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 Early 1990, cyclo-oxygenase (COX) existed in 2 distinct isoforms While COX-1 and COX-2 are structurally similar While COX-1 and COX-2 are structurally similar COX-2 contains a side pocket COX-2 contains a side pocket

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

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

7. Classification and Basic Differences of COXIBs ClassificationDrugSelectivity Chemical structure First generation CelecoxibRofecoxib30272SulfonamideSulfone Second generation ValdecoxibEtoricoxibLumiracoxib61344433SulfonamideSulfone Phenylacetic acid derivative

8. COX-1 vs COX-2

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

10. Cyclo-oxygenase I (COX-1) Only isoenzyme found in platelets Only isoenzyme found in platelets Thromboxane A 2 (TXA 2 ) formation Thromboxane A 2 (TXA 2 ) formation Also plays a role in Also plays a role in Protection of GI mucosa Protection of GI mucosa Renal hemodynamics Renal hemodynamics Platelet thrombogenesis Platelet thrombogenesis

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

12. Cyclo-oxygenase II (COX-2) “Inducible” form “Inducible” form Primarily responsible for synthesis of prostanoids involved in acute and chronic inflammatory states 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 However, this distinction is somewhat simplified COX-2 also constitutively expressed under physiological conditions in severe tissues COX-2 also constitutively expressed under physiological conditions in severe tissues Brain Brain Spinal cord Spinal cord Kidney Kidney Vascular endothelium Vascular endothelium COX-1 also be unregulated to a certain degree in inflammation 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 Theoretically, selective inhibition of COX-2 would provide Anti-inflammatory effects Anti-inflammatory effects Without disrupting gastric cytoprotection and platelet function Without disrupting gastric cytoprotection and platelet function

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

18. Thromboxane A 2 (TXA 2 ) & Prostacyclin (PGI 2 )

19. Thromboxane A 2 (TXA 2 ) Synthesized by COX-1 in platelet Synthesized by COX-1 in platelet Vasoconstriction Vasoconstriction Smooth muscle proliferation Smooth muscle proliferation Platelet aggregation Platelet aggregation

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

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

23. Therapeutic Use

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

25. Therapeutic Use

26. Clinical Safety

27. Gastrointestinal (GI) Tract

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

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

30. Gastrointestinal (GI) Tract Many large RCTs Many large RCTs COXIBs caused fewer GI AEs compared to NSAIDs 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 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 1 st large scale trial 1 st large scale trial Significantly fewer clinically important upper GI events (POBs) with rofecoxib compared to naproxen 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. CLASS Study Celecoxib (greater dose - 400 mg bid): a lower incidence of symptomatic ulcers and ulcers complications combined (diclofenac, ibuprofen) 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 No GI benefit if pts took low-dose aspirin concomitantly

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) Successive Celecoxib Efficacy and Safety Study I (13,274 OA pts) Celecoxib: significantly fewer serious upper GI events Celecoxib: significantly fewer serious upper GI events No statistical significance in pts taking aspirin concomitantly 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 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 the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison

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

42. High-risk Patients High-risk pts with history of NSAID-related complicated peptic ulcers High-risk pts with history of NSAID-related complicated peptic ulcers Celecoxib as effective as NSAID plus PPI Celecoxib as effective as NSAID plus PPI However, significant proportion of pts still had recurrent ulcer complications over period of 24 wks However, significant proportion of pts still had recurrent ulcer complications over period of 24 wks Gastroenterology 2004; 127: 1038-43. Gastroenterology 2004; 127: 1038-43. Am J Med 2005; 118: 1271-8. 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 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 13-month cumulative incidence of recurrent ulcer bleeding 0% combined Rx 0% combined Rx 8.9% celecoxib 8.9% celecoxib Lancet 2007; 369: 1621-6. 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 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 But did not seem to be necessary for pts aged 66-74 Arthritis Rheum 2007; 57:748-55. 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 Pts with risk factors are in need for “gastroprotective” PPI irrespective of the COX-2 selectivity of applied NSAID Age > 70 Age > 70 Past ulcerations Past ulcerations Multiple NSAIDs / aspirin taken esp. high dose Multiple NSAIDs / aspirin taken esp. high dose Anticoagulant Anticoagulant Steroid Steroid Positive for Helicobacter pylori Positive for Helicobacter pylori

46. Cardiovascular (CV) System

47. First evidence that COXIBs might increase CV risk emerged from VIGOR study First evidence that COXIBs might increase CV risk emerged from VIGOR study Rofecoxib group: 5-fold increase in thromboembolic events (primarily Rofecoxib group: 5-fold increase in thromboembolic events (primarily acute MI) 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 3 yr period of study in 2,586 pts with history of colorectal adenomas Rofecoxib 25 mg OD / placebo Rofecoxib 25 mg OD / placebo Rofecoxib pts had greater risk of developing thrombotic events Rofecoxib pts had greater risk of developing thrombotic events Relative Risk (RR) 1.92 Relative Risk (RR) 1.92 95% CI 1.19-3.11 95% CI 1.19-3.11 Withdrawal of rofecoxib Withdrawal of rofecoxib

