The theoretical threat from blood pressure medicine’s effects on COVID-19 caused many patients on these medications to make panicked calls to their healthcare providers. However, a group of professional associations and researchers moved quickly to counter this fear — and to recommend that patients infected with COVID-19 should continue taking renin-angiotensin system (RAS) blockers in the absence of a clear reason to stop them.
Patients on blood pressure medication that block the renin-angiotensin system (RAS) should continue taking their medication during the COVID-19 pandemic, and COVID-19 patients should continue these medications in the absence of a clear reason to stop them, many professional societies recommend.
The professional societies issued formal statements in response to the theoretical threat that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) could increase the likelihood of infections and worsen their severity by encouraging a potential pathway for the SARS-CoV-2 virus to enter lung cells. Contrary to the theoretical risk, the three largest observational studies to date found no signals of harm from continuing these medications.
“This has been an active debate and an example of how little bits and pieces of basic science can lead you down paths that can really get you twisted around,” says Stephen C. Textor, MD, professor of medicine with specialties in nephrology and hypertension at the Mayo Clinic in Rochester, Minn., who was on the committee that wrote the Endocrine Society scientific statement on hypertension.
“We had a lot of discussion about it,” says Gail Kurr Adler, MD, PhD, associate professor of medicine in the division of endocrinology, diabetes, and hypertension at Brigham and Women’s Hospital in Boston. “We decided that we should keep everybody on their ACE inhibitors and ARBs because there was not enough data to stop effective, good treatments, and there is a lot of cardiovascular risk with stopping them. The medical associations came out very quickly to say don’t stop them. Now there is good observational data that these medications are safe in COVID-19.”
The Theoretical Threat
A pair of letters in BMJ and the Lancet in mid-March raised two potential areas of concern that sparked the discussion.
One concern relates to how coronaviruses can gain access into cells. Like other coronavirus family members, SARS-CoV-2 has a spike protein on its surface that can attach to receptors on angiotensin-converting enzyme 2 (ACE2) and gain entry. Because some animal studies have shown that ACE inhibitors and ARBs increase the expression of ACE2 — which is expressed in the epithelial cells of the lungs — the writers proposed that this mechanism could contribute to more severe infections among patients taking the drugs.
“We had a lot of discussion about it. We decided that we should keep everybody on their ACE inhibitors and ARBs because there was not enough data to stop effective, good treatments, and there is a lot of cardiovascular risk with stopping them. The medical associations came out very quickly to say don’t stop them. Now there is good observational data that these medications are safe in COVID-19.” – Gail Kurr Adler, MD, PhD, associate professor of medicine, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Boston, Mass.
Second, the investigators noted that patients with hypertension, diabetes, and cardiovascular disease were at highest risk for severe infection. Because these patients are likely to be taking ACE inhibitors and ARBs, they posed the question: Could the drugs be contributing to the severity of their infections?
The two letters “got so much press that patients were calling us and asking what to do. Some universities and practices actually released statements saying that you should be holding these medicines in anybody because of this theoretical risk,” says Jordana Cohen, MD, assistant professor in the division of renal-electrolyte and hypertension at the Perelman School of Medicine at the University of Pennsylvania.
The prospect that patients might decide on their own to stop taking their medications, just in case they became infected, was a big concern. “The possibility of adverse events from stopping these drugs likely would outweigh any theoretical change in the COVID course if they were ever infected,” Textor says.
Professional Societies Push Back
A large group of professional societies quickly pushed back with official recommendations saying that there was no evidence to support the withholding of these medications, so they should be continued in the absence of indications for stopping them. At least 14 groups, including the European Society of Hypertension, American Heart Association, and Heart Failure Society of America, went on the record.
Cohen says that the first retrospective studies on the use of the medications in COVID-19 patients reported confusing outcomes—some found the medications were beneficial, some found them to be harmful, and some found neither.
Evidence Weighs In
The weight of evidence shifted when the May 1 New England Journal of Medicine published three of the largest observational studies yet, with none showing evidence of harm with the use of ACE inhibitors and ARBs.
One was a database study of 8,910 COVID-19 patients hospitalized in 11 countries on three continents. That study found that neither ACE inhibitors nor ARBs were associated with an increased risk of in-hospital death.
