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Should patients with COVID-19 avoid ibuprofen or RAAS antagonists?


Researchers have hypothesized that treatments that increase angiotensin-converting enzyme 2 (ACE2) may also increase the risk of novel coronavirus disease (COVID-19). This speculation and other concerns have led some officials and organizations to question whether ibuprofen or other drugs such as renin angiotensin aldosterone system (RAAS) antagonists should be avoided as treatments in patients with COVID-19. Health agencies and professional organizations have said they are not recommending against these medications.

The Food and Drug Administration on March 19 advised patients that it was “not aware of scientific evidence connecting” nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen “with worsening COVID-19 symptoms.”

“The agency is investigating this issue further and will communicate publicly when more information is available,” the FDA said. “However, all prescription NSAID labels warn that ‘the pharmacological activity of NSAIDs in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.’ ” The FDA also noted that other over-the-counter and prescription medications are available for pain relief and fever reduction, and patients who “are concerned about taking NSAIDs and rely on these medications to treat chronic diseases” should talk to a health care provider.

A World Health Organization spokesperson said during a press conference on March 17 that the organization was looking into concerns about ibuprofen use in patients with COVID-19 and suggested that in the meantime patients take acetaminophen for fever instead. On March 18, the WHO said that it was not recommending against the use of ibuprofen.

“At present, based on currently available information, WHO does not recommend against the use of ibuprofen,” the organization said. “We are also consulting with physicians treating COVID-19 patients and are not aware of reports of any negative effects of ibuprofen, beyond the usual known side effects that limit its use in certain populations. WHO is not aware of published clinical or population-based data on this topic.”

A spokesperson for the National Institute of Allergy and Infectious Diseases said on March 18, “More research is needed to evaluate reports that ibruprofen and other over-the-counter anti-inflammatory drugs may affect the course of COVID-19. Currently, there is no conclusive evidence that ibuprofen and other over-the-counter anti-inflammatory drugs increase the risk of serious complications or of acquiring the virus that causes COVID-19. There is also no conclusive evidence that taking over-the-counter anti-inflammatory drugs is harmful for other respiratory infections.”

The European Medicines Agency (EMA) on March 18 said, “There is currently no scientific evidence establishing a link between ibuprofen and worsening of COVID‑19. EMA is monitoring the situation closely and will review any new information that becomes available on this issue in the context of the pandemic.”

In correspondence published March 11 in the Lancet Respiratory Medicine, Lei Fang, MD, of the department of biomedicine at University Hospital Basel (Switzerland), and colleagues suggested that patients with hypertension and diabetes mellitus may be at increased risk of COVID-19 because these comorbidities “are often treated with angiotensin converting enzyme (ACE) inhibitors.” In addition, “ACE2 polymorphisms that have been linked to diabetes mellitus, cerebral stroke, and hypertension” also may play a role, the researchers said (Lancet Respir Med. 2020 Mar 11.

“ACE2 is substantially increased in patients with type 1 or type 2 diabetes, who are treated with ACE inhibitors and angiotensin II type-I receptor blockers (ARBs). Hypertension is also treated with ACE inhibitors and ARBs, which results in an upregulation of ACE2. ACE2 can also be increased by thiazolidinediones and ibuprofen.”

A March 16 statement from the Heart Failure Society of America (HSFC), American College of Cardiology (ACC), and American Heart Association (AHA) addressed concerns about using RAAS antagonists in COVID-19.

“Patients with underlying cardiovascular diseases appear to have an increased risk for adverse outcomes with [COVID-19],” the organizations said. “Although the clinical manifestations of COVID-19 are dominated by respiratory symptoms, some patients also may have severe cardiovascular damage. [ACE2] receptors have been shown to be the entry point into human cells for SARS-CoV-2, the virus that causes COVID-19. In a few experimental studies with animal models, both [ACE] inhibitors and angiotensin receptor blockers (ARBs) have been shown to upregulate ACE2 expression in the heart. Though these have not been shown in human studies, or in the setting of COVID-19, such potential upregulation of ACE2 by ACE inhibitors or ARBs has resulted in a speculation of potential increased risk for COVID-19 infection in patients with background treatment of these medications.”

ACE2, ACE, angiotensin II, and other RAAS system interactions “are quite complex, and at times, paradoxical,” the statement says. “In experimental studies, both ACE inhibitors and ARBs have been shown to reduce severe lung injury in certain viral pneumonias, and it has been speculated that these agents could be beneficial in COVID-19.

“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. The HFSA, ACC, and AHA recommend 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. 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. Therefore, 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.”

Dr. Fang and colleagues had no competing interests.

SOURCE: Fang L et al. Lancet Respir Med. 2020 Mar 11. doi: 10.1016/S2213-2600(20)30116-8.

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