The European Society of Cardiology (ESC) has issued a statement urging physicians and patients to continue treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), in light of a newly described theory that those agents could increase the risk of developing COVID-19 and/or worsen its severity.
The concern arises from the observation that the new coronavirus SARS-CoV-2 causing COVID-19 binds to angiotensin-converting enzyme 2 (ACE2) to infect cells, and both ACE inhibitors and ARBs increase ACE2 levels.
This mechanism has been theorized as a possible risk factor for facilitating the acquisition of COVID-19 infection and worsening its severity. However, paradoxically, it has also been hypothesized to protect against acute lung injury from the disease.
Meanwhile, a Lancet Respiratory Medicine article was published March 11 entitled, "Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?"
"We...hypothesize that diabetes and hypertension treatment with ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19," said the authors.
This prompted some media coverage in the United Kingdom and "social media-related amplification," leading to concern and, in some cases, discontinuation of the drugs by patients.
But on March 13, the ESC Council on Hypertension dismissed the concerns as entirely speculative, in a statement posted to the ESC website.
It said that the council "strongly recommend that physicians and patients should continue treatment with their usual antihypertensive therapy because there is no clinical or scientific evidence to suggest that treatment with ACE inhibitors or ARBs should be discontinued because of the COVID-19 infection."
The statement, signed by Council Chair Professor Giovanni de Simone, MD, on behalf of the nucleus members, also says that in regard to the theorized protective effect against serious lung complications in individuals with COVID-19, the data come only from animal, and not human, studies.
"Speculation about the safety of ACE-inhibitor or ARB treatment in relation to COVID-19 does not have a sound scientific basis or evidence to support it," the ESC panel concludes.
Three American professional cardiology societies have issued a joint statement urging continuation of renin–angiotensin–aldosterone system (RAAS) antagonists in patients, despite theoretical concerns that their use might worsen outcomes in the event of infection with COVID-19.
The new statement was issued jointly by the American Heart Association (AHA), American College of Cardiology (ACC), and Heart Failure Society of America (HFSA) on March 17.
It follows similar recent statements from the European Society of Cardiology (ESC), as reported yesterday by Medscape Medical News, and the European Society of Hypertension, Canadian Cardiovascular Society, and International Society of Hypertension, among others.
"We understand the concern — as it has become clear that people with cardiovascular disease are at much higher risk of serious complications including death from COVID-19," said AHA president Robert A. Harrington, MD, chair of the department of medicine at Stanford University, California, in a statement.
"However, we have reviewed the latest research — the evidence does not confirm the need to discontinue ACE inhibitors or angiotensin-receptor blockers (ARBs), and we strongly recommend all physicians to consider the individual needs of each patient before making any changes to ACE inhibitors or ARB treatment regimens."
In the Event of Diagnosis With COVID-19, Individualize Treatment
As with the ESC and other statements, the new AHA/ACC/HFSA statement is in response to an article suggesting theoretical harm published March 11 in Lancet Respiratory Medicine.
The new coronavirus SARS-CoV-2 that causes COVID-19 infects human cells by binding to ACE2 receptors, and some animal studies have suggested this mechanism upregulates ACE2 expression in the heart.
The Lancet article speculates that in patients with diabetes and hypertension ACE2 upregulation from ACEIs and ARBs could increase the risk of developing severe and fatal COVID-19.
The authors suggested that the medications may be partially responsible for the more severe and fatal course of COVID-19 seen in individuals with hypertension, diabetes, and cardiovascular disease.
This article received some media coverage and social media play in the United Kingdom, resulting in patients contacting their physicians and in some cases discontinuing their drugs.
In general, the three American cardiology societies advise "continuation of RAAS antagonists for those patients who are currently prescribed such agents for indications for which these agents are known to be beneficial, such as heart failure, hypertension, or ischemic heart disease."
However, they say, "In the event patients with cardiovascular disease are diagnosed with COVID-19, individualized treatment decisions should be made according to each patient's hemodynamic status and clinical presentation."
No Evidence of Harm or Benefit...More Research Needed
There is also a theory that ACE inhibitors and ARBs might be paradoxically beneficial in coronavirus infection.
This comes from the fact that ACE2 converts angiotensin II to vasodilatory angiotensin 1-7, thereby potentially exerting a hypotensive effect, and in animal studies both types of drugs have been shown to reduce severe lung injury in certain viral pneumonias.