A study in the Lombardy region of Italy compared 6,272 patients with confirmed COVID-19 with 30,759 controls matched according to age, sex, and municipality of residence. The study found no association between ACE inhibitors or ARBs with the likelihood of COVID-19 infection nor any association between the drugs and severe COVID-19 disease.
A study of more than 12,500 electronic health records of patients in the New York University health system found no positive association for ACE inhibitors or ARBs with either a COVID-19 infection or severe illness.
An editorial accompanying the studies said: “Professional scientific societies and experts have spoken with one voice in advising that patients should not discontinue ACE inhibitor or ARB therapy out of a concern that they are at increased risk for infection, severe illness, or death during the COVID-19 pandemic. These three studies support those recommendations.”
“The three New England Journal of Medicine observational studies had thousands of patients in each report. The results are quite consistent — from many different parts of the world, many different healthcare systems, and many different populations — all coming to the same general conclusion. I think that is extremely useful evidence for the patients who use these drugs and the physicians who prescribe them. There are millions of people taking these medications, and some of them would be understandably frightened. We can now give them a greater degree of reassurance,” says Daniel J. Drucker, MD, professor of medicine at the University of Toronto and editor-in-chief of Endocrine Reviews.
Need for Clinical Trials
Clinicians have little choice but to rely on observational studies on a topic that is rife with confounding effects that prevent the studies from answering basic questions such as: Are patients with conditions like hypertension, diabetes, and cardiovascular disease experiencing more severe COVID-19 because of these underlying conditions or because of the drugs they are taking to treat the conditions?
These kinds of questions emphasize the need for randomized clinical trials to help sort through the confounders and give more definitive answers, and these studies are on the way. Cohen is a co-principal investigator of a multi-center, international trial that plans to enroll 152 patients hospitalized with COVID-19 who are already using an ACE inhibitor or ARB. The patients will be randomly assigned to either stop or continue taking the medication, and their clinical course followed. The trial began enrolling patients on March 31 and is expected to run for three or four months. It is “essentially unfunded” with the healthcare providers and sites participating on a volunteer basis, Cohen says.
A large number of researchers must be stepping up in a similar fashion, because more than 1,000 studies addressing various aspects of COVID-19 are registered at ClinicalTrials.gov, including more than 600 interventional studies and randomized clinical trials. At least a dozen of them are addressing the use of ACE inhibitors and ARBs.
The Case for Beneficial Effects
And while clinicians await these results, they can also consider the unsettled science surrounding ACE2 expression and activity. While some studies have shown that the RAS blockers increase ACE2 levels, others do not. And although there is a theoretical risk from raising ACE2 levels, there is also an important possibility that the opposite could be true.
“The three New England Journal of Medicine observational studies had thousands of patients in each report. The results are quite consistent … all coming to the same general conclusion. I think that is extremely useful evidence for the patients who use these drugs and the physicians who prescribe them. There are millions of people taking these medications, and some of them would be understandably frightened. We can now give them a greater degree of reassurance.” – Daniel J. Drucker, MD, professor of medicine, University of Toronto, Toronto, Canada; editor-in-chief, Endocrine Reviews
A JAMA Cardiology paper noted that ACE2 “plays a major anti-inflammatory role in RAS signaling by converting angiotensin II, the quintessential perpetrator of inflammation, to angiotensin 1-7, which carries anti-inflammatory properties.” ACE2 production declines with age such that “older individuals, especially those with hypertension and diabetes, have reduced ACE2 expression and upregulation of angiotensin II proinflammatory signaling.” The authors posit that lower levels of ACE2 could contribute to making COVID-19 worse, so by restoring them to earlier levels, ACE inhibitors and ARBs could have a beneficial effect.
Cohen notes that some studies show that these medications reduce inflammation in viral pneumonia, and Adler points to data suggesting that ACE2 is beneficial in some experimental models of lung disease.
In the face of the theoretical pros and cons, clinicians must make decisions based on the available evidence. Like Adler and her colleagues at Brigham and Women’s, Textor says that at the Mayo Clinic they “dug into the issue” and concluded that “it is a mistake to react to the theoretical issue when there has been no observed effect at all.”
Seaborg is a freelance writer based in Charlottesville, Va. In the May issue, he wrote about recommendations from the editors of The Journal of Clinical Endocrinology & Metabolism regarding treatment of certain COVID-19 patients with underlying endocrine conditions.