Top

Drug Safety

Published in:

01-11-2003 | Leading Article

Balancing Gastroprotection and Cardioprotection with Selective Cyclo-Oxygenase-2 Inhibitors

Clinical Implications

Author: Dr Emma A. Meagher

Published in: Drug Safety | Issue 13/2003

Abstract

NSAIDs have been the mainstay of treatment in the management of pain and inflammation associated with chronic inflammatory disorders. They are effective. However, complications arising from chronic NSAID use are common and are primarily due to gastrointestinal (GI) toxicity in the form of gastritis, peptic erosions and ulceration and GI bleeds. GI toxicity has been attributed to the blockade of the cyclo-oxygenase (COX)-1-mediated generation of the cytoprotective prostanoids, such as prostaglandin (PG) E₂ and PGI₂ (prostacyclin). More recently, selective COX-2 inhibitors (‘coxibs’) were designed to inhibit the production of COX-2-dependent inflammatory prostanoids and to leave intact the cytoprotective COX-1 products.

The coxibs, while exhibiting similar efficacy to traditional NSAIDs in controlled clinical trials of their efficacy in chronic inflammatory conditions, such as osteoarthritis and rheumatoid arthritis, have been associated with a reduced incidence of surrogate or actual indices of GI toxicity.

However, concerns regarding cardiovascular safety in high-risk patients have evolved. These concerns were driven initially by the concept that inhibition of COX-2-derived endothelial PGI₂ without concomitant inhibition of platelet thromboxane A₂ would result in increased cardiovascular risk. This was borne out in the Vioxx Gastrointestinal Outcomes Research study of rofecoxib, but not demonstrated in the Celecoxib Long Term Arthritis Safety Study trial.

Further elucidation of the relative roles of COX-1- and COX-2-generated prostanoids has enabled a greater understanding of the biology of these pathways. However, it is still not completely clear how this understanding may be appropriately translated into clinical medicine.

Celebrex (celecoxib). US Product Information. Peapack (NJ): Pharmacia, 2001

Goldenberg M. Celecoxib, a selective cyclooxygenase-2 inhibitor for the treatment of rheumatoid arthritis and osteoarthritis. Clin Ther 1999; 21: 1497–513PubMedCrossRef

Scott L, Lamb H. Rofecoxib. Drugs 1999; 58: 499–507PubMedCrossRef

Smith WL. Prostanoid biosynthesis and mechanisms of action. Am J Physiol 1992; 263: F181–91PubMed

FitzGerald GA. Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001; 345(6): 433–42PubMedCrossRef

Marnett LJ, Rowlinson SW, Goodwin DC, et al. Arachidonic acid oxygenation by COX-1 and COX-2: mechanisms of catalysis and inhibition. J Biol Chem 1999; 274: 22903–6PubMedCrossRef

Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol 1998; 38: 97–120PubMedCrossRef

Wang LH, Hajibeigi A, Xu XM, et al. Characterization of the promoter of human prostaglandin H synthase-1 gene. Biochem Biophys Res Commun 1993; 190: 406–11PubMedCrossRef

O’Neill GP, Ford-Hutchinson AW. Expression of mRNA for cyclooxygenase-1 and cyclooxygenase-2 in human tissues. FEBS Lett 1993; 330: 156–60PubMed

10.

Bakhle YS, Botting RM. Cyclooxygenase-2 and its regulation in inflammation. Mediators Inflamm 1996; 5: 305–23PubMedCrossRef

11.

Crofford LJ, Wilder RL, Ristimäki AP, et al. Cyclooxygenase-1 and -2 expression in rheumatoid synovial tissues: effects of interleukin-1β, phorbol ester, and corticosteroids. J Clin Invest 1994; 93: 1095–101PubMedCrossRef

12.

Schonbeck U, Sukhova GK, Graber P, et al. Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am J Pathol 1999; 155: 1281–91PubMedCrossRef

13.

Gimbrone Jr MA, Topper JN, Nagel T, et al. Endothelial dysfunction, hemodynamic forces, and atherogenesis. Ann N Y Acad Sci 2000 May; 902: 230–9PubMedCrossRef

14.

