Journal of Thrombosis and Thrombolysis

, Volume 38, Issue 1, pp 11–23

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

  • Dominick J. Angiolillo
  • Catherine Datto
  • Shane Raines
  • Neville D. Yeomans
Article

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.

Keywords

NSAID Low-dose aspirin Naproxen Naproxen/esomeprazole magnesium Safety profile Tolerability 

References

  1. 1.
    Laine L (2001) Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient. Gastroenterology 120:594–606PubMedCrossRefGoogle Scholar
  2. 2.
    Lanza FL, Chan FK, Quigley EMM (2009) Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol 104:728–738PubMedCrossRefGoogle Scholar
  3. 3.
    Silverstein FE, Faich G, Goldstein JL et al (2000) Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib long-term arthritis safety study. JAMA 284:1247–1255PubMedCrossRefGoogle Scholar
  4. 4.
    Fries JF, Williams CA, Bloch DA, Michel BA (1991) Nonsteroidal anti-inflammatory drug-associated gastropathy: incidence and risk factor models. Am J Med 91:213–222PubMedCrossRefGoogle Scholar
  5. 5.
    Solomon DH, Glynn RJ, Rothman KJ et al (2008) Subgroup analyses to determine cardiovascular risk associated with nonsteroidal antiinflammatory drugs and coxibs in specific patient groups. Arthritis Rheum 59:1097–1104PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Trelle S, Reichenbach S, Wandel S et al (2011) Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 342:c7086PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Roth SH, Anderson S (2011) The NSAID dilemma: managing osteoarthritis in high-risk patients. Phys Sportsmed 39:62–74PubMedCrossRefGoogle Scholar
  8. 8.
    Scheiman JM, Hindley CE (2010) Strategies to optimize treatment with NSAIDs in patients at risk for gastrointestinal and cardiovascular adverse events. Clin Ther 32:667–677PubMedCrossRefGoogle Scholar
  9. 9.
    Rostom A, Moayyedi P, Hunt R (2009) Canadian consensus guidelines on long-term nonsteroidal anti-inflammatory drug therapy and the need for gastroprotection: benefits versus risks. Aliment Pharmacol Ther 29:481–496PubMedCrossRefGoogle Scholar
  10. 10.
    Serrano P, Lanas A, Arroyo MT, Ferreira IJ (2002) Risk of upper gastrointestinal bleeding in patients taking low-dose aspirin for the prevention of cardiovascular diseases. Aliment Pharmacol Ther 16:1945–1953PubMedCrossRefGoogle Scholar
  11. 11.
    Kim C, Beckles GL (2004) Cardiovascular disease risk reduction in the Behavioral Risk Factor Surveillance System. Am J Prev Med 27:1–7PubMedCrossRefGoogle Scholar
  12. 12.
    Bhatt DL, Scheiman J, Abraham NS et al (2008) ACCF/ACG/AHA 2008 Expert Consensus Document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation 118:1894–1909PubMedCrossRefGoogle Scholar
  13. 13.
    Chan FKL, Abraham NS, Scheiman JM, Laine L (2008) Management of patients on nonsteroidal anti-inflammatory drugs: a clinical practice recommendation from the first international working party on gastrointestinal and cardiovascular effects of nonsteroidal anti-inflammatory drugs and anti-platelet agents. Am J Gastroenterol 103:2908–2918PubMedCrossRefGoogle Scholar
  14. 14.
    Desai SP, Solomon DH, Abramson SP et al (2008) Recommendations for use of selective and nonselective nonsteroidal antiinflammatory drugs: an American College of Rheumatology white paper. Arthritis Rheum 59:1058–1073CrossRefGoogle Scholar
  15. 15.
    National Institute for Health and Clinical Excellence. Osteoarthritis: the care and management of osteoarthritis in adults. NICE clinical guideline 59, 2008. http://www.nice.org.uk/nicemedia/pdf/CG59NICEguideline.pdf. Accessed 24 Jan 2013
  16. 16.
    Zhang W, Moskowitz RW, Nuki G et al (2008) OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthr Cartilage 16:137–162CrossRefGoogle Scholar
  17. 17.
    Yeomans N, Lanas A, Labenz J et al (2008) Efficacy of esomeprazole (20 mg once daily) for reducing the risk of gastroduodenal ulcers associated with continuous use of low-dose aspirin. Am J Gastroenterol 103:2465–2473PubMedCrossRefGoogle Scholar
  18. 18.
    Yeomans ND (2011) Reducing the risk of gastroduodenal ulcers with a fixed combination of esomeprazole and low-dose acetyl salicylic acid. Expert Rev Gastroenterol Hepatol 5:447–455PubMedCrossRefGoogle Scholar
  19. 19.
    Lai KC, Lam SK, Chu KM et al (2002) Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med 346:2033–2038PubMedCrossRefGoogle Scholar
  20. 20.
    Abraham NS, El-Serag HB, Johnson ML et al (2005) National adherence to evidence-based guidelines for the prescription of nonsteroidal anti-inflammatory drugs. Gastroenterology 129:1171–1178PubMedCrossRefGoogle Scholar
  21. 21.
