By Lazar Mandinoz, MD, PhD, Senior Medical Director, Parexel
Acute respiratory infections, including influenza, respiratory syncytial virus, and bacterial pneumonia, are well-recognized triggers for heart failure exacerbations and increasing the risk of arrhythmias and myocardial infarction. The underlying cardiovascular disease (CVD) is usually associated with increased severity of respiratory infections and higher mortality. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), also has a profound and direct impact on the cardiovascular system. It is thus important for clinical researchers involved with COVID-19 to understand the underlying pathophysiology, and be aware of the most significant current evidence and uncertainties in this area.
COVID-19 and Cardiovascular Comorbidity
A meta-analysis, including six carefully selected studies with a total of 1,527 patients from China, summarized the prevalence and effect of CVD on COVID-19.1 This analysis, compared with a 2018 National Report on cardiovascular and metabolic diseases in China, suggests that people with hypertension and diabetes were not more prone to COVID-19, as they had a similar prevalence of these conditions, but the prevalence of CVD in patients with COVID-19 was considerably higher. However, more important than the general prevalence of hypertension, CVD, and diabetes in patients with confirmed COVID-19 is the finding that patients with these comorbidities were susceptible to the most adverse complications of COVID-19, including death. Thus, preliminary results on mortality risk assessment of comorbidity based on China CDC data showed that CVD, along with hypertension, appears to be the riskiest comorbidity.
COVID-19 and Acute Myocardial Injury
Clinical studies of influenza and other acute inflammations have shown that patients with atherosclerotic CVD are at higher risk of acute coronary syndrome. Thus, patients with underlying CVD, more prevalent in older adults, are likely to be susceptible to higher risks of adverse outcomes during the severe and aggressive inflammatory responses to COVID-19 than younger, healthier individuals. The COVID-19 pandemic supports these concepts while also providing novel insights into the incidence and consequences of myocardial injury associated with SARS-CoV-2.
Based on all the evidence thus far, a reasonable hypothesis is that initial measurement of cardiac damage biomarkers immediately after hospitalization for COVID-19, as well as longitudinal monitoring during a hospital stay, may help to identify a subset of patients with possible cardiac injury. This approach might thereby predict the progression of COVID-19 towards a worse clinical picture.
COVID-19 and Thrombosis
Pro-inflammatory cytokines are upregulated in the lungs and other organs of SARS patients. Systemic inflammatory response leads to coagulation activation and acceleration, which in turn leads to increased incidence of major adverse cardiovascular events. About 90% of inpatients with pneumonia have increased coagulation activity, marked by increased D-dimer concentrations.
It has been shown that high levels of D-dimer are associated with increased 28-day mortality in COVID-19 patients who presented with severe infection or sepsis in the emergency department. Also, fibrinogen and fibrin/fibrinogen degradation products were significantly increased in COVID-19 patients, whereas antithrombin was decreased. Because blood coagulation is certainly deranged, routine monitoring of hemostasis tests appears advisable in patients with COVID-19. However, there are no specific recommendations at this time to adjust the antithrombotic therapy in patients with existing CVD.
COVID-19 and ACE Inhibitors/ARBs
In a few experimental studies with animal models, both angiotensin-converting enzyme 2 (ACE2) inhibitors and angiotensin receptor blockers (ARBs) have been shown to upregulate ACE2 expression in the heart. These results led to a hypothesis that treatment with ACE inhibitors or ARBs may increase the expression of the ACE2 receptor that, in turn, would lead to increased viral penetration in patient heart cells. On the other hand, experimental studies have shown that both ACE inhibitors and ARBs can reduce severe lung injury in certain viral pneumonias. These agents could be beneficial in COVID-19. It is fair to state that any effect from possible modulation of the ACE2 receptor on COVID-19 is not yet known; that will be tested in upcoming clinical trials.
Given the importance of renin-angiotensin-aldosterone system (RAAS) antagonists for patients with heart failure, hypertension, or ischemic heart disease, HFSA, ACC, and AHA issued a joint statement addressing concerns using these medications in COVID-19 on March 17, 2020. HFSA, ACC, and AHA acknowledged that no experimental or clinical data exist demonstrating beneficial or adverse outcomes with background use of any RAAS antagonists in COVID-19 patients. HFSA, ACC, and AHA recommend continuing the use of such agents for patients as currently prescribed, and advised against adding or removing any RAAS-related treatments beyond actions based on standard clinical practice.
COVID-19 and Statins
In 2014, statins were included in the treatment regimen for Ebola patients, along with ARBs. In Sierra Leone, local physicians treated approximately 100 Ebola patients with a combination of the two drugs, noting “remarkable improvement” in survival. Some studies had also shown that both drugs improved outcomes in experimental treatment of acute respiratory distress syndrome (ARDS). An approach to treating patients with severe COVID-19 infection might be hiding in plain sight.
Both statins and ARBs target the host response to infection, not the virus. They act largely on endothelial dysfunction, which is a common feature of many virus infections. Combination treatment with these two drugs appears to accelerate a return to homeostasis, allowing patients to recover on their own. The host response is a major determinant of the pathogenesis of infectious diseases.
Targeting the host response with widely available and inexpensive generic drugs, like statins, is strongly believed to improve the survival of COVID-19 patients. As a matter of fact, Massachusetts General Hospital is considering statins in treatment guidelines.
Impact of the COVID-19 Pandemic on CV Clinical Trials
A surge in serious adverse events (SAEs) in CV trials and CV outcome trials (CVOT) is expected, especially in the hot-spot countries. This puts an additional burden on the safety teams and adjudication process of clinical endpoint committees (CECs). At Parexel, we recommend that the team be prepared upfront to handle the higher influx of events and adjust the timelines accordingly. Similarly, we recommend biostats to model whether unusually high mortality and major adverse CV rates in all groups could adversely impact the primary hypothesis. At the same time, some CVOTs might be able to accumulate the primary endpoint events earlier than expected.
Pulmonary hypertension (PH) patients might be severely impacted by COVID-19 due to their underlying lung and heart conditions. Since this is a rare disease usually treated at PH centers of excellence, which could be inaccessible for enrolled patients, the mitigation plan should address avoiding disruption in trial conduct.
Careful monitoring is needed of the usage of ACE inhibitors, ARBs, heparin and other anticoagulants, statins, non-steroid anti-inflammatory drugs, and steroids. Afferent statistical analysis should be planned as much as possible. Parexel would positively consider collaboration with an academic institution to perform meta-analysis on the effect of these medications on the outcome of patients with COVID-19.
There are many imminent studies on potential COVID-19 treatments, including vaccines. Parexel is already involved in many of them. These trials will require careful patient selection and stratification of those with risk factors such as CVD, hypertension, and diabetes.
For a more complete exploration of the implications of COVID-19 on cardiovascular injury and the impact on clinical trials, please read our article COVID-19 and the Effect on Cardiovascular Diseases, CV Clinical Trials and CV Outcome Trials.
1Li B, Yang J, Zhao F, Zhi L, Wang X, Liu L, Bi Z, Zhao Y. Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China. Clin Res Cardiol. 2020 Mar 11 doi: 10.1007/s00392-020-01626-9. [Epub ahead of print]