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Welcome Ask The Experts March 24-27, 2007 New Orleans, LA

Welcome Ask The Experts March 24-27, 2007 New Orleans, LA. Christopher P. Cannon, MD Senior Investigator, TIMI Study Group Cardiovascular Division Brigham and Women's Hospital Associate Professor of Medicine Harvard Medical School Boston, MA. Cardiovascular Risk with COX-IIs-

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Welcome Ask The Experts March 24-27, 2007 New Orleans, LA

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  1. Welcome Ask The Experts March 24-27, 2007 New Orleans, LA

  2. Christopher P. Cannon, MDSenior Investigator, TIMI Study GroupCardiovascular DivisionBrigham and Women's HospitalAssociate Professor of MedicineHarvard Medical SchoolBoston, MA Cardiovascular Risk with COX-IIs- MEDAL Program: Multinational Etoricoxib and Diclofenac Arthritis Long-term

  3. Cardiovascular Outcomes with COX-2 Inhibitors: The MEDAL Program Christopher P Cannon, MD Senior Investigator, TIMI Study Group Associate Professor of Medicine Harvard Medical School Cardiovascular Division Brigham and Women’s Hospital Boston, Massachusetts

  4. Presenter Disclosure Information Christopher P. Cannon, MD Results of the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) Study Program: Cardiovascular Outcomes Following Long-term Treatment with Etoricoxib vs Diclofenac in Patients with Osteoarthritis and Rheumatoid Arthritis DISCLOSURE INFORMATION: The following relationships exist related to this presentation: Research grant support from Accumetrics, AstraZeneca, Merck, Merck/Schering-Plough, and Schering-Plough and has spoken at symposia sponsored by and served on scientific advisory boards for AstraZeneca, Bristol-Myers Squibb, Glaxo Smith Kline, Merck, Pfizer, Sanofi-Aventis, Merck/Schering-Plough, Schering-Plough, and Vertex Trial sponsor: Merck

  5. The COX-2 Hypothesis CO2H Arachidonic Acid COX-1 Constitutive PGs COX-2 Inducible PGs • GI cytoprotection • Platelet aggregation • Renal function (blood flow) • Inflammation • Fever • Pain • Headache • Carcinogenesis

  6. Arthritis: Background • >46 million individuals with arthritis in US • 1 in 5 adults in US are affected • Non-steroidal anti-inflammatory drugs (NSAIDs) are central to treating the pain and inflammation of arthritis • “COX-2 selective” NSAIDs and PPI each shown to ↓ GI ulcers and complications • Patients frequently need to switch NSAID agents due to lack of pain control  Different treatment options needed Arthritis Foundation. At: http://www.arthritis.org. Accessed October 2006. Decision Resources. Arthritic Pain. 2005.

  7. Rates of MI in Original Randomized Trials of Vioxx and Celecoxib VIGOR CLASS 1.0 1.0 0.8 0.8 0.6 0.6 Rates per 100 patient-years 0.4 0.4 0.2 0.2 0.0 0.0 Rofecoxib 50 mg qd (n=4047) Naproxen 500 mg bid (n=4029) Celecoxib 400 mg bid (n=3995) Diclofenac 75 mg tid (n=1999) Ibuprofen 800 mg bid (n=1998) Bombardier C NEJM. 2000;343:1520-8 Silverstein FE,JAMA. 2000;284:1247-55. Mukherjee D, Nissen SE, Topol EJ JAMA 2001;286(8):954-959.

  8. Celecoxib 400 mg/d Celecoxib 200 mg/d Placebo P=0.01 Cardiovascular Results From Chemo-prevention Trials of Rofecoxib and Celecoxib Confirmed Serious Thrombotic Events Composite CV Endpoint* 6 0.05 Placebo Rofecoxib 25 mg/d 5 0.04 P=0.008 4 0.03 % of patients 3 Probability of composite endpoint 0.02 2 0.01 1 0 0 0 6 12 18 24 30 36 0 6 12 18 24 30 36 Months Months *Includes death from cardiovascular causes, myocardial infarction, stroke, or heart failure. Bresalier et al. N Engl J Med. 2005;352:1092. Solomon et al. N Engl J Med. 2005;352:1071.