50. Cumulative Incidence of Confirmed Thrombotic Events

51. Cardiovascular (CV) System High-risk pts with CABG High-risk pts with CABG 3-fold increased risk of CV events in pts initially received iv parecoxib followed by oral valdecoxib 3-fold increased risk of CV events in pts initially received iv parecoxib followed by oral valdecoxib J Thorac Cardiovasc Surg 2003; 125: 1481-92. J Thorac Cardiovasc Surg 2003; 125: 1481-92. N Engl J Med 2005; 352: 1081-91. N Engl J Med 2005; 352: 1081-91. In addition, case reports of severe skin reactions -> valdecoxib was withdrawn In addition, case reports of severe skin reactions -> valdecoxib was withdrawn

52. Cardiovascular (CV) System CLASS study (intake of low-dose aspirin allowed) CLASS study (intake of low-dose aspirin allowed) Incidence of serious CV events not significantly different between celecoxib and NSAID (ibuprofen / diclofenac) Incidence of serious CV events not significantly different between celecoxib and NSAID (ibuprofen / diclofenac)

53. Cardiovascular (CV) System Celecoxib for the prevention of colorectal adenomatous polyps: Prevention of Spontaneous Adenomatous Polyps (PreSAP) Trial Celecoxib for the prevention of colorectal adenomatous polyps: Prevention of Spontaneous Adenomatous Polyps (PreSAP) Trial 1,561 pts with prior adenomatous polyps 1,561 pts with prior adenomatous polyps No significant difference in CV risk between celecoxib (400 mg/day) vs placebo No significant difference in CV risk between celecoxib (400 mg/day) vs placebo

54. Cardiovascular (CV) System Celecoxib for the prevention of sporadic colorectal adenoma: Adenoma Prevention with Celecoxib (APC) Celecoxib for the prevention of sporadic colorectal adenoma: Adenoma Prevention with Celecoxib (APC) Celecoxib 200 / 400 mg bid vs placebo Celecoxib 200 / 400 mg bid vs placebo Low-dose celecoxib 2.3 X Low-dose celecoxib 2.3 X High-dose celecoxib 3.4 X High-dose celecoxib 3.4 X Early termination of trial Early termination of trial

55. The Effects of Cyclooxygenase-2 Inhibitors and Nonsteroidal Anti-inflammatory Therapy on 24-hour Blood Pressure in Patients with Hypertension, Osteoarthritis, and Type 2 Diabetes Mellitus: Celecoxib Rofecoxib Efficacy and Safety in Comorbidities Evaluation Trial (CRESCENT)

56. CRESCENT 24-hr SBP (after 6 wks of Rx) 24-hr SBP (after 6 wks of Rx) HT, type 2 DM, OA HT, type 2 DM, OA Celecoxib / rofecoxib / naproxen Celecoxib / rofecoxib / naproxen Rofecoxib: significant increased SBP Rofecoxib: significant increased SBP But not by celecoxib or naproxen But not by celecoxib or naproxen Use of 3 drugs may result in different rates of CV events Use of 3 drugs may result in different rates of CV events

57. EDGE Study No significant differences between No significant differences between Etoricoxib Etoricoxib Diclofenac Diclofenac Same was true in pts taking aspirin Same was true in pts taking aspirin But in pts on etoricoxib, the non-aspirin group had more MIs But in pts on etoricoxib, the non-aspirin group had more MIs

58. MEDAL Programme Cardiovascular Outcomes Composite of major thrombotic CV events (at 18 months) similar with etoricoxib and diclofenac Composite of major thrombotic CV events (at 18 months) similar with etoricoxib and diclofenac Diclofenac (RR 1.4) Diclofenac (RR 1.4)

59. Cardiovascular (CV) System Nested case-control study in 486,378 pts Nested case-control study in 486,378 pts Elevated risk of acute MI was a Elevated risk of acute MI was a “class effect” of COXIBs “class effect” of COXIBs All COXIBs associated with higher MI risks compared to placebo / NSAIDs All COXIBs associated with higher MI risks compared to placebo / NSAIDs

60. Cardiovascular (CV) System Health-register data suggested that increased mortality in pts with previous MI caused by Health-register data suggested that increased mortality in pts with previous MI caused by COXIBs in all dosages COXIBs in all dosages NSAIDs in high dosages NSAIDs in high dosages

61. Cardiovascular (CV) System Meta-analyses of 17 case-control and 6 cohort studies calculated RR factors Meta-analyses of 17 case-control and 6 cohort studies calculated RR factors Rofecoxib (<25 mg/day) 1.33 Rofecoxib (<25 mg/day) 1.33 Rofecoxib (>25 mg/day) 2.19 Rofecoxib (>25 mg/day) 2.19 Celecoxib 1.06 Celecoxib 1.06 Diclofenac 1.4 Diclofenac 1.4 Naproxen 0.97 Naproxen 0.97 Piroxicam 1.06 Piroxicam 1.06 Ibuprofen 1.07 Ibuprofen 1.07

