COVID-19 Mortality: Does the Renin-Angiotensin System Play a Role?

COVID-19 Mortality: Does the Renin-Angiotensin System Play a Role?

March 2020

Mortality risk from coronavirus disease 2019 (COVID-19) seems to be associated with cardiovascular disease, diabetes and hypertension. And we know that these disorders share an underlying pathophysiology related to the renin-angiotensin system (RAS)—a hormone system that regulates blood pressure and fluid balance. That relationship may provide important clinical insights about how we treat COVID-19, but first we need to clearly understand the causal mechanism that lies at the heart of it—and there, we see conflicting information.

In a new viewpoint article, a team of authors has proposed key clinical research priorities to clarify the role of RAS inhibition in COVID-19 mortality—priorities that the international research community could rapidly address in a randomized control study. “In recent weeks some investigators have hypothesized that the use of RAS blockade could lead to improved outcomes from COVID-19. Others have suggested that avoidance or withdrawal of an RAS blockade could help,” said lead author Thomas Hanff, MD, MPH, a cardiovascular disease fellow at Penn and a student in the CCEB’s Master of Science in Clinical Epidemiology program. “Clinicians worldwide need to know if either of these ideas has merit.”

Indeed, there is evidence to support various interpretations. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the angiotensin-converting enzyme 2 (ACE2) to initiate the infection. In cardiovascular disease patients and in instances when we use drugs to inhibit RAS—such as ACE inhibitors or angiotensin receptor blockers to treat hypertension or heart failure—we see increased ACE2 levels, which may increase the virulence of SARS-CoV-2 within the lung and heart. But evidence from related coronaviruses suggests that SARSCoV-2 infection may reduce or suppress ACE2; this leads to a toxic over-accumulation of Angiotensin II, a peptide hormone that may increase the risk of acute respiratory distress syndrome at high levels. RAS inhibition could mitigate this dangerous effect.

While some trials may soon be underway, high-quality observational data is still needed to develop and guide nuanced hypotheses. As a first step, retrospective analysis of patients who test positive for SARS-CoV-2 in hospital-based cohorts could provide a rough picture of the effect, if not the magnitude, of RAS blockade. In admitted patients who test positive for SARS-CoV-2, we could compare the risk of severe disease versus mild disease that is associated with those who are already using RAS blockade. (The article also outlines further research priorities.)

Several biases and confounders will need to be considered, the authors note. Most important, patients who are admitted to the hospital for COVID-19 are usually sicker than patients who are able to recover at home, which creates selection bias. Analysts will also need to rule out any confounding as a result of age or of the underlying conditions that required RAS blockade in the first place.

These analyses would provide a necessary first step to clarify the role of a pharmacologic RAS blockade in COVID-19—and the role of RAS in COVID-19 more broadly. “We note that patients who require RAS inhibitors should not change their regimens without further evidence,” comments Dr. Hanff. “At the same time, if there is even a modest association (positive or negative) between RAS blockade and COVID-19 outcomes, this data could rapidly inform confirmatory trials that could save countless lives in the escalating pandemic.”

Read the article in the journal Clinical Infectious Diseases.

Authors: 

Authors: Thomas C. Hanff, MD, MPH; Michael O. Harhay, PhD, MPH; Tyler S. Brown, MD; Jordana B. Cohen, MD, MSCE; Amir M. Mohareb, MD

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