However, the three societies clarify: "Currently there are no experimental or clinical data demonstrating beneficial or adverse outcomes with background use of ACE inhibitors, ARBs, or other RAAS antagonists in COVID-19 or among COVID-19 patients with a history of cardiovascular disease treated with such agents."
Therefore, they urge, "Be advised not to add or remove any RAAS-related treatments, beyond actions based on standard clinical practice."
"These theoretical concerns and findings of cardiovascular involvement with COVID-19 deserve much more detailed research, and quickly. As further research and developments related to this issue evolve, we will update these recommendations as needed."
In an interview with Medscape Medical News, David Gurwitz, PhD, the author of the article speculating ARBs might represent a "tentative" SARS-CoV-2 therapeutic, said he has been in touch with clinicians in Italy in attempts to retrospectively gather data from their COVID-19 patients to correlate antihypertensive class use with outcomes.
"We are working as quickly as possible, but the Italian clinicians are extremely busy so it may take some time. Things are very tough in Italy right now."
A warning from French health officials suggests that grave adverse events have been reported with the use of nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, in patients with COVID-19, and they recommend treatment instead with acetaminophen.
But many physicians, particularly outside of France, reacted on social networks saying there is currently insufficient evidence for such a recommendation.
The Spanish Ministry of Health agreed, stating on Sunday that there is no evidence that ibuprofen (or other NSAIDs) makes COVID-19 infection worse.
And British physicians broadly agreed, although they say acetaminophen is a better choice for infection in general.
And one US expert says evidence of risks to people with COVID-19 beyond those already well-known with infections in general and NSAIDs have not been established.
On March 14, the French government reported "serious adverse events" associated with NSAIDs in people with COVID-19. Soon after, the French Health Minister Olivier Véran tweeted that "taking anti-inflammatory drugs (ibuprofen, cortisone...) could be an aggravating factor of the [COVID-19] infection."
"If you have a fever, take paracetamol," he tweeted. "If you are already on anti-inflammatory drugs or in doubt, ask your doctor for advice."
Paracetamol is a generic term for acetaminophen commonly used outside the United States.
In a statement on its website, Reckitt Benckiser, manufacturer of the Nurofen brand of ibuprofen, said: "Appropriate use of ibuprofen and paracetamol is still currently being recommended by most European health authorities as part of the symptomatic treatment of COVID-19. Reckitt Benckiser is not aware of any evidence that ibuprofen adversely impacts the outcome in patients suffering from COVID-19 infection."
The company "has neither received new safety information nor been involved in the evaluation of any adverse events regarding the use of ibuprofen in COVID-19," it adds.
"As with any medicine, we would remind consumers and their caregivers to carefully read and follow the instructions provided on the packaging and in the patient information leaflet."
No Evidence of Any Unique Risk of NSAIDs in COVID-19
Gregory Poland, MD, a professor of medicine and infectious disease and director of the Vaccine Research Group at the Mayo Clinic, in Rochester, Minnesota, said that, without clarification of any new data detailing effects, additional risks of NSAIDs related to COVID-19 are questionable.
Poland told Medscape Medical News: "I think there is far inadequate information to make a blanket statement like that [which the French Health Minister has made]."NSAIDs, often recommended to relieve fever and symptoms of influenza as well as COVID-19, are well-known to have potential adverse effects on the stomach and kidneys in the very groups considered at higher risk of COVID-19 — older patients and those with comorbidities or compromised immune systems. In those patients, acetaminophen is commonly recommended as an alternative to treatment of fever anyhow.
"I think what [the French] are recommending is an overextension of the known concerns," Poland observed.
"I know of no published data on the use of NSAIDs with COVID-19 that represents any sort of unique risk," he stressed.
I think what [the French] are recommending is an overextension of the known concerns. I know of no published data on the use of NSAIDs with COVID-19 that represents any sort of unique risk. Dr Gregory Poland
Poland cautioned against a rush to draw conclusions in times when stress and panic are exceptionally high. He relayed a report from a colleague in which four severe COVID-19 cases were described as being among patients who were taking NSAIDs, seeming to draw an association between the two.
"There was an inappropriate inference of cause and effect," he said. "This is a mistake we commonly see — people will assume causality and more often than not, it's not the case."