62. CV System - Conclusions Data from large-scale clinical trial and epidemiologic studies Data from large-scale clinical trial and epidemiologic studies COXIBs and NSAIDs (except naproxen) as a group can potentially increase the risk of CV events COXIBs and NSAIDs (except naproxen) as a group can potentially increase the risk of CV events And apparently there is a dose-dependent gradient among the various COXIBs and NSAIDs And apparently there is a dose-dependent gradient among the various COXIBs and NSAIDs

63. Recommendations for the Use of NSAIDs according to Gastrointestinal and Cardiovascular Risks CV risk GI risk LowModerateHigh LowNSAID NSAID + PPI / misoprostol or COXIB COXIB + PPI High NSAID + PPI / misoprostol Avoid NSAID or COXIB

64. Recommendations for the Use of NSAIDs according to Gastrointestinal and Cardiovascular Risks a Gastrointestinal risk is arbitrarily defined as low (no risk factors), moderate (presence one or two risk factors), or high (more than two risk factors, previous ulcer complications, or concomitant use of corticosteroids or anticoagulants). All patients with a history of ulcers who require NSAIDs should be tested for H. pylori and if infection is present, eradication therapy should be given. a Gastrointestinal risk is arbitrarily defined as low (no risk factors), moderate (presence one or two risk factors), or high (more than two risk factors, previous ulcer complications, or concomitant use of corticosteroids or anticoagulants). All patients with a history of ulcers who require NSAIDs should be tested for H. pylori and if infection is present, eradication therapy should be given. b High cardiovascular risk is arbitrarily defined as the requirement for low-dose aspirin for primary cardiovascular event prevention (calculated 10-year cardiovascular risk >10%) or secondary prevention of serious cardiovascular events. b High cardiovascular risk is arbitrarily defined as the requirement for low-dose aspirin for primary cardiovascular event prevention (calculated 10-year cardiovascular risk >10%) or secondary prevention of serious cardiovascular events. c Naproxen is the preferred NSAID in patients with a high cardiovascular risk. Abbreviation: COX2, cyclo-oxygenase 2. c Naproxen is the preferred NSAID in patients with a high cardiovascular risk. Abbreviation: COX2, cyclo-oxygenase 2.

65. Kidney

66. Kidney COX-2 also constitutively expressed COX-2 also constitutively expressed in kidney in kidney Is regulated in response to alterations in intravascular volume Is regulated in response to alterations in intravascular volume COXIBs may transiently COXIBs may transiently Decrease urinary Na + excretion Decrease urinary Na + excretion Can induce mild to moderate BP elevation Can induce mild to moderate BP elevation

67. COXIBs and NSAIDs COXIBs and NSAIDs Similar effects for kidney damage Similar effects for kidney damage Renal insufficiency Renal insufficiency Na + retention with HT Na + retention with HT Peripheral edema Peripheral edema Hyperkalemia Hyperkalemia Papillary necrosis Papillary necrosis Kidney

68. Other Adverse Events (AEs)

69. Other (Common) Adverse Events Dizziness Dizziness Headache Headache Flu-like symptoms Flu-like symptoms Fatigue Anxiety Insomnia

70. Other Adverse Events As a sulfonamide, celecoxib can cause cutaneous adverse reactions without warning even in pts with no history of sulfonamide allergy As a sulfonamide, celecoxib can cause cutaneous adverse reactions without warning even in pts with no history of sulfonamide allergy Rash Rash Urticaria Urticaria Photoallergic dermatitis Photoallergic dermatitis Serious and potentially fetal AEs Serious and potentially fetal AEs Exfoliative dermatitis Exfoliative dermatitis Steven Johnson syndrome Steven Johnson syndrome Toxic epidermal necrolysis Toxic epidermal necrolysis

71. Other Adverse Events Other Adverse Events Etoricoxib 30-90 mg/day for up to 1 yr, the most frequently reported lab AEs Etoricoxib 30-90 mg/day for up to 1 yr, the most frequently reported lab AEs Increased level of SGOT Increased level of SGOT Increased level of SGPT Increased level of SGPT 1-2.1% 1-2.1% Hepatic dysfunction presents a contraindication Hepatic dysfunction presents a contraindication During long-term Rx with COXIBs, LFTs should be regularly monitored During long-term Rx with COXIBs, LFTs should be regularly monitored

72. Other Adverse Events Other Adverse Events Lumiracoxib withdrawn due to severe liver damage Lumiracoxib withdrawn due to severe liver damage

73. Conclusions

74. Conclusions CV risks of COXIBs apparently increase with dose and duration of exposure CV risks of COXIBs apparently increase with dose and duration of exposure If COXIBs indicated If COXIBs indicated The lowest effective dose The lowest effective dose For a limited time For a limited time BP as well as renal and hepatic function advisably monitored BP as well as renal and hepatic function advisably monitored

75. Conclusions COXIBs should not be prescribed in pts with COXIBs should not be prescribed in pts with Ischemic heart disease Ischemic heart disease Cerebrovascular disorders (stroke) Cerebrovascular disorders (stroke) Peripheral arterial disease Peripheral arterial disease

76. Thank You SN