    Goldstein JL, Howard KB, Walton SM et al (2006) Impact of adherence to concomitant gastroprotective therapy on nonsteroidal-related gastroduodenal ulcer complications. Clin Gastroenterol Hepatol 4:1337–1345PubMedCrossRefGoogle Scholar
  22. 22.
    Sturkenboom MCJM, Burke TA, Tangelder MJD et al (2003) Adherence to proton pump inhibitors or H2-receptor antagonists during the use of non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther 18:1137–1147PubMedCrossRefGoogle Scholar
  23. 23.
    Sturkenboom MCJM, Burke TA, Dieleman JP et al (2003) Underutilization of preventive strategies in patients receiving NSAIDs. Rheumatology (Oxford) 42(Suppl 3):iii23–iii31Google Scholar
  24. 24.
    van Soest EM, Sturkenboom MCJM, Dieleman JP et al (2007) Adherence to gastroprotection and the risk of NSAID-related upper gastrointestinal ulcers and haemorrhage. Aliment Pharmacol Ther 26:265–275PubMedCrossRefGoogle Scholar
  25. 25.
    Hochberg MC, Fort JG, Svensson O et al (2011) Fixed-dose combination of enteric-coated naproxen and immediate-release esomeprazole has comparable efficacy to celecoxib for knee osteoarthritis: two randomized trials. Curr Med Res Opin 27:1243–1253PubMedCrossRefGoogle Scholar
  26. 26.
    Goldstein JL, Hochberg MC, Fort JG et al (2010) Clinical trial: the incidence of NSAID-associated endoscopic gastric ulcers in patients treated with PN 400 (naproxen plus esomeprazole magnesium) vs. enteric-coated naproxen alone. Aliment Pharmacol Ther 32:401–413PubMedCrossRefGoogle Scholar
  27. 27.
    Sostek MB, Fort JG, Estborn L, Vikman K (2011) Long-term safety of naproxen and esomeprazole magnesium fixed-dose combination: phase III study in patients at risk for NSAID-associated gastric ulcers. Curr Med Res Opin 27:847–854PubMedCrossRefGoogle Scholar
  28. 28.
    European Medicines Compendium UK. Vimovo™, 2012. www.medicines.org.uk/EMC/medicine/23883/SPC/VIMOVO+500+mg+20+mg+modified-release-tablets/. Accessed 7 June 2012
  29. 29.
    Food and Drug Administration (FDA). VIMOVO™ prescribing information, 2010. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022511lbl.pdf. Accessed 17 May 2012
  30. 30.
    Singh G, Fort JG, Goldstein JL et al (2006) Celecoxib versus naproxen and diclofenac in osteoarthritis patients: SUCCESS-I Study. Am J Med 119:255–266PubMedCrossRefGoogle Scholar
  31. 31.
    Lanas A, García-Rodríguez LA, Arroyo MT et al (2006) Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations. Gut 55:1731–1738PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Laine L, Smith R, Min K et al (2006) Systematic review: the lower gastrointestinal adverse effects of non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther 24:751–767PubMedCrossRefGoogle Scholar
  33. 33.
    Goldstein JL, Lowry SC, Lanza FL et al (2006) The impact of low-dose aspirin on endoscopic gastric and duodenal ulcer rates in users of a non-selective non-steroidal anti-inflammatory drug or a cyclo-oxygenase-2-selective inhibitor. Aliment Pharmacol Ther 23:1489–1498PubMedCrossRefGoogle Scholar
  34. 34.
    Yeomans ND, Naesdal J (2008) Systematic review: ulcer definition in NSAID ulcer prevention trials. Aliment Pharmacol Ther 27:465–472PubMedCrossRefGoogle Scholar
  35. 35.
    Hawkey CJ, Wilson I, Naesdal J et al (2002) Influence of sex and Helicobacter pylori on development and healing of gastroduodenal lesions in non-steroidal anti-inflammatory drug users. Gut 51:344–350PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Hawkey CJ, Karrasch JA, Szczepanski L et al (1998) Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group. N Engl J Med 338:727–734PubMedCrossRefGoogle Scholar
  37. 37.
    Scheiman JM, Behler EM, Loeffler KM, Elta GH (1994) Omeprazole ameliorates aspirin-induced gastroduodenal injury. Dig Dis Sci 39:97–103PubMedCrossRefGoogle Scholar
  38. 38.
    Goldstein JL, Huang B, Amer F, Christopoulos NG (2004) Ulcer recurrence in high-risk patients receiving nonsteroidal anti-inflammatory drugs plus low-dose aspirin: results of a post hoc subanalysis. Clin Ther 26:1637–1643PubMedCrossRefGoogle Scholar
  39. 39.
    Capone ML, Tacconelli S, Sciulli MG et al (2004) Clinical pharmacology of platelet, monocyte, and vascular cyclooxygenase inhibition by naproxen and low-dose aspirin in healthy subjects. Circulation 109:1468–1471PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Dominick J. Angiolillo
    • 1
  • Catherine Datto
    • 2
  • Shane Raines
    • 2
  • Neville D. Yeomans
    • 3
    • 4
  1. 1.Division of CardiologyUniversity of Florida College of Medicine-JacksonvilleJacksonvilleUSA
  2. 2.AstraZenecaWilmingtonUSA
  3. 3.University of Western SydneySydneyAustralia
  4. 4.Office for ResearchAustin HospitalMelbourneAustralia

Personalised recommendations