1. cyclo-oxygenase 2 inhibitors and cardiovascular risk —where are we now? Sung-Hwan Park M.D Rheumatology, Internal Medicine Kangnam St Mary’s hospital The Catholic University of Korea

2. NSAIDs

5. Selective COX-2 inhibitors Developed to avoid side effects of conventional NSAIDs, including gastrointestinal and renal toxicity COX-2 is constitutively expressed in the kidney. regulated in response to alterations in intravascular volume COX-2 metabolites :maintenance of renal blood flow, mediation of renin release, and regulation of Na excretion COX-2 inhibition transiently decrease urine sodium excretion in some subjects and induce mild to moderate elevation of BP

6. Cox1 / Cox2 ratio of NSAIDs

7. Clinically Significant Elevations in BP Percent of Patients With Systolic Blood Pressure Increase From Baseline >20 mm Hg and Absolute >140 mm Hg 11.2% (n=411 ) 6.9% (n=549) 16.5% (n=399) 14.9% (n=543) Celecoxib 200 mg qdRofecoxib 25 mg qd* Study 1: Whelton et al P=0.03 Study 2: Whelton et al P<0.001

8. 9.5 4.9 0 2 4 6 8 10 7.7 4.7 0 2 4 6 8 CELEBREX® (celecoxib capsules) 200 mg qd (n=411)CELEBREX® (celecoxib capsules) 200 mg qd (n=549)Rofecoxib 25 mg qd (n=399)Rofecoxib (n=543) P=0.01 P<0.05 % of Patients Study 1: Whelton et alStudy 2: Whelton et al Celecoxib vs Rofecoxib: Incidence of Edema 1,2

9. Effects of celecoxib and rofecoxib on blood pressure and edema in patients > or =65 years of age with systemic hypertension and osteoarthritis. Rofecoxib caused the greatest increase in systolic BP in patients receiving ACE inhibitors or beta blockers, whereas those on calcium channel antagonists or diuretic monotherapy receiving either celecoxib or rofecoxib showed no significant increases in BP. Careful monitoring of BP is warranted after the initiation of celecoxib or rofecoxib therapy. Am J Cardiol. 2002 Nov 1;90(9):959-63

12. VIGOR(50mg) : MI risk x 4 Inhibition of Platelet inhibitory and vasodilator effect Cardioprotective effect of COX-1, Naproxen?, other NSAIDs

13. Cardioprotection and low dose aspirin Complete and irreversible inhibition of platelet COX-1 : Inhibition of TXA2 mediated platelet aggregation Pharmacokinetics and phamacodynamics --- different from low dose aspirin

14. Cardioprotection and low dose aspirin

16. COX-2 inhibitor and AMI

17. Rofecoxib >25 mg; X 2 MI First 90 days of exposure: risk No elevation in AMI risk after 90 days Similar RR of MI compared with no current NSAIDs, naproxen, ibubrufen, other NSAIDS Current rofecoxib(25mg) use was associated with AMI risk compared with celecoxib(200 mg). COX-2 inhibitor and AMI

29. Cardiovascular safety and NSAIDs

30. FDA News FOR IMMEDIATE RELEASE P05-16 April 7, 2005 Media Inquiries: Kathleen Quinn 301-827-6242 Consumer Inquiries: 888-INFO-FDA FDA Announces Series of Changes to the Class of Marketed Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) http://www.fda.gov/cder/drug/infopage/cox2/default.htmhttp://www.fda.gov/cder/drug/infopage/cox2/default.htm.

34. Inflammation, Atherosclerosis and Coronary artery disease

40. Selective COX-2 inhibition improves endothelial function in coronary artery disease Circulation. 2003 Jan 28;107(3):405-9 The patients received celecoxib (200 mg BID) or placebo for a duration of 2 weeks in a double-blind, placebo-controlled, crossover fashion. selective COX-2 inhibition improves endothelium-dependent vasodilation and reduces low-grade chronic inflammation and oxidative stress in coronary artery disease.

44. Circulation. 2004 Jul 20;110(3):301-8

46. Association between carotid atherosclerosis & markers of inflammation in RA patients and healthy subjects A significant linear trend for increased carotid artery IMT was associated with increasing ESR and CRP Increased carotid artery IMT and the presence of carotid plaque are associated with markers of systemic inflammation in patients with RA

50. Drug insight: cyclo-oxygenase 2 inhibitors and cardiovascular risk Cyclo-oxygenase (COX) 1 mediates the production of thromboxane A2 in platelets, leading to platelet aggregation and vasoconstriction. Conversely, COX2 catalyzes endothelial prostacyclin synthesis, which effectively counteracts thromboxane A2, triggering vasodilation and platelet inhibition. Selective COX2 inhibitors decrease prostacyclin production, potentially disrupting homeostasis and creating a prothrombotic state. Nat Clin Pract Cardiovasc Med. 2005 Jun;2(6):290-300. Spektor G, Fuster V. Zena and Michael A Wiener Cardiovascular Institute, Mount Sinai Medical Center, New York, NY 10029, USA.

