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Impact of concomitant low-dose aspirin on the safety and tolerability of naproxen and esomeprazole magnesium delayed-release tablets in patients requiring chronic nonsteroidal anti-inflammatory drug therapy: an analysis from 5 Phase III studies

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Abstract

Patients receiving chronic nonsteroidal anti-inflammatory drugs (NSAIDs) and concomitant low-dose aspirin (LDA) are at increased risk of gastrointestinal (GI) toxicity. A fixed-dose combination of enteric-coated (EC) naproxen and immediate-release esomeprazole magnesium (NAP/ESO) has been designed to deliver a proton-pump inhibitor followed by an NSAID in a single tablet. To examine safety data from 5 Phase III studies of NAP/ESO in LDA users (≤325 mg daily, administered at any time during the study), and LDA non-users, data were analyzed from 6-month studies assessing NAP/ESO versus EC naproxen in patients with osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis (n = 2), 3-month studies assessing NAP/ESO vs celecoxib or placebo in patients with knee osteoarthritis (n = 2), and a 12-month, open-label, safety study of NAP/ESO (n = 1). In an analysis of two studies, incidences of endoscopically confirmed gastric ulcers (GUs) and duodenal ulcers (DUs) were summarized by LDA subgroups. In the pooled analysis from all five studies, incidences of treatment-emergent adverse events (AEs) (including prespecified NSAID-associated upper GI AEs and cardiovascular AEs), serious AEs, and AE-related discontinuations were stratified by LDA subgroups. Overall, 2,317 patients received treatment; 1,157 patients received NAP/ESO and, of these, 298 received LDA. The cumulative incidence of GUs and DUs in the two studies with 6-month follow-up was lower for NAP/ESO vs EC naproxen in both LDA subgroups [GUs: 3.0 vs 27.9 %, respectively, for LDA users, 6.4 vs 22.4 %, respectively, for LDA non-users (both P < 0.001); DUs: 1.0 vs 5.8 % for LDA users, 0.6 vs 5.3 % for LDA non-users]. The incidence of erosive gastritis was lower in NAP/ESO- vs EC naproxen-treated patients for both LDA users [18.2 vs 36.5 %, respectively (P = 0.004)] and LDA non-users [19.8 vs 38.5 %, respectively (P < 0.001)]. Among LDA users, incidences of NSAID-associated upper GI AEs were: NAP/ESO, 16.1 %; EC naproxen, 31.7 %; celecoxib, 22.1 %; placebo, 23.2 %. Among LDA non-users, incidences of NSAID-associated upper GI AEs were: NAP/ESO, 20.3 %; EC naproxen, 36.6 %; celecoxib, 18.5 %; placebo, 18.9 %. For LDA users, incidences of cardiovascular AEs were: NAP/ESO, 3.0 %; EC naproxen, 1.0 %; celecoxib, 0 %; placebo, 0 %. For LDA non-users, incidences of cardiovascular AEs were: NAP/ESO, 1.0 %; EC naproxen, 0.6 %; celecoxib, 0.3 %; placebo, 0 %. NAP/ESO appears to be well-tolerated in patients receiving concomitant LDA. For LDA users, AE incidence was less than that observed for EC naproxen. For most AE categories, incidences were similar among NAP/ESO, celecoxib and placebo groups. The safety of NAP/ESO appeared similar regardless of LDA use.

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Acknowledgments

These studies were sponsored and conducted by POZEN Inc. Lisa Suchower of AstraZeneca provided assistance in the statistical analysis of the data. Medical writing support was provided by Rhian Harper Owen, on behalf of Complete Medical Communications, funded by AstraZeneca.

Conflict of interest

Neville D. Yeomans has previously consulted for AstraZeneca, Pfizer, Merck and Glaxo, but has no current financial involvement with any pharmaceutical company. Dominick J. Angiolillo has received consulting fees or honoraria from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, Daiichi Sankyo, The Medicines Company, AstraZeneca, Merck, Evolva, Abbott Vascular and PLx Pharma, and has received fees for review activities from Johnson & Johnson, St. Jude, and Sunovion. He has also received institutional grants from Bristol-Myers Squibb, Sanofi-Aventis, GlaxoSmithKline, Otsuka, Eli Lilly, Daiichi Sankyo, The Medicines Company, AstraZeneca, Evolva, and has other financial relationships with the James and Esther King Biomedical Research Program. Shane Raines and Catherine Datto are employees of AstraZeneca.

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Authors and Affiliations

  1. Division of Cardiology, University of Florida College of Medicine-Jacksonville, ACC Building 5th Floor, 655 West 8th Street, Jacksonville, FL, 32209, USA

    Dominick J. Angiolillo

  2. AstraZeneca, 1800 Concord Pike, Wilmington, DE, 19850, USA

    Catherine Datto & Shane Raines

  3. University of Western Sydney, Sydney, NSW, Australia

    Neville D. Yeomans

  4. Office for Research, Austin Hospital, Studley Road, Heidelberg, Melbourne, VIC, 3084, Australia

    Neville D. Yeomans

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  1. Dominick J. Angiolillo
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Correspondence to Dominick J. Angiolillo.

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Angiolillo, D.J., Datto, C., Raines, S. et al. Impact of concomitant low-dose aspirin on the safety and tolerability of naproxen and esomeprazole magnesium delayed-release tablets in patients requiring chronic nonsteroidal anti-inflammatory drug therapy: an analysis from 5 Phase III studies. J Thromb Thrombolysis 38, 11–23 (2014). https://doi.org/10.1007/s11239-013-1035-4

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