PUB - Publikationen an der Universität Bielefeld

Background Non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of adverse cardiovascular events via suppression of cyclooxygenase (COX)-2-derived prostacyclin (PGI2) formation in heart, vasculature, and kidney. The Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION) trial and other large clinical studies compared the cardiovascular risk of traditional NSAIDs (i.e. naproxen), which inhibit both COX isozymes, with NSAIDs selective for COX-2 (i.e. celecoxib). However, whether pharmacologically equipotent doses were used - that is, whether a similar degree of COX-2 inhibition was achieved - was not considered. We compared drug target inhibition and blood pressure response to celecoxib at the dose used by most patients in PRECISION with the lowest recommended naproxen dose for osteoarthritis, which is lower than the dose used in PRECISION.Methods Sixteen healthy participants (19-61 years) were treated with celecoxib (100 mg every 12h), naproxen (250 mg every 12h), or placebo administered twice daily for seven days in a double-blind, crossover design randomized by order. On Day 7 when drug levels had reached steady state, the degree of COX inhibition was assessed ex vivo and in vivo. Ambulatory blood pressure was measured throughout the final 12h dosing interval.Results Both NSAIDs inhibited COX-2 activity relative to placebo, but naproxen inhibited COX-2 activity to a greater degree (62.9{\textpm}21.7\%) than celecoxib (35.7{\textpm}25.2\%; p\<0.05). Similarly, naproxen treatment inhibited PGI2 formation in vivo (48.0{\textpm}24.9\%) to a greater degree than celecoxib (26.7{\textpm}24.6\%; p\<0.05). Naproxen significantly increased blood pressure compared to celecoxib (differences in least-square means of mean arterial pressure: 2.5 mm Hg (95\% CI: 1.5, 3.5); systolic blood pressure: 4.0 mm Hg (95\% CI: 2.9, 5.1); diastolic blood pressure: 1.8 mm Hg (95\% CI: 0.8, 2.8); p\<0.05 for all). The difference in systolic blood pressure relative to placebo was associated with the degree of COX-2 inhibition (p\<0.05).Conclusions Celecoxib 200 mg/day inhibited COX-2 activity to a lesser degree than naproxen 500 mg/day, resulting in a less pronounced blood pressure increase. While the PRECISION trial concluded the non-inferiority of celecoxib regarding cardiovascular risk, this is based on a comparison of doses that are not equipotent.ClinicalTrials.gov identifier: NCT02502006 (https://clinicaltrials.gov/study/NCT02502006)Clinical PerspectiveNaproxen 250 mg twice a day inhibited COX-2 activity to a greater degree than celecoxib 100 mg twice a day.The degree of COX-2 inhibition was associated with the increase in systolic blood pressure with NSAID treatment relative to placebo.Dose and its pharmacological potency achieved in vivo should be considered when evaluating the relative cardiovascular safety of COX-2-selective vs. non-selective NSAIDs.Competing Interest StatementThe authors have declared no competing interest.Clinical TrialNCT02502006 (https://clinicaltrials.gov/study/NCT02502006)Funding StatementResearch reported in this publication was supported by a Translational Medicine and Therapeutics Postdoctoral Fellowship from the PhRMA Foundation, and funding from the National Heart, Lung, and the Blood Institute (HL117798) and National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR001878). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.Not ApplicableThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The study protocol was approved by the University of Pennsylvania Institutional Review Board (IRB$\#$820715), and all participants provided informed consent.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.Not ApplicableI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Not ApplicableI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.Not ApplicableData available on request due to privacy/ethical restrictions.