Federation (Silwa et al., study #70 in Table S1) utilizes a survey method to better understand specific conditions that increase the risk of developing severe COVID-19 and to better characterize CV complications in hospitalized patients. Considering the high global prevalence of CVD and its suggested link with COVID-19, it is imperative that robust studies be conducted to further investigate these issues.

Myocarditis and cardiac injury in COVID-19

Cardiac injury has been documented in the earliest COVID-19 patients in Wuhan, China. A number of COVID-19 related myocarditis cases have been reported (19,20). The pathophysiology of COVID-19-related myocarditis is thought to be a combination of direct viral injury and cardiac damage due to the host’s immune response. The prevalence of myocarditis among COVID-19 patients is unclear, partly because the early reports often lacked the specific diagnostic modalities to assess myocarditis (21). Fulminant myocarditis has been described in the literature and due to its aggressive course and high mortality, physicians should maintain a high index of suspicion. One study suggests that up to 7% of deaths in COVID-19 might be due to myocarditis but further research is needed (22).

We identified 5 ongoing clinical trials of observational design with the aim to better define the relationship between COVID-19 infection and myocarditis. All five studies use biomarkers and/or imaging to evaluate patients (Table S1, studies 71–75). One study (Minville et al., study #73 in Table S1) plans to use multiple imaging modalities to not only diagnose COVID-19 myocarditis but follow the patients daily to determine the evolution of their functional myocardial parameters during the acute infection. One study (Berry et al., study #71 in Table S1) of prospective, observational, multicenter, longitudinal cohort design will use advanced CV imaging to identify the proportion of patients with myocardial inflammation that is sub-clinical or clinically overt. The investigators will identify patients upon admission to the hospital with broad inclusion criteria (>18 years old hospitalized with COVID-19) and perform imaging with cardiac magnetic resonance imaging (MRI) at 28 days post discharge to identify myocardial inflammation which will be classified using the Lake Louise criteria (23). Furthermore, one of the studies (Delmas et al., study #72 in Table S1) investigates the clinical characteristics of SARS-CoV-2 myocarditis by using clinical, biological (troponin and proBNP), and imaging presentations to correlate with patient outcomes over 6 months post discharge.

Apart from myocarditis, there has been an interest in the impact of COVID-19 on major adverse cardiac events (MACE) and on myocardial injury—most often defined as elevation of troponin levels. Ongoing clinical trials attempted to quantify the incidence of myocardial injury and MACE in patients with COVID-19. The researchers use multiple modalities, including imaging, clinical observations and biochemical data to better describe the exact nature of cardiac injury. Other interventional trials study various drugs (including statins and colchicine) to evaluate their potential cardioprotective effects. Our search revealed 21 studies that discussed the relationship between cardiac injury and COVID-19 (Table S1, studies 76–96). Of these studies, 18 are observational and three are interventional. Interventions tested include aspirin, clopidogrel, atorvastatin, rivaroxaban and colchicine. The aim of the interventions is to assess if any will alter the natural course of the disease and provide CV protection in SARS-CoV-2 infected patients.

Of the 18 observational studies, 3 studies investigate the incidence of acute coronary syndrome (ACS) in the presence of COVID-19 while 6 studies characterize the incidence of MACE. One of the studies (Hao et al., study #83 in Table S1), in China, specifically looks at whether anxiety related to the pandemic increases the incidence of ACS. One study (Tarkin et al., study #96 in Table S1) identifies disease-specific patterns of myocardial injury in COVID-19 using non-invasive multi-modality cardiac imaging paired with cytokine/chemokine testing, immunophenotyping of peripheral blood cells, and coagulation profiles. The aim is to classify injury patterns based on immune cell profiles. Another study (Papa et al., study #85 in Table S1) plans to perform postmortem autopsies on the hearts of patients who died due to COVID-19. The primary objective is to understand the pathology and pathogenesis of cardiac injury in patients with COVID-19—with and without CV comorbidities. Three studies use transthoracic echocardiographic imaging to detect and classify the cardiac injury in patients with COVID-19. Four of the studies evaluated biomarkers of injury and stress such as troponin and proBNP.

Long term CV sequelae

The long term pulmonary and cardiac sequela of patients who recovered from COVID-19 pneumonia is unknown. As more is revealed about acute mortality in COVID-19, experts are becoming more concerned with the future morbidity that these patients will experience. Our search produced 12 studies concerning this topic (Table S1, studies 97–108). Seven of these studies were observational, while only one was interventional. Two studies (Monnet et al., study #108 and Katz et al., study #99 in Table S1) investigate the incidence of left ventricular dysfunction development and elevation of proBNP post COVID-19. One study (Katz et al., study #97 in Table S1) aims to investigate the incidence of decline in ejection fraction (EF) >10% at 30 days post discharge. Two other studies (Ortega Paz et al., study #98 and study #107 from Uppsala University in Table S1) investigate CV mortality at 1-year post COVID infection. Other researchers are examining the effect on cardiac electrophysiology and plan to follow COVID-19 survivors with serial ECGs. (University of Hong Kong, Study #102, Table S1). The remaining observational studies are less specific, casting a broader net as to the possible CV sequelae following SARS-Cov-2 infection.