McAdam BF, Catella-Lawson F, Mardini IA, et al. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2 [published erratum appears in Proc Natl Acad Sci U S A 1999; 96: 5890]. Proc Natl Acad Sci U S A 1999; 96: 272–7PubMedCrossRef

15.

Catella-Lawson F, McAdam B, Morrison BW, et al. Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids. J Pharmacol Exp Ther 1999; 289: 735–41PubMed

16.

McAdam BF, Mardini I, Habib A, et al. Effect of regulated expression of human cyclooxygenase isoforms on eicosanoid and isoeicosanoid production in inflammation. J Clin Invest 2000; 105: 1473–82PubMedCrossRef

17.

Rocca B, Secchiero P, Ciabattoni G, et al. Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets. Proc Natl Acad Sci U S A 2002 May 28; 99(11): 7634–9PubMedCrossRef

18.

Tanaka A, Hase S, Miyazawa T, et al. Upregulation of cyclooxygenase 2 by inhibition of cyclooxygenase 1: a key to nonsteroidal anti-inflammatory drug induced intestinal damage. J Pharm Exp Ther 2002; 300: 754–61CrossRef

19.

Qi Z, Hao CM, Langenbach RI, et al. Opposite effects of cyclooxygenase-1 and -2 activity on the pressor response to angiotensin II. J Clin Invest 2002 Jul; 110(1): 61–9PubMed

20.

FitzGerald GA. The choreography of cyclooxygenases in the kidney. J Clin Invest 2002 Jul; 110(1): 33–4PubMed

21.

Funk CD, Funk LB, Kennedy ME, et al. Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment. FASEB J 1991 Jun; 5(9): 2304–12PubMed

22.

Reilly IA, FitzGerald GA. Inhibition of thromboxane formation in vivo and ex vivo: implications for therapy with platelet inhibitory drugs. Blood 1987; 69: 180–6PubMed

23.

Steering Committee of the Physicians’ Health Study Research Group. Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1989; 321: 129–35

24.

Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 71–86

25.

Patrignani P, Panara MR, Greco A, et al. Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthase. J Pharmacol Exp Ther 1994; 271: 1705–12PubMed

26.

Cryer B, Feldman M. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. Am J Med 1998; 104: 413–21PubMedCrossRef

27.

Warner TD, Giuliano F, Vojnovic I, et al. Nonsteroid drug selectivities for COX-1 rather than COX-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci U S A 1999; 96: 7563–8PubMedCrossRef

28.

Ehrich EW, Dallob A, De Lepeleire I, et al. Characterization of rofecoxib as a cyclooxygenase-2 inhibitor and demonstration of analgesia in the dental pain model. Clin Pharmacol Ther 1999; 65: 336–47PubMedCrossRef

29.

Malmstrom K, Daniels S, Kotey P, et al. Comparison of rofecoxib and celecoxib, two cyclooxygenase-2 inhibitors, in postoperative dental pain: a randomized, placebo- and active-comparator-controlled clinical trial. Clin Ther 1999; 21: 1653–63PubMedCrossRef

30.

Morrison BW, Daniels SE, Kotey P, et al. Rofecoxib, a specific cyclooxygenase-2 inhibitor, in primary dysmenorrhea: a randomized controlled trial. Obstet Gynecol 1999; 94: 504–8PubMedCrossRef

31.

Simon LS, Weaver AL, Graham DY, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis. JAMA 1999; 282: 1921–8PubMedCrossRef

32.

Day R, Morrison B, Luza A, et al. A randomized trial of the efficacy and tolerability of the COX-2 inhibitor rofecoxib vs ibuprofen in patients with osteoarthritis. Arch Intern Med 2000; 160: 1781–7PubMedCrossRef

33.

Simon LS, Weaver AL, Graham DY, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis. JAMA 1999; 282: 1921–8PubMedCrossRef

34.

Thun MJ, Henley SJ, Patrono C. Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic and clinical issues. J Natl Cancer Inst 2002 Feb 20; 94(4): 252–66PubMedCrossRef

35.