  9. Meta-analysis of Randomized Trials ofCOX-2 Selective NSAIDs vs Placebo Kearney et al. BMJ. 2006;332:1302.

  10. ADAPT Trial 3-Year Risk of Cardiovascular or Cerebrovascular Death, MI, Stroke, CHF, or TIA 3.5 Placebo (referent) 5.68% (37/1070) Naproxen 220 BID 8.25% (40/713) Celecoxib 200 QD 5.54% (28/717) 3.0 2.5 2.0 Hazard Ratio vs. Placebo 1.5 1.0 0.5 0 Overall PLOS online 2006

  11. CV Events: Indirect Comparisons Imputed from Coxib Meta-analysis: Traditional NSAIDs vs Placebo Kearney, et al. BMJ. 2006;332;1302.

  12. Meta-analysis of Randomized Trials of COX-2 Selective vs Traditional NSAIDS Kearney et al. BMJ. 2006;332:1302.

  13. FDA Class Warning • 2005-6 FDA and European regulatory agencies added a warning of an increased thrombotic CV risk for all NSAIDs (both COX-2 selective and traditional) Cardiovascular Risk NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. (See WARNINGS and CLINICAL TRIALS). http://www.fda.gov/cder/drug/infopage/cox2/default.htm

  14. Effect of NSAIDs on Platelet AggregationSteady State % Inhibition from Baseline During Dosing Interval 100 90 80 Placebo Rofecoxib (25 mg) Diclofenac Ibuprofen 800 tid Naproxen 500 bid 70 60 50 40 30 20 10 0 -10 -20 Day 60 hours Day 62 hours Day 64 hours Day 68 hours Day (Hours)

  15. Cyclooxygenase Inhibitors and the Antiplatelet Effects of Aspirin Could NSAIDS block the effect of ASA? • Aspirin led to platelet inhibition • Treatment with ibuprofen prior to ASA blocked this effect -> no platelet inhibition after ASA • Rofecoxib and diclofenac had no reduction in the platelet inhibition of ASA.

  16. B A With aspirin Acetyl serine Platelet cyclooxygenase-1 Serine residue at position 529 Y Catalytic site C With ibuprofen + ASA Ibuprofen Arachidonic acid Channel of access Platelet Aspirin

  17. Questions arising with COX-2 selective and traditional NSAID therapies These studies raise many questions: • Does greater COX-2 selectivity increase CVrisk vs traditional NSAIDs? • Is high-dose naproxen, with its sustained antiplatelet effect, different? • Would use of aspirin attenuate the increased risk seen with NSAIDs? Need large randomized trials comparing CV outcomes between different NSAID agents • MEDAL aimed to address the first of these issues (but cannot address all of them)

  18. 3 Trials 46 countries 1380 sites • EDGE (OA): N=7,111 • EDGE II (RA): N=4,086 34,701 patients • MEDAL (OA/RA): N=23,504 • ≥ 50 years of age • OA of knee, hip, hand,or spine; or RA • Require long-term therapywith traditional NSAID orCOX-2 inhibitor • Broad CV risk • Allowed aspirin and PPIuse in appropriate patients R A N D O M I Z E Etoricoxib60 or 90 mg/d (OA)90 mg/d (RA) n=17,412 Mean duration of therapy=18 months Diclofenac150 mg/d (50 mg tid or 75 mg bid) n=17,289 Design: MEDAL Program Trials

  19. Baseline Patient Characteristics *Included hypertension, diabetes mellitus, dyslipidemia, family history of CV disease, or smoking.

  20. Diclofenac (323 events) Etoricoxib (320 events) Primary Endpoint: Cumulative Incidence of Thrombotic CV Events 7.0 6.0 Etoricoxib vs diclofenacHR = 0.95 95% CI = (0.81-1.11) 5.0 4.0 Cumulative incidence (%) with 95% CI 3.0 2.0 1.0 0 0 6 12 18 24 30 36 42 Months No. of patients at risk* Etoricoxib 16,819 13,359 10,733 8277 6427 4024 805 Diclofenac 16,483 12,800 10,142 7901 6213 3832 815 *Per protocol population.

