Recent and developing literature has begun reporting on the incidence of thromboembolic events associated with COVID‐19. Klok et al analyzed 184 SARS‐CoV2–positive intensive care unit (ICU) patients in two Dutch University Hospitals, reporting an incidence of thrombotic complications to be 31%, with pulmonary embolism (PE) comprising 81% of these complications.1 Moreover, Cui et al reports on a population of 81 ICU patients at the Union Hospital, Wuhan, an incidence of 25% in venous thromboembolism (VTE), also possibly related to worse prognosis.2 Wang et al collected data from 1026 COVID‐19–positive patients in 31 provincial administrative regions in China and found 40% of the patients as high risk for VTE according to the Padua Prediction Score, with 11% being predicted to go on to develop VTE.3 Other reports and studies have also discussed the role of acute PE in COVID‐19. Recent studies have also reported and advised on the use of prophylactic low molecular weight heparin (LMWH) in COVID‐19 patients, to prevent the severe outcomes associated with thromboembolic complications.
Elevation of inflammatory markers including D‐dimer, C‐reactive protein, ferritin, and interleukin‐6 levels contributing to a procoagulant profile has been reported in the current SARS‐COV2 pandemic.4 Although the exact causes of such an extreme procoagulant profile and an increased risk of thromboembolic events has not been completely established, potential risk factors have been outlined. Indeed, the increased risk of both venous and arterial thromboembolism in COVID‐19 exists and is linked to the excessive inflammation, endothelial pathomechanisms in acute lung injury, severe infection, endothelial dysfunction, platelet activation, immobilization, respiratory failure, mechanical ventilation, and central venous catheter use.3., 5. Whether the increased risk of a thromboembolic event is linked directly to the action of SARS‐CoV2 or to the secondary effects of the cytokine storm induced during the severe infection in COVID‐19 has not been established yet.
Ibuprofen has been a nonsteroidal anti‐inflammatory drug (NSAID) of much contention when various authorities in France, the UK, and the World Health Organization advised against its use based on case reports that have not yet been discovered upon extensive research. By being one of the most widely used NSAIDs worldwide, the implications on the use of ibuprofen and any correlation with adverse reactions in COVID‐19 should be taken into serious consideration. Even though previous research in the field of thromboembolism and NSAIDs is limited and less commonly reported, there are case reports, case control, meta‐analyses, and systematic reviews illustrating a possible correlation between the use of ibuprofen and the increased risk of thromboembolism development, including deep vein thrombosis (DVT) and PE.
The association between the use of ibuprofen and the development of vascular events was first notably brought into discussion by the meta‐analysis conducted by Kearney et al illustrating an increased risk of serious vascular events with high doses of ibuprofen and diclofenac.6 Five years after this research was published, a case‐control study in the Netherlands by Biere‐Rafi et al showed a three‐fold increase in risk for PE associated with the use of ibuprofen.7 This study included more than 20 000 Dutch participants and showed the risk of PE was greatest within the first 30 days of use, and lower in chronic users, possibly due to a compensatory effect.7 A population‐based case‐control study that was similar to Biere‐Rafi et al was conducted in Northern Denmark. Schmidt et al conducted research on a larger scale showing a two‐fold or more increase in the risk of VTE for long‐term use in all non‐aspirin NSAIDs.7., 8.
To add support to the evidence a meta‐analysis conducted in the UK combined data from six studies, with 21 401 VTE events, to show that NSAID users have a 1.8‐fold increase in risk compared with users who do not use NSAIDs, citing the increased risk of vascular events associated with ibuprofen.9 This paper was published in 2015 and was the first systematic review and meta‐analysis published on the topic, hence the data used was limited and conflicting. They believe further research and epidemiological data is needed in the area. Nevertheless, their results are statistically significant and they warn physicians to prescribe with caution.9 A more recent UK‐based case‐control study, in 2016, compared 24 079 current, recent, and remote NSAID users for knee osteoarthritis and their risk of VTE.10 Remote users (the control group) were classed as those with a prescription >365 days and recent users as those with <60 days. The results showed an increased risk of VTE for current users of ibuprofen and other NSAIDs compared with remote users in all categories—sex, age, and calendar period. The results also showed an increased effect of ibuprofen and other NSAIDs on subjects <70 years of age.10
No conclusion of causation between the effects of ibuprofen and thromboembolic event has been made and several limitations in the following area of research exist, including conflicting evidence on the role of ibuprofen on a vascular level. Whether ibuprofen is able to interact with SARS‐COV2 through any mechanism is also not clear. Nevertheless, careful consideration should be made on avoiding high dosage of ibuprofen in subjects at particular risk of thromboembolic events. Furthermore, factors including decreased mobility and the limited exercise rates resulting from nationwide lockdowns pose frail patients at increased risk of developing thromboembolic events. Therefore, considerations should be made on two fronts of action. First, patient advice should be considered regarding possible side effects and avoidance of high dosage of ibuprofen. Second, a need for a large‐scale study assessing any possible correlation between NSAIDs and the worsening or increased risk of thromboembolic event in COVID‐19 should be considered.
CONFLICTS OF INTEREST
The authors declare that they have no financial or other interest in the product or distributor of the product or the nature of any relationship between himself or herself and the manufacturer or distributor of the product.
AUTHOR CONTRIBUTIONS
All authors contributed in the collection of data and manuscript development. All authors read and approved the final manuscript.
Footnotes
Arian Arjomandi Rad and Robert Vardanyan equally contributed to this work.
Manuscript handled by: David Lillicrap
Final decision: David Lillicrap, 11‐May‐2020
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