Risk of ischemic stroke and the use of individual non-steroidal anti-inflammatory drugs: A multi-country European database study within the SOS Project

Abstract

Background and purposeA multi-country European study using data from six healthcare databases from four countries was performed to evaluate in a large study population (>32 million) the risk of ischemic stroke (IS) associated with individual NSAIDs and to assess the impact of risk factors of IS and co-medication.MethodsCase-control study nested in a cohort of new NSAID users. For each case, up to 100 sex- and age-matched controls were selected and confounder-adjusted odds ratios for current use of individual NSAIDs compared to past use calculated.Results49,170 cases of IS were observed among 4,593,778 new NSAID users. Use of coxibs (odds ratio 1.08, 95%-confidence interval 1.02–1.15) and use of traditional NSAIDs (1.16, 1.12–1.19) were associated with an increased risk of IS. Among 32 individual NSAIDs evaluated, the highest significant risk of IS was observed for ketorolac (1.46, 1.19–1.78), but significantly increased risks (in decreasing order) were also found for diclofenac, indomethacin, rofecoxib, ibuprofen, nimesulide, diclofenac with misoprostol, and piroxicam. IS risk associated with NSAID use was generally higher in persons of younger age, males, and those with a prior history of IS.ConclusionsRisk of IS differs between individual NSAIDs and appears to be higher in patients with a prior history of IS or transient ischemic attack (TIA), in younger or male patients. Co-medication with aspirin, other antiplatelets or anticoagulants might mitigate this risk. The small to moderate observed risk increase (by 13–46%) associated with NSAIDs use represents a public health concern due to widespread NSAID usage.

International Union of Basic and Clinical Pharmacology. CIX. Differences and Similarities between Human and Rodent Prostaglandin E2Receptors (EP1–4) and Prostacyclin Receptor (IP): Specific Roles in Pathophysiologic Conditions

“…In contrast, mostly EP3 agonists, such as sulprostone and misoprostol, which are used as clinical practice, are associated with an increased incidence of ischemic stroke or myocardial infarction in patients probably due to coronary constriction. Globally, these results suggest a strong role for the EP3 receptor in the control of arterial blood pressure (Guerci et al, 2013;Vital et al, 2013;Masclee et al, 2018;Mazhar et al, 2018;Schink et al, 2018). These in vivo observations are supported by the numerous in vitro data on the vasoconstrictor role of the EP3 receptor in human vasculature as mentioned previously (Qian et al, 1994;Norel et al, 2004a;Foudi et al, 2011;Longrois et al, 2012;Ozen et al, 2015).…”

Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective

“…Stroke events are characterized as either ischemic (blood supply to brain is blocked) or hemorrhagic (bleeding), of which ischemic strokes (IS) are more predominant [204]. A multinational European database study has shown that IS risk differs among individual NSAIDs and specifically it was found to be higher in patients with a previous history of IS or transient ischemic attack [205]. Since NSAIDs can predominantly cause gastrointestinal bleeding, risk of ICH cannot be excluded.…”

Acupuncture decreased the risk of stroke among patients with fibromyalgia in Taiwan: A nationwide matched cohort study

“…NSAIDs and opioids are frequently used for pain control in patients with fibromyalgia. Previous studies revealed that NSAIDs were associated with an increased risk of ischemic stroke [ 35 ] and hemorrhagic stroke [ 36 ]. Long-term use of opioid could induce oxidative stress to activate neuro-immune system and cause stroke [ 37 ].…”

“…revealed that NSAIDs were associated with an increased risk of ischemic stroke [35] and hemorrhagic stroke [36]. Long-term use of opioid could induce oxidative stress to activate neuroimmune system and cause stroke [37].…”