Note: This is the nineteenth of a series of clinical briefs on the coronavirus outbreak. The information on this subject is continually evolving. The content within this activity serves as a historical reference to the information that was available at the time of this publication. We continue to add to the collection of activities on this subject as new information becomes available.

Clinical Context

ACE inhibitors and ARBs have received added attention during the COVID-19 epidemic. A special report by Vaduganathan and colleagues, which is published in the current issue of the New England Journal of Medicine,^[1] described how these medications might be related to COVID-19. ACE2 is expressed in multiple organs, particularly in the heart and kidneys, but it is also present in lung alveolar cells, which are the target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Moreover, ACE2 is the binding site for SARS-CoV-2.

That has led to concern that ACE inhibitors and ARBs can increase susceptibility to COVID-19; however, the report delineates several problems with this theory. ACE inhibitors and ARBs have mixed effects on ACE2 in animal models, and little data exist on the effects of ACE inhibitors and ARBs on ACE2 activity in humans. The data that have been collected are conflicting, indicating that the effects on ACE2 may not be uniform across different molecules of ACE inhibitors and ARBs. Regardless of how ACE inhibitors and ARBs may affect ACE2 in the respiratory epithelium, no data suggest that these effects may promote higher rates or more virulent infections with SARS-CoV-2.

"Study Highlights" summarize the recommendations from 3 different published reports,^[1-3] including the paper by Vaduganathan and colleagues.

Study Synopsis and Perspective

The American Heart Association (AHA) has issued new guidance for patients with hypertension during the COVID-19 outbreak.^[4] At the same time, several new review articles have been published further exploring the possible relationship between the renin-angiotensin system (RAS) and the virus.

The AHA guidance, titled "What people with high blood pressure [(BP)] need to know about COVID-19," notes that individuals with raised BP may face an increased risk for severe complications if they are infected with the virus. Data from the outbreak in Wuhan, China, showed a 10.5% death rate among persons with COVID-19 who also had cardiovascular disease (CVD), 7.3% for persons with diabetes, 6.3% for persons with respiratory disease, 6% for persons with high BP, and 5.6% for persons with cancer.

The advisory reiterates previous recommendations that patients should not stop taking prescribed ACE inhibitors or ARBs for hypertension, heart failure, or heart disease. 

"These medications don't increase your risk of contracting COVID-19. They are vital to maintaining your [BP] levels to reduce your risk of heart attack, stroke, and worsening heart disease," the advisory states.

Under the heading "Caution is key," the guidance warns that some common habits or medicines and supplements can raise BP, including nonsteroidal anti-inflammatory drugs and decongestants.

"People with heart concerns should limit or avoid them, especially if their [BP] is uncontrolled," the advisory continues.

It also recommends people taking medication for mental health, corticosteroids, oral birth control, immunosuppressants, and some cancer medications monitor BP to make sure it is under control.

The guidance advocates limiting both alcohol and caffeine because too much can raise BP.

"Caffeine should be capped at [3] cups per day in general, and most people with high [BP] should avoid it," the guidance states.

Some herbal supplements, such as licorice, can also raise BP, it adds.

Latest on Angiotensin Drugs

Meanwhile, several additional commentators have reviewed evidence on the relationship between the RAS and COVID-19 infection. These include commentaries published in the New England Journal of Medicine,^[1] Lancet Respiratory Medicine,^[2] and Mayo Clinic Proceedings.^[3]

The controversy over use of ACE inhibitors and ARBs arose after it was discovered that the COVID-19 virus binds to the ACE2 receptor to gain entry into cells. This, together with reports, mainly from animal studies, that ACE inhibitors and ARBs may increase expression of ACE2, has raised concerns that use of these drugs may increase susceptibility to the virus, but other research shows that by reducing angiotensin 2 levels, these drugs may protect against lung injury in patients with COVID-19.

The latest commentaries give more detail on the potential benefits of ACE inhibitors and ARBs, and all reach the same conclusion: that patients should stay on their medication, which is in agreement with the major cardiology and hypertension societies.

The review in the Mayo Clinic Proceedings, published online on March 30,^[3] noted a report issued by the Italian Ministry of Health on March 20 that showed the most common comorbidities in a cohort of 481 patients who died with COVID-19 were hypertension (74%), diabetes (34%), ischemic cardiopathy (30%), and atrial fibrillation (22%).

Noting that the average age of patients who died with COVID-19 was 78.5 years, the report authors, led by Fabian Sanchis-Gomar, MD, University of Valencia, Valencia, Spain, and Stanford University School of Medicine, Stanford, California, stated, "Since hypertension prevalence increases in parallel with aging, this pattern may represent the expected prevalence for the given age group."

The Italian data also show that before hospitalization, 36% of patients who died with COVID-19 were taking ACE inhibitors and 16% were taking ARBs.

