4  Adverse cardiovascular effects of the proposed empirical/supportive treatments
Currently, there is no approved vaccination or effective drug for protecting against or treating COVID-19; only symptomatic therapy and empirical/supportive treatments are available. Many of the mortalities related to COVID-19 have been primarily attributed to original patient comorbidities instead of pneumonia (Wang et al., 2020). This highlights the importance of focusing on pre-existing comorbidities of COVID-19 patients, particularly those of the cardiovascular system. Attention to therapies with cardiovascular side effects being proposed and applied to patients with COVID-19, especially those with underlying CVD is important. Notably, many of the therapies proposed to ameliorate the poor prognosis of COVID-19 patients are associated with cardiovascular adverse effects. For example, treatment of patients with COVID-19 with non-steroidal anti-inflammatory drugs, glucocorticoids and anti-viral agents, such as ribavirin, lopinavir/ritonavir, INF-α and the antibiotic azithromycin, could further increase the cardiovascular risk of COVID-19 patients.
Excessive use of non-steroidal anti-inflammatory drugs and glucocorticoids is associated with deleterious effects on the cardiovascular system increasing the risk of events including, ischemia, MI, arrhythmias and HF (England, Thiele, Anderson, & Mikuls, 2018; Roubille et al., 2015). Although corticosteroids are sometimes prescribed for the treatment of patients with severe SARS-CoV infection for the possible relief of inflammation (Wong et al., 2004), recent evidence suggests corticosteroids may exacerbate lung injury associated with SARS-CoV-2 due to delayed viral clearance (Mehta, et al., 2020; Russell, Millar, & Baillie, 2020). The antiviral agents lopinavir and ritonavir have been tested in a randomized controlled, open-label trial in hospitalized adult patients with COVID-19 and concluded that no benefit was observed with lopinavir–ritonavir treatment beyond standard care. Moreover, about 14% of lopinavir–ritonavir recipients were unable to complete the full 14-day course of administration due primarily to the adverse events including the risks of QT prolongation (Cao et al., 2020). It is important to highlight that the adverse effects of these antivirals involve altering the cardiac electrical conduction system causing QTc and/or PR interval prolongation, which can lead to atrioventricular block and torsade de pointes arrhythmias increasing the risk of MI (Worm et al., 2010). Further, the use of these protease inhibitors can lead to metabolic disturbances such as hyperglycemia, hyperlipidemia and lipodystrophy, which may also contribute to adverse cardiovascular outcomes (Hill, Sawyer, & Gazzard, 2009; Tsiodras, Mantzoros, Hammer, & Samore, 2000). Recently, IFN-α2b was used in an uncontrolled exploratory study including 77 hospitalized adults with confirmed COVID-19 in Wuhan, China (Zhou et al., 2020). The trial showed that treatment with IFN-α2b markedly decreased the duration of detectable virus in the upper respiratory tract and also reduced the interval of the elevated inflammatory markers IL-6 and CRP in the blood. However, treatment with IFN-α has been associated with hypertension, hypertriglyceridemia and direct cardiotoxicities, including arrhythmias, MI and cardiomyopathy, which could exacerbate underlying cardiac dysfunction (Page 2nd et al., 2016). An open-label randomized trial has been conducted to test the efficacy of IFN beta-1b, lopinavir–ritonavir and ribavirin for treating patients admitted to hospital with COVID-19 and concluded early triple antiviral therapy was effective in alleviating symptoms and shortening the duration of hospital stay in patients with mild to moderate infections (Hung, et al., 2020). However, it is worth noting ribavirin has a US boxed warning issued for hemolytic anemia associated with use that may worsen underlying cardiac disease and lead to fatal and non-fatal MI (Durante-Mangoni et al., 2011). Numerous recent studies proposed the use of hydroxychloroquine and azithromycin as a treatment of COVID-19 in open-label non-randomized clinical trials, however, no positive results were produced (Arshad et al., 2020; Cavalcanti, et al., 2020; Gautret et al., 2020; Tang et al., 2020). Well known adverse effects associated with azithromycin or hydroxychloroquine include development of severe QT prolongation (Gibson et al., 2017), which worsened when azithromycin is combined with hydroxychloroquine to treat COVID-19 patients (Choi, Lim, Chung, Choi, & Yoon, 2018; Mercuro et al., 2020).
Currently, there are multiple in vitro experiments and preclinical studies being performed around the world to test novel COVID-19 therapies, which are quickly moving into clinical trials. Importantly, the early efficacy results have been limited to small-scale clinical studies in which the safety profiles have not been well-identified. The safety profiles will be critical for COVID-19 patients with underlying comorbidities such as cardiovascular dysfunction. Therefore, as there is a need for rapid clinical translation and a wide use of novel therapies for COVID-19, continued attention to safety profiles is important. The rapid spread of COVID-19 globally continues to impact susceptible populations, like elderly patients and individuals with underlying comorbidities. While underlying cardiovascular issues are impacted by COVID-19 infection, many existing and novel therapeutic strategies have direct adverse cardiovascular effects, highlighting the importance for consideration in new drug research and development.