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

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 Have similar amount of COX-2 inhibition, but greatly reduced (or no) COX-1 inhibition at standard doses Less inhibition of prostaglandins that protect the gastric mucosa, thereby ↓ 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.

CV Issues With COX-2 Selective and Traditional NSAIDs In placebo-controlled randomized trials, COX-2 selective NSAIDs ↑’ed the risk of thrombotic CV events Observational studies suggest ↑ CV risk for some traditional NSAIDs CV risk of high-dose naproxen may be different: Meta-analysis of randomized trials: CV risk of high-dose naproxen appears lower than COX-2 inhibitors 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) Kearney et al. BMJ. 2006;332:1302; Solomon et al. NEJM. 2005;352:1071; Bresalier et al. NEJM 2005;352:1092; FDA. At: http://www.fda.gov/bbs/topics/news/2005/NEW01171.html. Accessed October 2006; CHMP. At: http://www.emea.eu.int/pdfs/human/opiniongen/nsaids.pdf. Accessed October 2006.

Questions arising with COX-2 selective and traditional NSAID therapies These studies raise many questions: Does greater COX-2 selectivity increase CV risk vs. traditional NSAID? 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) The primary analysis will be of data from the MEDAL program, ie a combined analysis of data from the EDGE study in patients with OA, EDGE II in patients with RA, and the MEDAL study in patients with OA and RA. The MEDAL study was designed as an endpoint-driven CV outcomes study. A secondary analysis of CV event data derived from the MEDAL study alone will address whether etoricoxib will be non-inferior to diclofenac in the rates of confirmed CV events.

Goal To test the hypothesis, using non-inferiority statistical testing, that: The relative risk of thrombotic CV events with etoricoxib would not be greater than that with diclofenac for treatment of patients with osteoarthritis (OA) or rheumatoid arthritis (RA) The primary analysis will be of data from the MEDAL program, ie a combined analysis of data from the EDGE study in patients with OA, EDGE II in patients with RA, and the MEDAL study in patients with OA and RA. The MEDAL study was designed as an endpoint-driven CV outcomes study. A secondary analysis of CV event data derived from the MEDAL study alone will address whether etoricoxib will be non-inferior to diclofenac in the rates of confirmed CV events. Cannon et al. Am Heart J. 2006;152:237.

Study drugs Etoricoxib Highly selective COX-2 inhibitor Efficacy for OA/RA, available 62 countries (ex. U.S.) Diclofenac Effective treatment for OA/RA Most widely prescribed NSAID worldwide Does not interfere with antiplatelet effects of aspirin Ibuprofen and naproxen may interfere with aspirin FDA 2006 warning on interaction for ibuprofen Diclofenac inhibits both COX-1 and COX-2 at therapeutic doses But does not have sustained antiplatelet activity Capone et al. J Am Coll Cardiol 2005;45:1295; Catella-Lawson et al. N Engl J Med 2001;345:1809; FDA. At: http://www.fda.gov/cder/drug/infopage/ibuprofen/science_paper.htm. Accessed October 2006; Sikes et al. Eur J Gastroenterol Hepatol 2002;14:1101; Van Hecken et al. J Clin Pharmacol 2000;40:1109.

Design: MEDAL Program Trials 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 therapy with traditional NSAID or COX-2 inhibitor Broad CV risk Allowed aspirin and PPI use in appropriate patients The primary composite thrombotic CV endpoint was the first occurrence of the following fatal and non-fatal events: myocardial infarction (including silent infarction), unstable angina pectoris, intracardiac thrombus, resuscitated cardiac arrest, thrombotic stroke, cerebrovascular thrombosis, transient ischemic attack, peripheral venous thrombosis, pulmonary embolism, peripheral arterial thrombosis, and sudden and/or unexplained death. A composite thrombotic CV endpoint was chosen in an effort to be as comprehensive as possible when capturing adverse cardiac events. R A N D O M I Z E n=17,412 Etoricoxib 60 or 90 mg/d (OA) 90 mg/d (RA) Mean duration of therapy=18 months n=17,289 Diclofenac 150 mg/d (50 mg tid or 75 mg bid)

