ACE Inhibitors, ARBs, and COVID-19: New Insights, Advice

The COVID-19 pandemic is changing the way many physicians view the use of ACE inhibitors and angiotensin receptor blockers (ARBs), but experts caution against changing practice at this point given the lack of data showing any risk.

Concern over these drugs grew out of observational Chinese research showing greater morbidity and mortality among patients with hypertension who develop COVID-19. However, these studies did not adjust for confounding variables, “and thus it remains unclear if this association is related to the pathogenesis of hypertension or another associated comorbidity or treatment,” according to Ankit Patel, MD, PhD, and Ashish Verma, MBBS (both from Brigham and Women’s Hospital, Boston, MA), who wrote a viewpoint on the topic this week in JAMA.

Last week, professional societies around the world issued statements urging patients taking ACE inhibitors and ARBs to continue taking their treatment even if they develop COVID-19, unless told to do otherwise by their doctors.

“From our opinion, the potential harm associated with making changes to ACE inhibitors/ARBs are twofold,” Patel and Verma told TCTMD in an email. “One is based on potential medical errors that can take place whenever medications are changed that are systems-based (ie, pharmacy fills incorrect dose, patient takes two tablets instead of one, physician does not order appropriate labs to look at new side effects, etc.).”

They continued: “The other concern is the loss of benefits that are specific to ACE inhibitors/ARBs that are not recapitulated by other antihypertensive medications specifically in diabetic kidney disease and reduced ejection heart failure. Though these benefits with ACE inhibitors/ARBs are usually appreciated over long-term use, there are some benefits that can be lost even with short-term discontinuation. Also, though there is concern ACE inhibitors/ARBs could be harmful in COVID-19, we feel there is equal level of suggestion that they can be helpful. In this case, discontinuation of ACE inhibitors/ARBs may worsen COVID-19.” 

Not Enough Evidence

Anxiety over the link between COVID-19 and ACE inhibitors/ARBs stems from the known interplay between angiotensin-converting enzyme 2 (ACE2) and the virus that causes the disease, SARS-CoV-2. “ACE2 has been shown to be a co-receptor for viral entry for SARS-CoV-2 with increasing evidence that it has a protracted role in the pathogenesis of COVID-19,” Patel and Verma write.

It’s possible that ACE inhibitors could directly inhibit ACE2, but “ACE2 functions as a carboxypeptidase and is not inhibited by clinically prescribed ACE inhibitors,” they say in their JAMA paper. “In addition, there is concern that the use of ACE inhibitors and ARBs will increase expression of ACE2 and increase patient susceptibility to viral host cell entry and propagation.”

But so far, no clinical evidence has confirmed any of these theories. “In fact, there are some studies that suggest this increase in ACE2 could be protective,” Patel and Verma told TCTMD. “We wanted to ensure this information reached the practitioners. Additionally, there were viewpoints that were noting the potential harm of ACE inhibitors/ARBs that were published previously and we wanted to provide a more balanced perspective.”

For physicians who would normally be considering issuing new prescriptions of these drugs to patients now, “there is no data to suggest that initiating a new ACE inhibitor/ARB is particularly harmful in COVID-19,” they said. “As such, we would recommend that physicians maintain the same criteria for initiating ACE inhibitors/ARBs in patients with hypertension, diabetic kidney disease, and heart failure irrespective of COVID-19 status.”

And for patients already on these medications, Patel and Verma argue that they do not need to be taking additional precautions above and beyond the social distancing that is being advised globally. “The potential relation to how ACE inhibitors/ARBs could affect patients’ susceptibility to contract COVID-19 remains unclear. Though upregulation of ACE2 with these medications may suggest increase receptors for viral entry into human cells in the lab, we do not know the effect in the context of a human body,” they explained. “Additionally, we do not know if there is any impact ACE inhibitors/ARBs play in viral shedding, and we are not aware of any basic science data that would suggest it could either.”

In the near future, it would be good to see a combination of basic science and animal model data to help further the understanding of the pathophysiology of ACE2 and Sars-CoV-2 lung injury as well as the role ACE inhibitors and ARBs may play, they urged.

“To truly guide clinical decisions, we need prospective data for patients on ACE inhibitors and ARBs . . . and the impact on COVID-19 susceptibility to infection and risk of mortality with infection,” Patel and Verma said, adding that an ongoing trial is prospectively looking at the impact of the ARB losartan on hospitalized COVID-19 patients. “The information from this trial will be helpful to better guide patients on what should be done with these medications.”