Meanwhile, the Spanish Ministry of Health, while stressing there is no evidence that NSAIDs makes COVID-19 infection worse, did state, however, that ibuprofen package inserts mention that the use of the drug might mask the symptoms of infections, which could delay diagnosis and cause them to be diagnosed in more severe stages.
They emphasize, however, that this refers to infections in general, not specifically to COVID-19.
The Spanish ministry adds that it is nevertheless looking further into the issue of NSAIDs and COVID-19 and will publish its findings by May 2020.
French Experts Stand Their Ground
But in exclusive interviews with Medscape France, a rheumatologist and an infectious disease expert gave their take on the stance of their health ministry.
Francis Berenbaum, MD, PhD, a rheumatologist at Saint-Antoine Hospital in Paris told Medscape France that in patients with rheumatological diseases who are on long-term treatment with NSAIDs therapy should not be stopped unless a patient starts having COVID-19 symptoms such as fever.
For other people, if they develop a fever and COVID-19 symptoms, they should not take NSAIDs because it can worsen the disease (although he acknowledges this is also known in several other viral diseases including flu), so it's better to take paracetamol unless there is a liver condition that prevents the latter.
Meanwhile, Christian Perronne, MD, PhD, an infectious disease specialist in Garches, France, told Medscape France he believes the advice to avoid NSAIDs in COVID-19 infection is common sense.
Perronne told Medscape Medical News he has not personally witnessed cases of COVID-19 worsening with NSAIDs, noting that there is not, as yet, enough perspective in France, but said this has been demonstrated by Chinese results.
NSAIDs are not suitable for respiratory infections, he stressed. He said he never gives NSAIDs in principle in respiratory infections, only in exceptional cases, when you cannot do otherwise.
An investigation requested by the French National Agency for the Safety of Medicines and Health Products (ANSM) last year confirmed that NSAIDs can have an aggravating role in the event of severe infection, Perronne stressed, noting it stated in a press release last April of a risk of serious infectious complications, causing hospitalizations, sequelae, or even death, with NSAID use in such instances.Of note, France has tighter restrictions on the sale of NSAIDs than other countries, and beginning this year, the products, including paracetamol and ibuprofen, are no longer available over-the-counter in the country.
UK: Acetaminophen Better for Some, But Not Necessarily Due to COVID-19
Meanwhile, UK experts agree that acetaminophen is a preferable choice over NSAIDs in those at risk for COVID-19 because of the known safety reasons.
"There is a good reason to avoid ibuprofen as it may exacerbate acute kidney injury brought on by any severe illness, including severe COVID-19 disease," Rupert Beale, MB, PhD, group leader in cell biology of infection at the Francis Crick Institute, London, UK, told the UK Science Media Center. But, he added, "There isn't yet any widely accepted additional reason to avoid it for COVID-19."
Tom Wingfield, PhD, a senior clinical lecturer and honorary consultant physician with the Liverpool School of Tropical Medicine, UK, agreed.
"In the UK, paracetamol would generally be preferred over NSAIDs such as ibuprofen to relieve symptoms caused by infection such as fever," he told the UK Science Media Center.
"This is because, when taken according to the manufacturer's and/or a health professional's instructions in terms of timing and maximum dosage, it is less likely to cause side effects."
He underscored that more clarity is needed to determine the significance of the message from the French Health Ministry regarding the effect of NSAIDs on COVID-19.
"It is not clear from the French Minister's comments whether the advice given is generic 'good practice' guidance or specifically related to data emerging from cases of COVID-19, but this might become clear in due course," Wingfield said.
Corticosteroids and COVID-19
Poland noted that the French Health Ministry also recommends against the use of cortisone in COVID-19, which is consistent with recommendations by the World Health Organization and Centers for Disease Control and Prevention.
"Corticosteroids, though having a different mechanism of action than NSAIDs, are still noninflammatory and therefore seem [ideal] to use in an inflammatory disease," he explained.
"But the reasons for the recommendation against them is the observation that with SARS I, they not only did not improve the clinical course, but in fact appeared to have short-term and mid-term adverse effects in delaying viral clearance," Poland said.
However, experts recommend that patients taking cortisone or other steroids for chronic diseases should not stop them, except on advice from their physician. This advice was reiterated by the French rheumatologist Berenbaus in his interview with Medscape Medical News.
Separately, the UK Society for Endocrinology has issued advice on coronavirus for patients with adrenal or pituitary insufficiency who are taking hydrocortisoneor other steroids.
Poland has reported no relevant financial relationships
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