  21. Diclofenac (272 events) Diclofenac (216 events) Etoricoxib (272 events) Etoricoxib (216 events) Cumulative Incidence of ArterialThrombotic CV and APTC Events Arterial Thrombotic CV Events APTC Events (CVD/MI/Stroke) 7.0 7.0 6.0 6.0 Etoricoxib vs diclofenacHR = 0.96 95% CI = (0.81-1.13) Etoricoxib vs diclofenacHR = 0.96 95% CI = (0.79-1.16) 5.0 5.0 4.0 4.0 Cumulative incidence (%) with 95% CI Cumulative incidence (%) with 95% CI 3.0 3.0 2.0 2.0 1.0 1.0 0 0 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42 Months Months No. of patients at risk No. of patients at risk Etoricoxib 16,819 13,362 10,735 8277 6427 4024 805 Etoricoxib 16,819 13,366 10,745 8282 6429 4026 805 Diclofenac Diclofenac 16,483 12,801 10,144 7903 6214 3832 815 16,483 12,814 10,155 7906 6218 3832 816

  22. Thrombotic CV Event Types *Events per 100 patient-years. Per protocol population

  23. Event Rates Etoricoxib Diclofenac HR† Primary Endpoint: Thrombotic CV Events Across Prespecified Subgroups* Etoricoxib Lower Diclofenac Lower <65 0.85 0.88 0.96 Age ≥65 to <75 1.63 1.64 0.99 ≥75 2.51 3.10 0.81 Gender Male 1.94 2.32 0.83 Female 1.00 0.95 1.04 Yes 2.12 1.75 1.21 Diabetes No 1.14 1.25 0.91 Yes 3.12 3.33 0.94 Established ASCVD No 1.02 1.06 0.96 Established ASCVD or ≥2 CV Risk Factors Yes 2.00 1.93 1.04 No 0.81 0.95 0.85 Low-dose aspirin use at baseline Yes 1.67 1.87 0.89 No 1.01 1.01 1.00 OA 1.16 1.22 0.95 Disease RA 1.40 1.49 0.94 60mg 1.00 1.07 0.92 Etoricoxib dose 90mg 1.43 1.49 0.97 0.5 1 1.5 2 Hazard Ratio (Etoricoxib vs Diclofenac) *Per protocol population; †P=NS for all treatments by subgroup interactions.

  24. Percent of patients Etori 60 mg/d Etori 90 mg/d 0.3 Diclo 150 mg/d 0.2 2.2 1.6 0.8 0.7 0.8 0.8 4.7 7.1 0.3 1.8 -6 -4 -2 0 2 4 6 0 2 4 6 8 10 0.4 0.2 2.4 1.2 1.2 0.6 1.0 0.9 6.6 9.0 0.3 3.2 Pre-specified Safety Endpoints by Dose: Pooled MEDAL Program Absolute difference in incidences (%) [95% CI] Etoricoxib 60 mg/d Etoricoxib Lower Diclofenac Lower CHF D/C: Hypertension D/C: Edema D/C: Renal Dys. D/C: Clinical GI AEs D/C: Hepatic AEs Etoricoxib 90 mg/d CHF D/C: Hypertension D/C: Edema D/C: Renal Dys. D/C: Clinical GI AEs D/C: Hepatic AEs

  25. Renovascular Effects of NSAIDs & COX-2 Inhibitors Arachidonic Acid NSAIDs COXIBs COX-2 PGE2 /PGI2 • Sodium Retention • Peripheral edema • Hypertension • CHF • Acute Renal Failure • Prerenal azotemia • ATN • Hyperkalemia • Type 4 Renal Tubular Acidosis • Hyponatremia Perazella, M. Expert Opin Drug Saf. 2002;1:53-64.

  26. Effect of Naproxen and Coxibs on Blood Pressure in the Elderly Changes in BP on Day 14 of Treatment 7 Placebo (n=16) Naproxen 500 mg bid (n=17) 6 Celecoxib 200 mg bid (n=17) Rofecoxib 25 mg qd (n=17) LS mean change from baseline ± SE Systolic BP Diastolic BP -3 Schwartz JL, et al. EULAR, 2001. Abstract SAT0055.

  27. Etoricoxib (176 events) POBs† No. of patients at risk Etoricoxib 17412 13704 10972 8400 6509 4063 821 Diclofenac 17289 13190 10396 8027 6306 3867 820 Cumulative Incidence of Confirmed Upper GI Events (Perforations, Ulcers, and Bleeds)* 3.0 Diclofenac (246 events) 2.5 Etoricoxib vs diclofenacHR = 0.69 95% CI = (0.57-0.83) 2.0 1.5 Cumulative incidence (%) with 95% CI 1.0 0.5 0 0 6 12 18 24 30 36 42 Months *ITT (14 days) population. 50.6% of patients were on gastroprotective agents. †No significant difference in perforations, obstructions, or major bleeds.

