Evidence Mounts that RAS-Blocking Medications Pose No Danger to COVID-19 Patients

Eric Seaborg
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Many professional societies staked out the early position that COVID-19 patients should continue their blood pressure medications in the absence of a clear reason to stop them. And the early evidence to date has reinforced those recommendations.

It will take at least several months for more definitive answers from clinical trials, but the three largest observational studies to date found no signals of harm among patients taking inhibitors of the renin-angiotensin system (RAS) pathway.

Published in the May 1, 2020, New England Journal of Medicine, the studies are “definitely the biggest and most authoritative” so far, said Matthew Sparks, MD, assistant professor of medicine at Duke University. “The good news is, they do not show a signal for harm. The bad news is, it is retrospective data. This is a very challenging answer to get at with retrospective data. The only way we are going to know is with clinical trials, which are currently ongoing,”

The controversy was sparked by letters that appeared in BMJ and The Lancet in mid-March that raised a theoretical threat that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) could increase the likelihood of COVID-19 infections and worsen their severity by encouraging a potential pathway for the SARS-CoV-2 virus to enter lung cells.

The letters received a great deal of attention in the general press as well as from medical professionals, according to 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 letters noted two related areas of concern. First, they noted a possible link between severe COVID-19 infections and ACE inhibitors or ARBs based on studies showing that people who might be taking the drugs (on the basis of their pre-existing conditions) were in the groups experiencing more severe infections.

Second, they posited an explanation of why the drugs could worsen infections. Analysis of the molecular structure of the SARS-CoV-2 virus revealed a spike protein on its surface that can attach to receptors on angiotensin-converting enzyme 2 (ACE2) to gain entry into cells. Because some animal studies have shown that ACE inhibitors and ARBs may increase the expression of ACE2, and because ACE2 is expressed in the epithelial cells of the lungs, intestines, kidney, and blood vessels, patients taking the drugs could theoretically experience more severe infections.

The two letters “got so much press that patients were calling us and asking what to do,” Cohen said. “Some universities and practices actually released statements saying that you should be holding these medicines in anybody right now because of this theoretical risk, and that was with no data at the time.

“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,” said Stephen C. Textor, MD, professor of medicine with specialties in nephrology and hypertension at the Mayo Clinic in Rochester, Minn. Many experts were concerned that patients might stop taking their medications on their own, just in case they became infected.

Professional societies quickly pushed back with statements and 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.

By the end of March, the Nephrology Journal Club website, NephJC, had collected 14 such recommendations.

“After examining the available evidence, we advise that inhibitors of the renin-angiotensin system (RAS) pathway should be continued in patients with COVID-19 who are taking these drugs for evidence-based indications,” a group led by Sparks, who is co-curator of the NephJC COVID page, wrote in CJASN in early April. That article pointed out that although some studies have shown that the drugs increase ACE2 levels, others do not, so there is no evidence to conclude that RAS inhibitors are linked to upregulation of ACE2. (They set up a website with the latest COVID-19 information related to nephrology at www.nephjc.com/covid19.)

Observational studies

Cohen said that the first retrospective studies on the use of the medications in COVID-19 patients added to the confusion by showing opposing effects—some found the medications were beneficial, some found them to be harmful, and some found neither.

But the weight of evidence shifted with publication of the large New England Journal of Medicine studies, and “none of the three studies showed evidence of harm with continued use of ACE inhibitors and ARBs,” according to an editorial accompanying the studies.

One was a database study of 8910 patients who had been 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 case-control study in the Lombardy region of Italy compared 6272 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 SARS-CoV-2 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.

“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,” the editorialists write, and “these three studies support those recommendations.”

But “the only way we are going to know the answer is with clinical trials because there are too many confounders in the decision to start and stop these drugs,” Sparks said. “The good news is, when the retrospective studies tried to match patients with propensity scoring, they have not found a signal for harm.”

Among the questions that observational studies can’t answer is an obvious one: 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?

Beneficial effects?

And there is also that question of the drugs raising ACE2 levels—if that happened, would the effects necessarily be bad?

A JAMA Cardiology paper noted that in addition to its role as a pathway for the virus to enter cells, 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.” The authors note that 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.” They posit that lower levels of ACE2 could contribute to making COVID-19 worse, and that by restoring them to earlier levels, ACE inhibitors and ARBs could have a beneficial effect.

Cohen said that this paper illustrates that “there is so much that we don’t fully understand about factors that influence ACE2 expression and activity, and how that in turn may impact the development and severity of COVID-19. There are some studies that show that these medicines reduce inflammation in viral pneumonia and that they could potentially be helpful. There is some genuine theoretical risk and there are some genuine theoretical benefits.”

Clinical trials

Sparks and Cohen both emphasized the need for randomized clinical trials to sort out the confounders and give more definitive answers. 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. The investigators will follow the patients to rank their outcomes based on their need for mechanical ventilation, need for renal replacement therapy, organ failure, and mortality. The trial began enrolling patients on March 31, 2020, 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 said.

A large number of researchers must be stepping up in a similar fashion, because more than 1000 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.

Of course, clinicians must make decisions based on the evidence available now. Textor said 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.”

Sparks summarizes the weight of evidence and guidance from expert opinion: “When you see a patient with COVID-19, you should do exactly what you would do with any infection in regard to their RAS blockade. If their blood pressure is fine, they have no hyperkalemia, and they have no other reason to stop their medication, then you continue it. If you do have a reason, then you stop it. COVID-19 should not figure into the equation on what to do.”