Regarding these figures, Sanchis-Gomar and colleagues commented, "One cannot definitively conclude risk-benefits of these therapies due to confounding variables of age, hypertension, as well as the impact of yet unidentified comorbidities on outcome with the COVID-19 pandemic."

Nonetheless, the latest information released March 31 by the Centers for Disease Control and Prevention (CDC)^[5] suggested diabetes is the most common comorbidity in COVID-19 cases. Data on 7162 cases of COVID-19 for whom data on underlying health conditions were reported showed 37.6% of these patients had one or more underlying health conditions or risk factors: the most common being diabetes, chronic lung disease, and CVD.

Of 457 patients admitted to intensive care units with completed information on comorbidities, 32% had diabetes, 29% had CVD, and 21% had chronic lung disease, the CDC data noted.

The authors of all 3 commentaries expanded on mechanisms supporting a positive role for ACE inhibitors or ARBs in COVID-19 infection.

In a letter to Lancet Respiratory Medicine published on March 26,^[2] responding to one of the first reports suggesting potential for harm with these drugs, a group led by Christopher Tignanelli, MD, University of Minnesota, Minneapolis, Minnesota, wrote, "It is equally plausible that patients with hypertension have an overactive RAS, which has been postulated to mediate acute lung injury during COVID-19 infection." 

They reported that angiotensin 2 is believed to cause pulmonary inflammation, fibrosis, and edema; ACE2 activation results in low amounts of angiotensin 2, and impaired ACE2 activity results in excessive amounts of angiotensin 2.

In concordance with this hypothesis, new data from China^[6] showed serum angiotensin 2 was significantly higher in a group of 12 patients infected with COVID-19 vs patients without COVID-19 and was linearly associated with viral load and lung damage.

Referencing studies showing protective effects against severe acute respiratory syndrome (SARS)-induced lung injury with the ARB losartan in mice and with recombinant ACE2 in patients with SARS, Tignanelli and colleagues said this supports the initiation of clinical trials assessing recombinant human ACE2 infusions and losartan in patients with COVID-19.^[2]

"Although controversy exists about the role of RAS inhibition in COVID-19, no evidence is available to support the routine discontinuation of [ACE inhibitors] or ARBs. Preclinical evidence suggests that RAS blockade might attenuate progression of COVID-19. We argue that clinical equipoise exists and, before the medical community makes recommendations for patients to withhold potentially life-saving drugs, there is a critical and urgent need for multicenter trials to test this hypothesis in patients with COVID-19," they concluded.

The authors of the Mayo Clinic Proceedings report^[3] added, "While hypertension is one of the most common comorbidities associated with a poor prognosis of COVID-19, hypertension has also been found to be associated with decreased levels of [ACE2] expression."

They also suggested that COVID-19 binding to ACE2 may attenuate residual ACE2 activity, increasing angiotensin 2 levels, and cited studies suggesting that the binding of ARBs to the angiotensin 2 type 1 receptor (AT₁R) may stabilize the AT₁R-ACE2 complex and prevent the COVID-ACE2 interaction.

They concluded, "We speculate that RAS dysregulation may play a central role in COVID-19 associated lung injury," but they added that "whether RAS modulation may have a beneficial effect in selected patients with severe COVID-19 at risk for acute lung injury/acute respiratory distress syndrome is entirely unknown at the present time."

Finally, in the review published online in the New England Journal of Medicine on March 30,^[1] a group led by Muthiah Vaduganathan, MD, Brigham and Women's Hospital, Boston, Massachusetts, noted that clinical trials are underway to test the safety and efficacy of RAS modulators, including recombinant human ACE2 and the ARB losartan in patients with COVID-19.

They concluded, "Abrupt withdrawal of RAS inhibitors in high-risk patients, including those who have heart failure or have had myocardial infarction, may result in clinical instability and adverse health outcomes... Until further data are available, we think that [renin-angiotensin-aldosterone system (RAAS)] inhibitors should be continued in patients in otherwise stable condition who are at risk for, being evaluated for, or with COVID-19."

Clinical Implications

• ACE2 is the binding site for SARS-CoV-2. ACE inhibitors and ARBs have mixed effects on ACE2 in animal models, and little data exist on the effects of ACE inhibitors and ARBs on ACE2 activity in humans. The data that have been collected is conflicting, indicating that the effects on ACE2 may not be uniform across different molecules of ACE inhibitors and ARBs.
• Three current analyses suggest insufficient evidence to routinely recommend the discontinuation of ACE inhibitors or ARBs according to the threat of COVID-19 infection.
• Implications for the Healthcare Team: The healthcare team should seek to inform patients about the known dangers of discontinuation of ACE inhibitors or ARBs whereas any potential benefit of this choice for COVID-19 infections is unproven.

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