By Neal S. Parikh, MD, MS

Assistant Professor of Neurology and Neuroscience, Weill Cornell Medical College

Dr. Parikh reports no financial relationships related to this field of study.

SYNOPSIS: COVID-19 infection may be associated with an increased risk of blood clotting and related thrombotic events, but there are insufficient data to support indiscriminately discontinuing medications that play a critical role in the management of chronic cardiovascular disease.

SOURCES: Zhang Y, Xiao M, Zhang S, et al. Coagulopathy and antiphospholipid antibodies in patients with Covid-19. N Engl J Med 2020;382:e38.

Mehra MR, Desai SS, Kuy S, et al. Cardiovascular disease, drug therapy, and mortality in Covid-19. N Engl J Med 2020; May 1. doi: 10.1056/NEJMoa2007621. [Online ahead of print].

COVID-19 infection has taken the world by storm. The first few months of the pandemic have been met by a powerful demonstration of insightful clinical investigation. Clinicians quickly noticed that patients with COVID-19 infection appear to face an increased risk of cardiovascular events and high rates of mortality, and researchers are striving to understand precisely why this is the case.

Even before clinicians had accrued sufficient COVID-19 patient care experience, investigators were aware of the virus’s biology. Early in the pandemic, it was known that COVID-19 gains entry into the human body by binding to the angiotensin-converting enzyme 2 (ACE2) receptor. Angiotensin-converting enzyme 1 is the site of action of a commonly used drug class, namely angiotensin-converting enzyme inhibitors (ACE inhibitors). ACE1 and ACE2 are involved in a complex feedback loop. On this basis, it was hypothesized that the use of ACE inhibitors, and the related drug class of angiotensin receptor blockers (ARBs), may increase the expression of ACE2, thereby increasing the entry of COVID-19 into the lungs. This gave rise to the concern that the use of ACE inhibitors and ARBs may increase the severity of COVID-19. At the population level, indiscriminate cessation of these drugs would lead to uncontrolled hypertension, heart failure, and other unintended consequences. Thus, understanding whether these commonly used drugs truly contribute to mortality in COVID-19 demanded investigation.

Mehra and colleagues sought to address this critical question. In a remarkable feat, considering the short period between the first case of COVID-19 and the publication of their manuscript, the authors performed a large, multicenter, observational study using data from 169 hospitals. They tabulated patients’ demographics and comorbidities in addition to their medication history. Then, they performed multivariable regression analyses to evaluate whether the use of ACE inhibitors or ARBs was associated with an independently increased risk of in-hospital mortality. Of 8,910 hospitalized patients, 515 (6%) died in the hospital. Patients who died were older and had a higher burden of coexisting conditions, such as heart disease, diabetes, and pulmonary disease.

In their statistical models, older age and heart disease were independently associated with in-hospital mortality, but use of ACE inhibitors and ARBs was not. In fact, ACE inhibitors may have been protective. The authors appropriately noted that they made many statistical comparisons, and their data are retrospective, so it is not justified to conclude that ACE inhibitors are truly protective. However, their data do allay concerns about the safety of these medications in COVID-19.

As clinicians see more cases of COVID-19, they begin to accumulate observations that inform additional hypotheses to explain why this virus dramatically increases the risk of thrombotic events and death. Doctors caring for patients with COVID-19 began to notice a high rate of blood clotting in their patients. To explain this, they investigated whether COVID-19 infection results in antiphospholipid antibody production, which is characteristic of its namesake, sometimes-catastrophic, blood clotting disorder. Provocatively, Zhang and colleagues reported three cases of patients with COVID-19 with positive antibodies. Whether COVID-19 induces a prothrombotic state, and the optimal management of this condition requires further work.

COMMENTARY

COVID-19 clinical investigation sets the bar for clinical research. Physicians and investigators have promptly identified and answered critical questions with robust methods, without neglecting pathophysiology or underestimating the value of empiric clinical observation. Taken together, the data discussed herein demonstrate that COVID-19 is associated with a high rate of in-hospital mortality, but that ACE inhibitors and ARBs likely should not be discontinued, and certainly not in the population at large. Meanwhile, there are emerging data that COVID-19 may, as is the case with other infections, result in a prothrombotic state linked to the generation of antiphospholipid antibodies. If confirmed, future work surely will investigate antithrombotic regimens and perhaps therapies to quell the production of these antibodies. Apart from prevention and mitigation of infection, therapies to prevent complications of COVID-19 are needed urgently.