The use of non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, does not lead to higher rates of death or severe disease in patients who are hospitalised with COVID-19, according to a new observational study of more than 72,000 people in the UK published in The Lancet Rheumatology journal.
NSAIDs are common treatments for acute pain and rheumatological diseases such as rheumatoid arthritis and osteoarthrosis. Early in the pandemic, there was debate on whether the use of such drugs increased the severity of COVID-19, which led to urgent calls for investigations between NSAIDs and COVID-19.
The ISARIC CCP-UK (International Severe Acute Respiratory and emerging Infection Consortium Clinical Characterisation Protocol United Kingdom) study, which is the largest of its kind, provides clear evidence that the continued use of NSAIDs in patients with COVID-19 is safe.
In the study, around a third of patients (30.4%. 1,279 out of 4,211) who had taken NSAIDs prior to hospital admission for COVID-19 died, a rate which was similar (31.3%. 21,256 out of 67,968) in patients who had not taken NSAIDs. In patients with rheumatological disease, the use of NSAIDs did not increase mortality.
Prof Ewen Harrison, of the University of Edinburgh and lead author of the study, said: “NSAIDs are commonly used to treat people all over the world for a range of conditions, from minor aches and pains to chronic conditions such as arthritis and cardiovascular disease.
Many people rely on them to be able to carry out their day-to-day activities. When the pandemic began over a year ago, we needed to be sure that these common medications would not lead to worse outcomes in people with COVID-19. We now have clear evidence that NSAIDs are safe to use in patients with COVID-19, which should provide reassurance to both clinicians and patients that they can continue to be used in the same way as before the pandemic began.”
The study collected data on the medication patients had been prescribed, were currently taking, or had taken within 14 days prior to being admitted to hospital, as well as demographic information, and medical history. The study cohort included patients with confirmed or highly suspected COVID-19 infection admitted to 255 healthcare facilities in England, Scotland, and Wales, between January and August 2020. Of the 72,179 patients eligible for the study, 5.8% (4,211) had taken NSAIDs prior to admission
Modelling analyses were used to estimate the effects of NSAIDs taken prior to hospitalisation on mortality rates in hospital, disease severity, admission to critical care, requirement for invasive or non-invasive ventilation, use of supplemental oxygen, or development of acute kidney injury, which were then compared to patients who had not taken NSAIDs.
Those who took NSAIDs were no more likely to be admitted to critical care, need invasive or non-invasive ventilation, or require oxygen.
The authors noted some limitations to the study. Despite being the largest ongoing prospective study of patients admitted to hospital, it only represents 60% of hospitalised patients in the UK over the time of the study and it did not include patients with severe COVID-19 who were not hospitalised.
However, it would be expected that most patients who had severe COVID-19 would have been admitted to hospital and therefore included in the study, the authors said. The study did not determine whether patients continued to be given NSAIDs while they were in hospital, so the authors cannot make any recommendations on this.
Additionally, the study could not capture how long patients were taking NSAIDs prior to hospital admission and whether they were being taken for long-term conditions or short-term symptom relief. In the UK, ibuprofen is the most commonly used NSAID, so it is unclear whether the results of this study are generalisable to other countries where other NSAIDs are more frequently used.
Further analyses performed suggested other non-ibuprofen NSAIDs had a similar safety profile to ibuprofen.
Further research and clinical trials may help definitively establish whether NSAIDs are safe in different populations and whether their anti-inflammatory effects have any impact on patients with COVID-19.
Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) commonly used during any infection accompanied by fever. It is an effective antipyretic and analgesic and is available over the counter (OTC). Acetaminophen and ibuprofen are the two most extensively used antipyretics .
Ibuprofen disappeared from the pharmacy shelves when quarantine measures were announced to combat the 2019 coronavirus (COVID-19) disease pandemic, which led to global shortages of ibuprofen . However, a while later information circulated on the news saying that ibuprofen should be avoided as it could worsen COVID-19 symptoms [3–5].
The concern with ibuprofen in the media during the COVID-19 outbreak was fueled by the Health Minister of France, who shared on social media that NSAIDs including ibuprofen could worsen COVID-19 infections . This was based solely on observation, and no reference to any published data was ever made. Such opinions are influenced by indication bias as patients usually step up to ibuprofen and other NSAIDs when their symptoms get worse.
Shortly thereafter, a correspondence published in the Lancet posed the theory that due to the port of entry of COVID-19, which binds to their target cells through angiotensin-converting enzyme 2 (ACE2), some drugs that upregulate the expression of ACE2, giving ibuprofen as an example, may facilitate infection with COVID-19 .
Later on, many health agencies shared statements reporting that the concern with ibuprofen and other NSAIDs had no solid evidence to support the recommendations to avoid its use in COVID-19-infected patients or the general population to minimize the risk of transmission [8–11].
Nevertheless, the theory and observation are worth further research. ACE2 plays an important role in the viral entry to cells and is also an important mediator in the renin-angiotensin system, which is important in the mechanism of multiple drugs, not only ibuprofen . In the search for literature related to the effect ibuprofen or NSAIDs may directly have on ACE2, only one animal study was found.
This study was in diabetic rats and reported an increase in ACE2 in the heart tissue after treatment with ibuprofen ; however, a similar effect cannot be easily extrapolated to non-diabetic human patients or lung tissue.
Nevertheless, if any of these speculations and observations that ibuprofen worsens symptoms or increases the risk of transmission are true, the implications for the healthcare systems may be huge because of its wide OTC use not only in the context of COVID-19-associated fever but also in patients that chronically use it for pain [14, 15].
Implications of public fear based on little clinical evidence could be that patients with chronic pain switch from NSAIDs to alternatives such as opioids, which could worsen the opioid epidemic. Alternatively, if higher doses of acetaminophen are used to avoid NSAIDs, an increase in liver injury cases may occur.
Contrarily, a few animal studies demonstrated that ACE2 plays a critical role in viral-induced lung injury, showing worse survival in ACE2 knockout mice, and proposed a potential benefit of ACE2 through the removal of angiotensin II in viral-mediated lung injury [16, 17].
This possibly means that upregulating ACE2 might be beneficial. In fact, recombinant ACE2 did seem to improve lung injury in a phase II trial involving acute respiratory distress syndrome (ARDS) patients .
With the theoretical, anecdotal observations and serious implications together with theories of benefit, the aim of our study was to provide an evaluation of outcomes in COVID-19-infected patients taking ibuprofen or other NSAIDs, both acutely and/or chronically, which is essential to rule out any drug safety concerns and determine whether comorbid conditions and age confound this association. In addition, results may set a path to further study whether ACE2 upregulation has a valid therapeutic potential.
More information: Thomas M Drake et al, Non-steroidal anti-inflammatory drug use and outcomes of COVID-19 in the ISARIC Clinical Characterisation Protocol UK cohort: a matched, prospective cohort study, The Lancet Rheumatology (2021). DOI: 10.1016/S2665-9913(21)00104-1