Akashi H, Han HJ, Iizaka M, et al. Growth-suppressive effect of non-steroidal anti-inflammatory drugs on 11 colon-cancer cell lines and fluorescence differential display of genes whose expression is influenced by sulindac. Int J Cancer 2000 Dec 15; 88(6): 873–80PubMedCrossRef

36.

Thomas T, Nadackal TG, Thomas K. Aspirin and non-steroidal anti-inflammatory drugs inhibit amyloid-beta aggregation. Neuroreport 2001 Oct 29; 12(15): 3263–7PubMedCrossRef

37.

Asanuma M, Nishibayashi-Asanuma S, Miyazaki I, et al. Neuroprotective effects of non-steroidal anti-inflammatory drugs by direct scavenging of nitric oxide radicals. J Neurochem 2001 Mar; 76(6): 1895–904PubMedCrossRef

38.

Broe GA, Grayson DA, Creasey HM, et al. Anti-inflammatory drugs protect against Alzheimer disease at low doses. Arch Neurol 2000 Nov; 57(11): 1586–91PubMedCrossRef

39.

North GL. Celecoxib as adjunctive therapy for treatment of colorectal cancer. Ann Pharmacother 2001 Dec; 35(12): 1638–43PubMedCrossRef

40.

Fournier DB, Gordon GB. COX-2 and colon cancer: potential targets for chemoprevention. J Cell Biochem 2000; 77(S34): 97–102CrossRef

41.

Steinbach G, Lynch PM, Phillips RKS, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000; 342: 1946–52PubMedCrossRef

42.

Seno H, Oshima M, Ishikawa TO, et al. Cyclooxygenase 2- and prostaglandin E(2) receptor EP(2)-dependent angiogenesis in Apc (Delta 716) mouse intestinal polyps. Cancer Res 2002 Jan 15; 62(2): 506–11PubMed

43.

Chulada PC, Thompson MB, Mahler JF, et al. Genetic disruption of Ptgs-1, as well as Ptgs-2, reduces intestinal tumorigenesis in Min mice. Cancer Res 2000 Sep 1; 60(17): 4705–8PubMed

44.

Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of non-steroidal antiinflammatory drugs. N Engl J Med 1999; 340: 1888–99PubMedCrossRef

45.

Laine L, Harper S, Simon T, et al. A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis. Gastroenterology 1999; 117: 776–83PubMedCrossRef

46.

Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib versus nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000; 284: 1247–55PubMedCrossRef

47.

Hawkey C, Laine L, Simon T, et al. The Rofecoxib Osteoarthritis Endoscopy Multinational Study Group. Comparison of the effect of rofecoxib (a cyclooxygenase 2 inhibitor), ibuprofen, and placebo on the gastroduodenal mucosa of patients with osteoarthritis: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2000; 43: 370–7PubMedCrossRef

48.

Silverstein FE, Faich G, Goldstein JL, et al. 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 2000; 284: 1247–55PubMedCrossRef

49.

Bombardier C. Laine L, Reicin A. Comparison of upper gastrointestinal toxicity of refecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000; 343: 1520–8PubMedCrossRef

50.

FDA Advisory Committee. Briefing Information: NDA 21-042/s007 Vioxx (rofecoxib) (2001). Available from URL: http://www.fda.gov./ohrms/docket/ac/cdero/htm arthritis [Accessed 2002 Feb 28]

51.

FDA Advisory Committee. Briefing Information: NDA 20-998/s009 Celebrex (celecoxib) (2001). Available from URL: http://www.fda.gov [Accessed 2002 Feb 28]

52.

Juni P, Rutjes AW, Dieppe PA. Are selective COX-2 inhibitors superior to traditional nonsteroidal anti-inflammatory drugs? BMJ 2002; 324(7349): 1287–8PubMedCrossRef

53.

FitzGerald GA, Smith B, Pedersen AK, et al. Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation. N Engl J Med 1984; 310: 1065–8PubMedCrossRef

54.

Cheng Y, Austin SC, Rocca B, et al. Role of prostacyclin in the cardiovascular response to thromboxane A2. Science 2002 Apr 19; 296(5567): 539–41PubMedCrossRef

55.