52. Drug insight: cyclo-oxygenase 2 inhibitors and cardiovascular risk The VIGOR study findings of increased cardiovascular risk with rofecoxib were subsequently confirmed by large meta- analyses, observational studies and recent APPROVe trial publication. The APC trial findings of increased cardiovascular risk with Celebrex (celecoxib) conflict with those in the ADAPT trial, the upcoming PreSAP publication, a case-control study by Graham et al. and prior large clinical trials, meta-analyses and observational studies of this drug. Therefore, while an adverse class effect is a possibility for COX2 inhibitors, the published data are inconsistent. Nat Clin Pract Cardiovasc Med. 2005 Jun;2(6):290-300. Spektor G, Fuster V. Zena and Michael A Wiener Cardiovascular Institute, Mount Sinai Medical Center, New York, NY 10029, USA.

53. Drug insight: cyclo-oxygenase 2 inhibitors and cardiovascular risk Improved endothelial function has also been reported with celecoxib, leading to endothelium-dependent vasodilation, and associated decreases in C-reactive protein and LDL cholesterol. The addition of meloxicam to low-dose aspirin and heparin has improved clinical outcomes after acute coronary syndromes. These are the first studies suggesting improvement in endothelial function and reduction of inflammation with COX2 inhibition. Thus, more randomized controlled trials are needed to study the relative cardiovascular effects of different COX2 inhibitors, alone and in combination with aspirin. Nat Clin Pract Cardiovasc Med. 2005 Jun;2(6):290-300. Spektor G, Fuster V. Zena and Michael A Wiener Cardiovascular Institute, Mount Sinai Medical Center, New York, NY 10029, USA.

54. Risk factors for peptic ulcer bleeding Odds ratio 012348 Current smoking Diabetes Heart failure Dyspepsia in past year Previous peptic ulcer Warfarin use Oral corticosteroid use NSAID use 567

55. Bombardier et al 2000 † Perforation, obstruction, bleeding or symptomatic peptic ulcer. Rofecoxib carries a lower overall risk of upper GI events than naproxen naproxen, 500 mg twice daily rofecoxib, 50 mg once daily Duration of follow-up (months) Cumulative incidence of a confirmed upper GI event † (%) 5 3 4 2 0 1 0 42 10 8 6 12 n=8076

56. Hawkey & Skelly 2002 Risk of ulcer complications with celecoxib remains high among patients with other risk factors More than one risk factor ibuprofen, 800 mg three times daily, or diclofenac, 75 mg twice daily celecoxib, 400 mg twice daily Patients with ulcer complications (%) 2 0 1 No risk factor n=8059

57. Laine et al 2004 Risk of peptic ulceration is similar between non-selective and COX-2 selective NSAIDs with concomitant low-dose aspirin placebo n=410 aspirin n=406 rofecoxib + aspirin n=399 ibuprofen n=400 Cumulative incidence of ulcers (%) *** p<0.001 versus placebo + aspirin 0 2 4 6 8 10 12 14 16 18 ***

58. Silverstein et al 2000 Annualised incidence (6-month data) (%) Upper GI ulcer complications Upper GI ulcer complications + symptomatic peptic ulcers Celecoxib +aspirin2.014.7 NSAID + aspirin2.126.0 Celecoxib alone0.44 p<0.05 1.40 p<0.05 NSAID alone1.272.91 Concomitant aspirin therapy increases the rate of upper GI ulcer complications with celecoxib

59. Huang et al 2002 H. pylori infection and NSAID use synergistically increase the risk of peptic ulcer disease Patients with peptic ulcer (%) NSAID users controls 100 80 40 20 0 60 H. pylori- positive n=180 H. pylori- negative n=205 H. pylori- positive n=127 H. pylori- negative n=149

60. Patient-related factors: – age >60 years – history of peptic ulcer disease/upper GI complications. Drug-related factors – use of a relatively toxic NSAID – use of a high dose of NSAID (or two NSAIDs used concurrently) – concurrent use of an anticoagulant – concurrent use of a corticosteroid. Risk factors for upper GI complications occurring with NSAIDs

61. NSAIDs induced gastropathy Age > 65 yrs Prior ulcer disease or Cx High dose NSAIDs Multiple NSAIDs Concomittent steroid Tx Concomitant anticoagulation Rofecoxib Celecoxib Risk factor Dose reduction Misoprostol, rebamipide H2-blocker or PPI Coxib Preventive measure

62. Cardioprotective Rationale Cardioprotection –Inflammation plays an important role in artherosclerotic disease –COX-2 is highly expressed in artherosclerotic plaques –Pilot studies indicate that Celebrex improves cardiovascular function in patients with artherosclerotic disease

63. Thromboembolic Rationale Thromboembolic Events –Includes CV death, myocardial infarction and stroke –Current studies (mechanistic) suggest Vioxx/Arcoxia to be pro-oxidant, leading to inflammation and thromboembolic events –Current mechanistic studies suggest Celebrex stimulates nitric oxide production leading to lower thromboembolic events –Major epidemiology study (Ray) and VIGOR demonstrate Vioxx has higher thromboembolic events than NSAIDs

64. Cardiorenal Rationale Cardiorenal Events –Includes hypertension and edema –Vioxx induces significantly more hypertension and edema in treated hypertensive patients vs Celebrex (as seen in 2 clinical trials) –Celebrex has a similar cardiorenal profile compared to NSAIDs

65. Statins in rheumatoid arthritis--two birds with one stone? Lancet. 2004 Jun 19;363(9426):2011-2. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet. 2004 Jun 19;363(9426):2015-21 Atorvastatin reduces arterial stiffness in patients with rheumatoid arthritis. Ann Rheum Dis. 2004 Dec;63(12):1571-5