No evidence of severe adverse events, acute health care utilization, long-term survival, or quality of life in patients with COVID-19, as a result of the use of NSAIDs – WHO’s Scientific Brief.

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Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs, and have a wide range of uses. NSAIDs include nonselective cyclooxygenase (COX) inhibitors (such as ibuprofen, aspirin (acetylsalicylate), diclofenac, and naproxen), as well as selective COX2 inhibitors (such as celecoxib, rofecoxib, etoricoxib, lumiracoxib, and valecoxib). 

Concerns have been raised that NSAIDs may be associated with an increased risk of adverse effects when used in patients with acute viral respiratory infections, including COVID-19.1,2 This review aimed to assess the effects of prior and current use of NSAIDs in patients with acute viral respiratory infections on acute severe adverse events (including mortality, the acute respiratory distress syndrome (ARDS), acute organ failure, and opportunistic infections), on acute health care utilization (including hospitalization, intensive care unit (ICU) admission, supplemental oxygen therapy, and mechanical ventilation) as well as on quality of life and long-term survival.

Methods

A rapid systematic review was carried out on 20 March 2020 on NSAIDs and viral respiratory infections using MEDLINE, EMBASE, and WHO Global Database. The review included studies conducted in humans of any age with viral respiratory infections exposed to systemic NSAIDs of any kind. All studies on COVID-19, the Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS) were included irrespective of their sample size.

Review of the evidence

A total of 73 studies were included (28 studies in adults, 46 studies in children, and one study in adults and children). All studies were concerned with acute viral respiratory infections or conditions commonly caused by respiratory viruses, but none specifically addressed COVID-19, SARS, or MERS. The review showed very low certainty evidence on mortality among adults and children.3 Effects of NSAIDs on the risk for ischemic and haemorrhagic stroke and myocardial infarction in adults with acute respiratory infections are unclear.4,5 Moderate to high certainty evidence showed little or no difference between ibuprofen and acetaminophen (paracetamol) among children with fever with regard to effects on death from all causes, hospitalization for any cause, acute renal failure, and acute gastrointestinal bleeding.6-9 Most studies report that no severe adverse events occurred, or that only mild or moderate adverse events were observed. 10-13 There was no evidence regarding the effects of NSAID use on acute health care utilization, explicit quality of life measures, or long-term survival.

Limitations

No direct evidence from patients with COVID-19, SARS, or MERS was available. Therefore, all evidence included should be considered indirect evidence with respect to the use of NSAIDs prior to or during the management of COVID-19. Only one randomized controlled trial included a sufficiently large number of participants to identify rare severe adverse events. The remaining evidence derives from smaller randomized controlled trials, which are likely to be underpowered for detecting rare severe adverse events, and from case-control and cohort studies with methodological limitations. Studies included not only patients with confirmed viral respiratory infections and known pathogens, but also those with conditions commonly caused by respiratory viruses, such as upper respiratory tract infections and fever in children. It is likely that not all participants had viral respiratory infections. NSAIDs are a diverse set of drugs with different risk profiles for different populations and conditions. Not all studies distinguished between different types of NSAIDs. Some of the older studies are likely to have included patients taking specific NSAIDs that are no longer available owing to adverse effects.

Conclusion

At present there is no evidence of severe adverse events, acute health care utilization, long-term survival, or quality of life in patients with COVID-19, as a result of the use of NSAIDs. 

References

  1. 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. Published 2020 Mar 30. doi:10.3332/ecancer.2020.1023
  2. Non-steroidal anti-inflammatory drugs and covid-19. BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m1185 (Published 27 March 2020)
  3. Epperly H, Vaughn FL, Mosholder AD, Maloney EM, Rubinson L: Nonsteroidal Anti-Inflammatory Drug and Aspirin Use, and Mortality among Critically Ill Pandemic H1N1 Influenza Patients: an Exploratory Analysis. Japanese journal of infectious diseases 2016, 69(3):248-251
  4. Wen Y-C, Hsiao F-Y, Lin Z-F, Fang C-C, Shen L-J: Risk of stroke associated with use of nonsteroidal anti-inflammatory drugs during acute respiratory infection episode. Pharmacoepidemiology and drug safety 2018, 27(6):645-651
  5. Wen Y-C, Hsiao F-Y, Chan KA, Lin Z-F, Shen L-J, Fang C-C: Acute Respiratory Infection and Use of Nonsteroidal Anti-Inflammatory Drugs on Risk of Acute Myocardial Infarction: A Nationwide Case-Crossover Study. The Journal of infectious diseases 2017, 215(4):503-509
  6. Grimaldi-Bensouda L, Abenhaim L, Michaud L, Mouterde O, Jonville-Béra AP, Giraudeau B, David B, Autret-Leca E: Clinical features and risk factors for upper gastrointestinal bleeding in children: A case-crossover study. European Journal of Clinical Pharmacology 2010, 66(8):831-837.
  7. Le Bourgeois M, Ferroni A, Leruez-Ville M, Varon E, Thumerelle C, Bremont F, Fayon MJ, Delacourt C, Ligier C, Watier L et al: Nonsteroidal Anti-Inflammatory Drug without Antibiotics for Acute Viral Infection Increases the Empyema Risk in Children: A Matched Case-Control Study. J Pediatr 2016, 175:47-53.e43.
  8. Lesko SM, Mitchell AA: Renal function after short-term ibuprofen use in infants and children. Pediatrics 1997, 100(6):954-957.
  9. Lesko SM, Mitchell AA: An Assessment of the Safety of Pediatric Ibuprofen: A Practitioner-Based Randomized Clinical Trial. JAMA: The Journal of the American Medical Association 1995, 273(12):929-933.
  10. Moore N, Charlesworth A, Van Ganse E, LeParc JM, Jones JK, Wall R, Schneid H, Verriere F: Risk factors for adverse events in analgesic drug users: results from the PAIN study. Pharmacoepidemiol Drug Saf 2003, 12(7):601-610.
  11. Narayan K, Cooper S, Morphet J, Innes K: Effectiveness of paracetamol versus ibuprofen administration in febrile children: A systematic literature review. J Paediatr Child Health 2017, 53(8):800-807.
  12. Pierce C, Voss B: Efficacy and safety of ibuprofen and acetaminophen in children and adults: A meta-analysis and qualitative review. Annals of Pharmacotherapy 2010, 44(3):489-506.
  13. Rainsford KD, Adesioye J, Dawson S: Relative safety of NSAIDs and analgesics for non-prescription use or in equivalent doses. InflammoPharmacology 2000, 8(4):351-359.

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