Effect of COVID-19 on elective cardiac procedures

COVID-19 has caused disruptions in scheduled invasive procedures and required triage of patients awaiting CVD treatment (24,25). Our search presented 2 studies that delve into this topic, one of which was interventional and the other observational (Table S1, studies 109–110). One study (Pilgrim et al., study #110 in Table S1) is investigating the effect of the pandemic on deferral of valvular replacement in patients with severe aortic stenosis on morbidity and mortality while an interventional study (Nia et al., study #109 in Table S1) provides digital cardiac counselling to patients awaiting cardiac procedures to assess its effect on mortality and MACE.

Effect of social isolation

Due to the highly infectious nature and rate of spread of SARS-CoV-2, the global community largely determined that social isolation was necessary to curb exponential spread that threatened to overwhelm the healthcare system (26). Social isolation further functions as a tool to flatten the infection rate curve and thus protect those at a higher risk of attaining the disease. Conversely, others fear that due to a decrease in physical activity levels during this social isolation, decompensation of CV comorbid conditions might occur (27). We identified several studies investigating the effect of social isolation on CV comorbidities. Our search displayed seven studies that assessed the effect of social isolation on CV health (Table S1, studies 111–117). Four of these studies were observational and the remaining three were interventional.

One study (Berard et al., study #111 in Table S1) utilizestelephonic interviews at various intervals to assess compliance to medication, exercise routine and diet during quarantine. This study also measures anxiety levels due to social isolation and will see if that affects adherence to lifestyle changes. One large observational study (Centre Hospitalier Universitaire Dijon, study #112 in Table S1) investigates medication compliance during social isolation while another (Brunner et al., study #113 in Table S1) assesses changes in physical activity during the quarantine. We furthermore identified interventional trials investigating the success of digital telemedicine platforms providing advice and counselling regarding compliance and telerehabilitation done by a physiotherapist (Kortianou et al., study #115 in Table S1) during this period of social isolation. The large randomized interventional trial (study #116 done at the University Hospital, Tours; Table S1) called CONQUEST investigates whether a phone call made by a general practitioner and medical student is successful at identifying patients at risk of decompensation from their chronic condition and if this approach is able to prevent hospitalization. Another interventional study (Burlacu et al., study #114 in Table S1) investigates an electronic platform to assist patients with counseling regarding chronic CV conditions given their inability to attend routine follow up visits in the clinic.

Other relevant studies

Our search also produced 5 studies that did not fit within the above criteria (Table S1, studies 118–122). These studies looked at a variety of different concepts, including technology assistance in patient risk stratification for CV interventional procedures, the evolution of psychosocial, CV, and immune markers in healthcare professionals to assess the effects of pandemic work burden, statin therapies, and treatment and outcomes for ST segment elevation myocardial infarction (STEMI) care with primary percutaneous coronary intervention during the pandemic. Four of these studies are observational and one is interventional. The one observational study (Masana et al., study #121 in Table S1) investigates whether simvastatin therapy interferes with some of the inflammatory pathways activated by COVID-19 to produce the cytokine storm responsible for ARDS. The primary outcome compares the clinical course and prognosis of patients on statin therapy to statin-naive patients. A large retrospective multicenter registry study (Università degli Studi del Piemonte Orientale “Amedeo Avogadro”, study #122 in Table S1) aims to estimate the real impact of COVID-19 pandemic on treatment and outcome of STEMI by primary angioplasty, and to identify risk factors for delay or deferral in seeking treatment.

Limitations

Our trial review was limited in that full trial data is not available for any of the clinical trials. Furthermore, we did not include clinical trials that were not registered with ClinicalTrials.gov and therefore could be missing key clinical trials. Another limitation is the dynamic nature of COVID-19 research with new trials registered on a daily basis with ClinicalTrials.gov. This means that an update to this systematic review might be useful in the future to include new trials registered and review the data available from completed trials in our review that is currently not available.


Conclusions

Our search on ClinicalTrials.gov produced a variety of studies that investigate relationships between COVID-19 and the CV system. Our search identified the main areas with ongoing research that has the ability to resolve controversies regarding current management of patients with COVID-19 including the ideal thromboprophylaxis regimen, arrhythmogenic potential of patients with COVID-19 and appropriate monitoring of these patients and long term morbidity related to COVID-19 and the CV system. The key finding of our analysis is that the majority of the ongoing studies are observational in nature and not randomized controlled trials. Review of these ongoing studies can aid medical professionals and researchers in outlining current areas of clinical equipoise and help with planning future prospective research study topics and design.


Acknowledgments

Funding: This work was supported by the Freeman Heart Association Endowment in Cardiovascular Disease under Dr. Anand Prasad.


Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at http://dx.doi.org/10.21037/jxym-20-110

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jxym-20-110). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.


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doi: 10.21037/jxym-20-110
Cite this article as: Fichardt H, Fernandes G, Prasad A. COVID-19 and the cardiovascular system: a systematic review of the clinical trial landscape. J Xiangya Med 2021;6:2.