'Stay on Angiotensin Drugs' Still the Message as Trials Begin

Debra L. Beck

April 06, 2020

Editor's note: Find the latest COVID-19 news and guidance in Medscape's  Coronavirus Resource Center.

Much remains unknown about the novel coronavirus SARS-CoV-2 and the disease it causes, COVID-19, but there appears to be consensus within the cardiology community that patients ill with the disease need not routinely discontinue the angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs).

In fact, there seems to be a growing chorus of experts suggesting that these drugs may actually be of benefit in COVID-19.

"[T]he biological plausibility of salutary effects of ACEs/ARBs in those with COVID-19 is intriguing," write the authors of a viewpoint article, Chirag Bavishi, MD, MPH, Medical School of Brown University, Providence, Rhode Island; Thomas M Maddox, MD, MSc, Washington University School of Medicine in St. Louis, Missouri; and Frank Messerli, MD, University of Bern, Switzerland.

Several papers discussing this topic have been published in the last week, including the one by Bavishi et al published online April 3 in JAMA Cardiology.

Trials to test renin–angiotensin–aldosterone system (RAAS) blockers in COVID-19 patients are underway. Currently in the planning stage are two randomized controlled trials to test the initiation of the ARB losartan in patients with COVID-19 in the outpatient setting (ClinicalTrials.gov identifier NCT04311177) and in the in-patient setting (ClinicalTrials.gov identifier NCT04312009).

Still, both trials will be small and won't be completed before the spring of 2021. Other trials are also underway, but will take time. An observational study is beginning in Italy.

"Trials testing RAAS antagonists, including ones we are about to implement, in my opinion, form a strategic line of research toward secondary preventions, ie, halting disease progression in the early stages," said Majd AlGhatrif, MD, National Institute on Aging and Johns Hopkins University, Baltimore, Maryland, lead author of a second viewpoint article published online April 3 in JAMA Cardiology.

"In this active phase of the pandemic, early results can allow implementing these preventive measures at a scale compatible with that of the pandemic given the abundance of these medications in the market. If non-early results are conclusive, these will still be valuable, as we are expecting an additional cycle or two of this infection. We would rather not have these flares, but we better be prepared should they happen," he added in comments to theheart.org | Medscape Cardiology.

All major cardiology professional societies, including the European Society of Cardiology, The American College of Cariology, American Heart Association, Heart Failure Society of America, British Cardiovascular Society, and Canadian Cardiovascular Society, have all published guidance suggesting that ACE inhibitors and ARBs should be continued in patients with COVID-19, unless there is a clear reason to stop them.

Despite the consensus that there is no reason to discontinue ACE inhibitors or ARBs in patients with COVID-19, most suggest that given the current lack of strong evidence of benefit for these agents, they should not be initiated in the absence of a clear clinical indication.

The controversy, which is not much of a controversy anymore, revolves around the discovery that SARS-CoV-2 binds to ACE2 receptors to enter cells. Reports, mainly from animal studies, that ACE inhibitors and ARBs may increase expression of ACE2 led to concerns that users of these drugs may have increased susceptibility or severity of COVID-19.

Not only do experts in this field think this isn't the case, but rather they suspect just the opposite may be true: ACE inhibitors and ARBs may actually protect against lung injury in COVID-19.

AlGhatrif and colleagues point out that, based on animal studies, ACE2 expression declines with age, which is consistent with profound proinflammatory, age-associated changes in the renin–angiotensin system leading to higher angiotensin signaling. In fact, the upregulation of ACE2 in patients treated with ACE inhibitors and ARBs is, "in a way, restorative of physiological function," they write.

But this creates a paradox: if ACE2 is the gateway into the body for SARS-CoV-2, "how can the reduction in ACE2 levels in older persons and those with CVD predispose for greater COVID-19 severity?" AlGhatrif and colleagues ask.

They resolve this paradox with the hypothesis that greater expression of ACE2 leads to higher predisposition to the disease. The higher rate of COVID-19 found in young people in South Korea, the only country testing large numbers of younger and asymptomatic individuals, supports this idea. However, when it comes to severity, reductions in ACE2 in older individuals with cardiovascular disease and its associated upregulation of the angiotensin 2 proinflammatory pathway seems to predispose these people to more severe disease.

This has been clearly seen in Italy, where the mean age of those who have died in one case series was 79.5 years.

AlGhatrif said their hypothesis extends the discussion beyond just the potential role of RAAS intervention in COVID-19 to suggest that "age-associated reduction in ACE2, counterintuitively, underpins the greater disease severity observed in the elderly."

Other writers have focused more on the role of ACE2 rather than the role of its potential reduction with aging, or other conditions, as a potential predisposing factor for severe outcomes, he said.

"Hence, compared with younger individuals, older persons with CVD who already have reduced ACE2 levels will be expected to be more predisposed to exaggerated inflammation with further reduction in ACE2 expression in the context of COVID-19, manifesting in greater disease severity," write AlGhatrif and colleagues.

"First, one must recognize the scarcity of data on the topic, particularly in humans," AlGhatrif told theheart.org | Medscape Cardiology. "Nonetheless, the urgency of the situation makes it imperative to use inductive reasoning to guide our next steps toward protecting our patients."

The authors have disclosed no financial relationships relevant to these viewpoint articles.  

JAMA Cardiol. Published online April 3, 2020. Viewpoint: Bavishi et al, AlGhatrif et al

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