Selective COX-2 Inhibitors: Good or Bad Guys?

1. Selective COX-2 Inhibitors: Good or Bad Guys? Nimmaanrat S, MD, FRCAT, MMedPM (University of Sydney)

2. Basic Science

3. Pharmacology of Selective COX-2 Inhibitors (COXIBs) • Early 1990, cyclo-oxygenase (COX) existed in 2 distinct isoforms • While COX-1 and COX-2 are structurally similar • COX-2 contains a side pocket

4. Pharmacology of Selective COX-2 Inhibitors (COXIBs)

5. Pharmacology of Selective COX-2 Inhibitors (COXIBs)

6. Pharmacology of Selective COX-2 Inhibitors (COXIBs) • Ratio of affinities to COX-1 and COX-2 determines how “selective” a compound is • NSAIDs inhibit COX-1 and COX-2 with different ratios • Differences in selectivity lead to some variability in • Clinical action • Safety profiles

7. Classification and Basic Differences of COXIBs

8. COX-1 vs COX-2

9. Cyclo-oxygenase I (COX-1) • Constitutive enzyme • “House keeping” enzyme • Expresses ubiquitously • Mediates physiological responses

10. Cyclo-oxygenase I (COX-1) • Only isoenzyme found in platelets • Thromboxane A2 (TXA2) formation • Also plays a role in • Protection of GI mucosa • Renal hemodynamics • Platelet thrombogenesis

11. Cyclo-oxygenase II (COX-2) • Highly expressed by cells involved in inflammation(eg. macrophage, monocytes, synoviocytes) • Unregulated by bacterial lipopolysaccharides, cytokines, growth factors, tumor promoters

12. Cyclo-oxygenase II (COX-2) • “Inducible” form • Primarily responsible for synthesis of prostanoids involved in acute and chronic inflammatory states

14. COX-1 and COX-2 • However, this distinction is somewhat simplified • COX-2 also constitutively expressed under physiological conditions in severe tissues • Brain • Spinal cord • Kidney • Vascular endothelium • COX-1 also be unregulated to a certain degree in inflammation

15. Development of COXIBs

16. Development of COXIBS • Theoretically, selective inhibition of COX-2 would provide • Anti-inflammatory effects • Without disrupting gastric cytoprotection and platelet function

17. Development of COXIBS • Hypothesis: selective inhibition of COX-2 will have • Therapeutic actions similar to NSAIDs • Without GI side effects

18. Thromboxane A2 (TXA2) & Prostacyclin (PGI2)

19. Thromboxane A2 (TXA2) • Synthesized by COX-1 in platelet • Vasoconstriction • Smooth muscle proliferation • Platelet aggregation

20. Prostacyclin (PGI2) • In contrast, PGI2, a product of arachidonic acid (AA) from COX-2 in vessel walls plays important role in homeostatic defense mechanism that promotes • Vasodilatation • Inhibition of platelet function

21. NSAIDS and COXIBs • NSAIDs block both COX-1 and COX-2 production to a similar extent • In contrast, COXIBs inhibits PGI2 production • Thus, COXIBs may create an imbalance between TXA2 and PGI2 • This might be the dominant mechanism that can lead to increased risk of thrombosis

23. Therapeutic Use

24. Therapeutic Use • Postoperative pain • Osteoarthritis (OA) • Rheumatoid arthritis (RA) • Acute gouty arthritis • Chemoprevention • Its role in carcinogenesis, apoptosis and angiogenesis • Celecoxib approved for Rx of familial adenomatous polyp (FAP)

25. Therapeutic Use

26. Clinical Safety

27. Gastrointestinal (GI) Tract

28. Gastrointestinal (GI) Tract • Common reported adverse events (AEs) were related to GI tract • Dyspepsia • Diarrhea • Nausea • Abdominal pain • Flatulence

29. Gastrointestinal (GI) Tract • Upper GI complications have also occurred in pts treated with COXIBs • Perforation • Ulcers • Bleedings • PUBs

30. Gastrointestinal (GI) Tract • Many large RCTs • COXIBs caused fewer GI AEs compared to NSAIDs • However, most, if not all, of the GI benefits will be lost in pts who take low-dose aspirin

31. Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis:Vioxx Gastrointestinal Outcome Research(VIGOR) study Group

32. VIGOR Study • 1st large scale trial • Significantly fewer clinically important upper GI events (POBs) with rofecoxib compared to naproxen

33. 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

34. Celecoxib (greater dose - 400 mg bid): a lower incidence of symptomatic ulcers and ulcers complications combined (diclofenac, ibuprofen) No GI benefit if pts took low-dose aspirin concomitantly CLASS Study

35. Celecoxib versus Naproxen and diclofenac in Osteoarthritis Patients:Successive Celecoxib Efficacy and Safety Study I (SUCCESS-I)

36. SUCCESS - I • Successive Celecoxib Efficacy and Safety Study I (13,274 OA pts) • Celecoxib: significantly fewer serious upper GI events • No statistical significance in pts taking aspirin concomitantly

37. SUCCESS- I

38. Gastrointestinal Side Effects of Etoricoxib in Patients with Osteoarthritis: Results of the Etoricoxib versus Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness (EDGE) Trial

39. EDGE Trial • Cumulative discontinuation rate significantly lower with etoricoxib than diclofenac

40. Assessment of Upper Gastrointestinal Safety of Etoricoxib and Diclofenac in Patients with Osteoarthritis and Rheumatoid Arthritis in theMultinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison

41. MEDAL Programme • Largest RCT: 34,701 pts • Overall upper GI clinical events (POBs / ulcers) and uncomplicated GI events significantly less common with etoricoxib than diclofenac • Benefit maintained in pts taking PPI (proton pump inhibitor) or low-dose aspirin • But no difference in complicated GI events

42. High-risk Patients • High-risk pts with history of NSAID-related complicated peptic ulcers • Celecoxib as effective as NSAID plus PPI • However, significant proportion of pts still had recurrent ulcer complications over period of 24 wks • Gastroenterology 2004; 127: 1038-43. • Am J Med 2005; 118: 1271-8.

43. High-risk Patients • Celecoxib plus PPI more effective than celecoxib alone for prevention of ulcer bleeding in very high-risk pts • 13-month cumulative incidence of recurrent ulcer bleeding • 0% combined Rx • 8.9% celecoxib • Lancet 2007; 369: 1621-6.

44. High-risk Patients • Addition of PPI to celecoxib conferred extra GI protection for pts aged 75 yrs or older • But did not seem to be necessary for pts aged 66-74 • Arthritis Rheum 2007; 57:748-55.

45. GI AEs: Conclusions • Pts with risk factors are in need for “gastroprotective” PPI irrespective of the COX-2 selectivity of applied NSAID • Age > 70 • Past ulcerations • Multiple NSAIDs / aspirin taken esp. high dose • Anticoagulant • Steroid • Positive for Helicobacter pylori

46. Cardiovascular (CV) System

47. Cardiovascular (CV) System • First evidence that COXIBs might increase CV risk emerged from VIGOR study • Rofecoxib group: 5-fold increase in thromboembolic events (primarily acute MI)

48. Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial: Adenomatous Polyp Prevention on Vioxx (APPROVe)

49. Cardiovascular (CV) System • 3 yr period of study in 2,586 pts with history of colorectal adenomas • Rofecoxib 25 mg OD / placebo • Rofecoxib pts had greater risk of developing thrombotic events • Relative Risk (RR) 1.92 • 95% CI 1.19-3.11 • Withdrawal of rofecoxib

50. Cumulative Incidence of Confirmed Thrombotic Events