Usage of Ibuprofen and Angiotensin-Converting Enzyme Inhibitors (ACEi) in Coronavirus 2019 (COVID-19) Patients: Should They Be Used?

By: Evan Cheung, PharmD (c/o 2020)

            On March 11^th, 2020, a research article was published in the Lancet journal that informed the public about a hypothesized issue regarding the use of ibuprofen in COVID-19 patients.¹ Because of the information found in this article, patients and medical professions are wary of utilizing nonsteroidal anti-inflammatory drugs (NSAIDs) to treat fever in patients diagnosed with COVID due to the proposed risk of worsening symptoms. This hypothesis was made based on the notion that the COVID-19 virus binds to a specific receptor, angiotensin-converting enzyme 2 (ACE2), that facilitates its ability to enter the cell. In turn, ibuprofen has been shown to upregulate ACE2 expressions in the body.² Fang et. al also hypothesized the risk of certain co-morbidities (e.g diabetes, cerebral stroke, hypertension) and utilizing certain medications (e.g ACEi and angiotensin II receptor blockers [ARBs]) that can increase the expression of ACE2 and increase the risk of COVID-19 infection in these patient population.² 

It is important to note that the claims made in the Lancet journal are not made based on clinical, scientific evidence that directly links the worsening of symptoms in COVID-19 patients to the use of ibuprofen and other NSAIDs. The claims are based on proposed mechanisms of the virus’s ability to enter the host cell. In a systematic review of SARS-CoV2 and SARS-CoV from 2002, no strong evidence was found suggesting the usage or non-usage of ibuprofen for COVID-19.³ Although there are limited sources that evaluate the effect of ibuprofen in SARS-CoV2, a study conducted on indomethacin 1 mg/kg on canine coronavirus demonstrated “potent direct antiviral activity against SARS-CoV and CCoV.”⁴ Both SARS-CoV and SARS-CoV2 share a common target receptor, the ACE2.⁵ However, the SARS-CoV2 receptor is longer than that of SARS-CoV with a “completely different receptor binding region.”⁵ Thus, the study with indomethacin does not necessarily provide sufficient evidence of the usage of indomethacin or other NSAIDs like ibuprofen to provide the same effect on SARS-CoV2. In an article published by the Annals of the Rheumatic Disease, ibuprofen was shown to reduce interleukin-6 in human tissues and sputum, granting benefit in reducing the risk of fatal cytokine storm associated with COVID-19.⁶ It is advised by the writers of the article that NSAIDs used for the treatment of chronic inflammatory disease (e.g arthritis) should not be discontinued due to the increased risk of infection caused by untreated conditions.⁶ With the lack of clinical evidence that links COVID-19 to decline in health in patients taking ibuprofen, clinical judgment by a healthcare practitioner should be used to determine the necessity of NSAIDs for COVID-19 symptom treatment. 

For ACEi and ARB, it had also been hypothesized by Fang et. al, that both medications can increase the expression of ACE2.² Similar to the hypothesis made with ibuprofen, both classes of medication have limited evidence to link the use of medication with an increased risk of worsening symptoms in COVID-19.^7-9 On the contrary, there are counter-hypothesis that state “elevated ACE2 membrane expression and tissue activity by administration of ARB and/or infusion of soluble ACE2 could confer protective properties against inflammatory tissue damage in COVID-19 infection.”^7,8 Due to the uncertainty in linking the types of medications to COVID-19 symptom worsening and the known benefits of decreased mortality in cardiac patients taking the medication, the ACEi should be continued unless the patient develops conditions in which the ACEi is contraindicated.^7,9

Sources:

1. APhA coronavirus watch: NSAIDs okay for COVID-19 patients. American Pharmacist Association. 2020 Apr.  https://www.pharmacist.com/article/apha-coronavirus-watch-nsaids-okay-covid-19-patients
2. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020;8(4):e21. doi: 10.1016/S2213-2600(20)30116-8
3. Russell B, Moss C, Rigg A, Van Hemelrijck M. COVID-19 and treatment with NSAIDs and corticosteroids: should we be limiting their use in the clinical setting? Ecancermedicalscience. 2020;14:1023. doi:10.3332/ecancer.2020.1023. eCollection 2020.
4. Amici C, Di Caro A, Ciucci A, Chiappa L, et al. Indomethacin has a potential antiviral activity against SARS coronavirus. Antivir Ther. 2006; 11(8):1021-30. PMID: 17302372.
5. Ceccarelli M, Berretta M, Venanzi Rullo E, et al. Differences and similarities between Severe Acute Respiratory Syndrome (SARS)-CoronaVirus (CoV) and SARS-CoV-2. Would a rose by another name smell as sweet? Eur Rev Med Pharmacol Sci. 2020; 24(5):2781-83. doi.10.26355/eurrev_202003_20551
6. Giollo A, Adami G, Gatti D, et al. Coronavirus disease 19 (Covid-19) and non-steroidal anti-inflammatory drugs (NSAID). Annals of the Rheumatic Diseases 2020. doi: 10.1136/annrheumdis-2020-217598
7. Alexandre J, Cracowski JL, Richard V, Bouhanick B; in name of the “Drugs and COVID-19” working group of the French Society of Pharmacology and Therapeutics (SFPT). Renin-angiotensin-aldosterone system and COVID-19 infection. Ann Endocrinol (Paris). 2020;81(2-3):63-67. doi:10.1016/j.ando.2020.04.005
8. Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19. N Engl J Med. 2020;382(17):1653-1659. doi: 10.1056/NEJMsr2005760
9. Rico-Mesa JS, White A, Anderson AS. Outcomes in Patients with COVID-19 Infection Taking ACEI/ARB. Curr Cardiol Rep. 2020;22(5):31. doi: 10.1007/s11886-020-01291-4