COVID-19: Considerations regarding the use of ACE inhibitors and ARBs

The novel coronavirus disease (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread rapidly throughout the United States, with over 450,000 cases as of April 9, 2020. Certain subpopulations may have a higher chance of infection and of developing severe symptoms in response to COVID-19, including individuals with a range of cardiovascular risk factors taking ACE inhibitors and ARBs.

A meta-analysis of 1527 patients in China found that the most common cardiovascular metabolic co-morbidities were hypertension, cardia-cerebrovascular disease, and diabetes. The prevalence of these diseases was greater in severe cases than in non-severe cases—the incidence of hypertension was 28.8% in severe cases and only 14.1% in non-severe cases. Similarly, cardia-cerebrovascular disease accounted for 16.7% of severe cases and only 6.2% of non-severe cases.

  • What are ACE inhibitors and ARBs?
  • How are these medications being linked to COVID-19?
  • Current recommendations regarding the use of ACE inhibitors and ARBs

Respiratory failure is the principal cause of death in most COVID-19 cases, but possible routes for cardiac injury proposed by Tan and Aboulhosn in an article published in the International Journal of Cardiology include indirect injury through an overactive inflammatory immune response or severe hypoxia caused by acute respiratory distress syndrome (ARDS).

Additionally, concern has recently arisen over whether ACE inhibitors or angiotensin receptor blockers (ARBs) used by many individuals as a treatment for cardiovascular disease may increase the risk of SARS-CoV-2 infection, however there are conflicting viewpoints to this end.

What are ACE inhibitors and ARBs?

ACE inhibitors and ARBs are two classes of medications reliably used to treat a range of heart conditions, including heart failure, hypertension (high blood pressure), and coronary artery disease, as well as to prevent kidney damage from diabetes.

These medications work by interfering with the renin-angiotensin-aldosterone system (RAAS) which is a signaling pathway that works to regulate blood pressure and sodium levels in the bloodstream. ACE inhibitors work by blocking the protein angiotensin-converting enzyme 1 (ACE1), which converts angiotensin I to angiotensin II, the latter of which causes constriction of blood vessels, increased blood pressure, and increased sodium levels.

By blocking ACE1, ACE inhibitors effectively lower the levels of angiotensin II in the blood. ARBs block the angiotensin II type 1 receptor, preventing the activity of angiotensin II.

Either reducing angiotensin II levels or inhibiting its downstream functions promotes the dilation of blood vessels and lowers blood pressure and sodium levels, ameliorating many of the symptoms of the aforementioned heart and kidney conditions.

How are these medications being linked to COVID-19?

Studies have shown that the SARS-CoV-2 virus that causes COVID-19 uses the ACE2 receptor as an entry point to infiltrate host cells in the respiratory tract. Spike proteins on the surface of the virus bind to ACE2 receptors, and once inside human cells, the virus can use the cell’s own resources to make copies of itself that then exit the cell and move on to infect other susceptible host cells.

At first glance, it may seem that ACE inhibitors would be perfect for fighting COVID-19, but the key here is that ACE1 and ACE2 are two different proteins. And, in animal models, treatment with ACE1 inhibitors and ARBs has actually been shown to increase levels of ACE2 in the blood. As a result, some researchers have hypothesized that, by upregulating ACE2 in the body, treatment with ACE inhibitors and ARBs could make patients more susceptible to COVID-19 by increasing the relative number of entry points for the SARS-CoV-2 virus.

However, many recent perspectives on the proposed link between ACE inhibitors/ARBs and COVID-19 assert that the research linking ACE inhibitors and ARBs to increased infection risk is incomplete and inconclusive.

While ARBs have been shown to increase levels of ACE2 in animals, the extent of this effect varies among organ systems and among the blockers used, and these results have not been adequately replicated in humans to date. Additionally, there is no real data to show that ACEIs or ARBs actually do aid SARS-CoV-2 entry into cells by increasing ACE2 expression, so the causal link is theoretical at best.

Furthermore, even if ACE2 is upregulated by ACE inhibitors and/or ARBs, some experts believe that the benefits of having more of this enzyme around could outweigh the risks. Unlike its counterpart ACE1—the target of ACE inhibitors—ACE2 confers considerable cardiovascular benefits.

It is found in numerous tissues of the body, including the small intestine, kidney, heart, lung, stomach, and liver. ACE2 not only contributes to the breakdown of angiotensin II but has also been shown to increase angiotensin-(1-7), a protein with substantial anti-inflammatory, vasodilating, antiapoptotic, and other beneficial functions.

As a result, a viewpoint recently published in the Journal of the American Heart Association suggested that increased ACE2 levels could actually have a protective effect on the cardiovascular system and help prevent the acute lung injury that is a common and sometimes fatal symptom of COVID-19.

Current recommendations regarding the use of ACE inhibitors and ARBs

Most experts agree that the proven benefits of using ACE inhibitors and ARBs for treatment of cardiovascular diseases exceeds the hypothetical risk of increased susceptibility to SARS-CoV-2 infection, however there have been widespread calls for more research regarding the extent of these blockers’ impacts on the RAAS pathway and their interaction with SARS-CoV-2.

Regarding use of ACE inhibitors and ARBs, the American Heart Association (AHA), Heart Failure Society of America (HFSA), and American College of Cardiology (ACC) released the following statement on March 17, 2020:

 “The AHA, the HFSA and the ACC recommend continuation of angiotensin converting enzyme inhibitors (ACE-i) or angiotensin receptor blocker (ARB) medications for all patients already prescribed for indications such as heart failure, hypertension or ischemic heart disease. Cardiovascular disease patients who are diagnosed with COVID-19 should be fully evaluated before adding or removing any treatments, and any changes to their treatment should be based on the latest scientific evidence and shared-decision making with their physician and health care team.”

A position statement released around the same time by the European Society of Cardiology was in consensus, announcing: “The Council on Hypertension strongly recommend that physicians and patients should continue treatment with their usual anti-hypertensive therapy because there is no clinical or scientific evidence to suggest that treatment with ACEi or ARBs should be discontinued because of the Covid-19 infection.”

On the other end of the spectrum, although ACE2 could have a net positive impact on COVID-19 patients through prevention of respiratory injury, there is not yet a great enough body of research supporting this claim for initiation of ACE inhibitors or ARBs to be supported as a viable therapy for individuals diagnosed with COVID-19 that are not currently taking these medications for underlying conditions.

Research and discussions regarding the relevance of COVID-19 to medications used to treat other conditions are ongoing in other settings, such as for patients receiving immunosuppressive medications for Ulcerative Colitis or Crohn’s Disease or among transplant recipients that require these medications to prevent allograft rejection.

Ultimately, treatment decisions should be made on an individualized basis, but there is currently insufficient evidence to support any universal recommendation for changes in course of treatment regarding ACE inhibitors or ARBs.