  28. Clinical Upper GI EventsStratified by Aspirin and PPI Use

  29. Conclusion • Comparable CV thrombotic event rates • Significantly lower upper GI clinical events (no difference in complicated upper GI events) Long-term treatment with COX-2 selective NSAID etoricoxib vs traditional NSAID diclofenac in largest arthritis trial to date These results with a new agent provide data to help physicians and guideline committees determine the optimal treatment for patients with arthritis Cannon CP, Curtis S, FitzGerald GA, et al. Lancet. 2006:368:1771-81.

  30. ACR Treatment Guidelines for Osteoarthritis • Acetaminophen <4 g/d is first-line pharmacologic intervention • Alternative pharmacologic agents for patients who fail to obtain adequate symptomatic relief with acetaminophen • Treatment choice following evaluation of risk factors for GI, renal, and CV toxicity • Options include COX-2 selective NSAIDs, traditional NSAIDs, or pure analgesics • Intraarticular therapy with hyaluronic acid or glucocorticoids is an alternative to oral therapy ACR. Arthritis Rheum. 2000;43:1905.

  31. COX Selectivity of COX-2 Selective and Traditional NSAIDs Ketorolac Flurbiprofen 3 Suprofen COX-1selectivity Indomethacin Ketoprofen 2 Naproxen Ampyrone Ibuprofen Aspirin Tolmetin 1 0 Relative inhibition(log[IC80 ratio, COX-2/COX-1]) -1 Niflumic Zomepirac Diflunisal Fenoprofen Piroxicam Tomoxiprol Diclofenac -2 COX-2selectivity Celecoxib Eclofenamate Nimesulide Sodium salicylate Meloxicam Etodolac -3 Valdecoxib -4 Etoricoxib Rofecoxib Lumiracoxib Antman et al. Circulation. 2005;112:759.

  32. Urinary TxB2 Urinary PGI-M Naproxen500 mg bid1 Diclofenac50 mg tid2 Ibuprofen800 mg/d3 Urinary Prostanoid Metabolites* Following Treatment With NSAIDs 40 20 0 -20 LS Mean Percent Change (SE) -40 -60 -80 -100 Placebo1 Etoricoxib90 mg/d1 Celecoxib200 mg bid1 *Assays performed in different laboratories. 1.Data on file, Merck; 2.Van Hecken et al. J Clin Pharmacol, 2000;40:1109; 3.McAdam et al. Proc Natl Acad Sci USA. 1999;96:272.

  33. Serum TxB2 (COX-1) WBA PGE2 (COX-2) Inhibition of COX-1 and COX-2 by NSAIDs* 40 20 0 -20 Weighted Average ChangeFrom Baseline -40 -60 -80 -100 Etoricoxib90 mg/d Celecoxib200 mg bid Diclofenac75 mg bid Ibuprofen800 mg tid Naproxen500 mg bid Placebo Placebo Study 091 (Preliminary Data).Data on file, Merck. Van Hecken et al. WBA = whole blood assay. *Assays performed in different laboratories. Data on file, Merck.; Van Hecken et al. J Clin Pharmacol, 2000;40:1109.

  34. Remaining Questions to be addressed (in randomized trials – not observational studies) • Naproxen • Does the lower risk seen in the meta-analysis comparing naproxen with COX-2 selective NSAIDs relate to its antiplatelet effect? • What is the CV risk of high-dose naproxen vs placebo? • Ibuprofen • Does it negate clinical benefit of aspirin? • Risk vs naproxen? • Aspirin effect • Would aspirin modify the risk the risk of COX-2 inhibitors (and some traditional NSAIDs) vs naproxen (or vs placebo)? For medical societies/guidelines committees • Should one type of agent be tried first? • Should choice of NSAID be individualized using patient characteristics (eg, increased risk of GI ulcer)

  35. ASA/NSAIDs/COX-2 Effects and CV Risk COX-2 COX-1

  36. Question & Answer

  37. Thank You! Please make sure to hand in your evaluation and pick up a ClinicalTrialResults.org flash drive

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