Wallberg-Jonsson S, Ohman ML, Dahlqvist SR. Cardiovascular morbidity and mortality in patients with seropositive rheumatoid arthritis in Northern Sweden. J Rheumatol 1997; 24: 445–51PubMed

56.

McEntegart A, Capell HA, Creran D, et al. Cardiovascular risk factors, including thrombotic variables, in a population with rheumatoid arthritis. Rheumatology (Oxford) 2001; 40: 640–4CrossRef

57.

Wallberg-Jonsson S, Johansson H, Ohman ML, et al. Extent of inflammation predicts cardiovascular disease and overall mortality in seropositive rheumatoid arthritis: a retrospective cohort study from disease onset. J Rheumatol 1999; 26: 2562–71PubMed

58.

Watson DJ, Rhodes T. Higher incidence of thromboembolic events among patients with rheumatoid arthritis vs osteoarthritis, and vs. no arthritis, in the general practice research database (GPRD) [abstract OP0109]. Presented at the Annual European Congress of Rheumatology; 2001 Jun 13-16; Prague, Czech Republic

59.

Konstam MA, Weir MR, Reicin A, et al. Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib. Circulation 2001 Nov 6; 104(19): 2280–8PubMedCrossRef

60.

Ott E, Nussmeier NA, Duke PC, et al. Efficacy and safety of the cyclooxygenase-2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg 2003 Jun; 125(6): 1481–92PubMedCrossRef

61.

Van Hecken A, Schwartz JI, Depre M, et al. Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers. J Clin Pharmacol 2000; 40: 1109–20PubMed

62.

Garcia Rodriguez LA, Varas C, Patrono C. Differential effects of aspirin and non-aspirin nonsteroidal antiinflammatory drugs in the primary prevention of myocardial infarction in postmenopausal women. Epidemiology 2000; 11: 382–7PubMedCrossRef

63.

Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001; 286: 954–9PubMedCrossRef

64.

Ray WA, Stein CM, Hall K, et al. Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease: an observational cohort study. Lancet 2002; 359: 118–23PubMedCrossRef

65.

Kimmel SE, Berlin JA, Reilly M, et al. Lower myocardial infarction risk amongst current users of non-aspirin non steroidal anti-inflammatory medications [abstract]. J Am Coll Cardiol 2002; 39: 318ACrossRef

66.

Swan SK, Rudy DW, Lasseter KC, et al. Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet. A randomized, controlled trial. Ann Intern Med 2000 Jul 4; 133(1): 1–9PubMed

67.

Whelton A, Maurath CJ, Verburg KM, et al. Renal safety and tolerability of celecoxib, a novel cyclo-oxygenase-2 inhibitor. Am J Ther 2000; 7(3): 139–75

68.

Whelton A. Renal aspects of treatment with non-steroidal anti-inflammatory drugs versus cyclo-oxygenase-2-specific inhibitors. Am J Med 2001; 110Suppl. 3A: S33–S42CrossRef

69.

Feldman M, McMahon AT. Do cyclooxygenase-2 inhibitors provide benefits similar to those of traditional nonsteroidal anti-inflammatory drugs, with less gastrointestinal toxicity? Ann Intern Med 2000 Jan 18; 132(2): 134–43PubMed

Title: Balancing Gastroprotection and Cardioprotection with Selective Cyclo-Oxygenase-2 Inhibitors
Clinical Implications
Author: Dr Emma A. Meagher
Publication date: 01-11-2003
Publisher: Springer International Publishing
Published in: Drug Safety / Issue 13/2003
Print ISSN: 0114-5916
Electronic ISSN: 1179-1942
DOI: https://doi.org/10.2165/00002018-200326130-00001

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Balancing Gastroprotection and Cardioprotection with Selective Cyclo-Oxygenase-2 Inhibitors

Clinical Implications

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 13/2003

Benefit-Risk Assessment of Transdermal Fentanyl for the Treatment of Chronic Pain

Reducing Medication Errors

Effects of NSAIDs on the Incidence of Hospitalisations for Renal Dysfunction in Users of ACE Inhibitors

Use of Antibiotic and Analgesic Drugs during Lactation

Risks versus Benefits of NSAIDs Including Aspirin in Myocarditis