Degree of Cyclooxygenase-2 Inhibition Modulates Blood Pressure Response

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BACKGROUND: Large clinical trials compared distinct nonsteroidal anti-inflammatory drugs in terms of their risk of adverse cardiovascular events. However, whether pharmacologically equipotent doses were used, that is, whether a similar degree of COX (cyclooxygenase)-2 inhibition was achieved, was not considered. We compared drug target inhibition and blood pressure (BP) response to celecoxib and naproxen. METHODS: Sixteen healthy participants were treated with celecoxib (200 mg/d), naproxen (500 mg/d), or placebo for 7 days in a double-blind, crossover design. The degree of COX inhibition was assessed ex vivo using established whole blood assays and in vivo by quantifying urinary metabolites of thromboxane A 2 (COX-1) and prostacyclin (COX-2). Ambulatory BP was measured throughout the final dosing interval. RESULTS: Both nonsteroidal anti-inflammatory drugs inhibited COX-2 activity relative to placebo, but naproxen inhibited COX-2 activity to a greater degree (62.9±21.7%) than celecoxib (35.7±25.2%; P <0.05). Similarly, naproxen treatment inhibited prostacyclin formation in vivo (48.0±24.9%) to a greater degree than celecoxib (26.7±24.6%; P <0.05). Naproxen significantly increased BP compared with celecoxib (mean arterial pressure, +2.5 [95% CI, 1.5–3.5] mm Hg; systolic BP, +4.0 [95% CI, 2.9–5.1] mm Hg; and diastolic BP, +1.8 [95% CI, 0.8–2.8] mm Hg; P <0.05 for all). The difference in systolic BP relative to placebo was associated with the degree of COX-2 inhibition ( P <0.05). CONCLUSIONS: Future studies should consider pharmacokinetic and pharmacodynamic properties, as well as patient-specific factors that may modulate the cardiovascular risk of nonsteroidal anti-inflammatory drug use. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02502006.

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