Statistical Considerations Non-inferiority comparison: Upper bound of 95% CI of the HR for etoricoxib vs diclofenac for primary endpoint must fall below 1.30 Event driven to a total of 635 events Sample size 34,500 provides 91% power CV Endpoints Thrombotic CV events (primary) Arterial thrombotic CV events APTC combined endpoint Adjudicated by independent blinded review committee Analytical Approaches Per protocol (primary) Patients >75% compliant with study drug and took non-study NSAIDs <10% of time on study ITT (within 14 days) ITT to end of study Independent confirmation of all analyses by Frontier Sciences: CM Hawkins, ScD and D DeMets, PhD

Baseline Patient Characteristics No. of Patients (%) Etoricoxib (n=17,412) Diclofenac (n=17,289) Mean age, years (SD) 63.2 (8.5) Female 12,925 (74.2) 12,823 (74.2) Osteoarthritis 12,533 (72.0) 12,380 (71.6) Rheumatoid arthritis 4878 (28.0) 4909 (28.4) Diabetes 1810 (10.4) 1855 (10.7) Hypertension 8109 (46.6) 8221 (47.6) Dyslipidemia 5097 (29.3) 5034 (29.1) Current smoker 2034 (11.7) 2037 (11.8) Established atherosclerotic CV disease 2014 (11.6) 2010 (11.6) ≥2 CV risk factors* or established atherosclerotic CV disease 6586 (37.8) 6639 (38.4) *Included hypertension, diabetes mellitus, dyslipidemia, family history of CV disease, or smoking.

Baseline Patient Medications No. of Patients (%) Etoricoxib (n=17,412) Diclofenac (n=17,289) Cardiac medications Low-dose aspirin use 6030 (34.6) 5976 (34.6) β-blocker 2806 (16.1) 2837 (16.4) ACE inhibitor or ARB 4571 (26.3) 4535 (26.2) Ca++ channel blocker 2096 (12.0) 2149 (12.4) Statin 2859 (16.4) 2890 (16.7) Diuretic 3129 (18.0) 3147 (18.2) Baseline Anti-arthritic medications* Traditional NSAID 14,209 (81.6) 14,174 (82.0) Acetaminophen 10,852 (62.3) 10,765 (62.3) COX-2 selective NSAID 4873 (28.0) 4939 (28.6) High-dose aspirin 173 (1.0) 185 (1.1) Glucocorticoid 2758 (15.8) 2762 (16.0) DMARD 2246 (12.9) 2208 (12.8) *Not mutually exclusive. DMARD = disease-modifying anti-rheumatic drug.

Primary Results Does the COX-2 selective NSAID etoricoxib have an increased risk of thrombotic CV events compared with the traditional NSAID diclofenac?

Primary Endpoint: Cumulative Incidence of Thrombotic CV Events 7.0 Etoricoxib (320 events) 6.0 Diclofenac (323 events) 5.0 Etoricoxib vs diclofenac HR = 0.95 95% CI = (0.81-1.11) 4.0 Cumulative incidence (%) with 95% CI 3.0 2.0 1.0 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.

Cumulative Incidence of Arterial Thrombotic CV and APTC Events Arterial Thrombotic CV Events APTC Events (CVD/MI/Stroke) 7.0 7.0 Etoricoxib (272 events) Etoricoxib (216 events) Diclofenac (272 events) Diclofenac (216 events) 6.0 6.0 Etoricoxib vs diclofenac HR = 0.96 95% CI = (0.81-1.13) Etoricoxib vs diclofenac HR = 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 6 12 18 24 30 36 42 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 16,483 12,801 10,144 7903 6214 3832 815 Diclofenac 16,483 12,814 10,155 7906 6218 3832 816

Summary of Primary and Secondary Thrombotic CV Endpoints and Analyses Etoricoxib Lower Diclofenac Lower Thrombotic Events Per Protocol 0.95 (0.81-1.11) ITT (14 days)* 0.96 (0.83-1.11) ITT (end of study)† 1.05 (0.93-1.19) Arterial Thrombotic Events Per Protocol 0.96 (0.81-1.13) ITT* (14 days)* 0.97 (0.83-1.14) ITT (end of study)† 1.03 (0.89-1.18) APTC Events Per Protocol 0.96 (0.79-1.16) ITT* (14 days)* 0.96 (0.80-1.15) ITT (end of study)† 1.02 (0.87-1.18) 1.3 0.5 1.0 2.0 Hazard Ratio (Etoricoxib vs Diclofenac) *Events included while on study drug and within 14 days of drug discontinuation. †Includes all events on and off study drug to end of study.

Thrombotic CV Event Types Etoricoxib (n=16,819) Diclofenac (n=16,483) HR (95% CI) Rate* Fatal Thrombotic CV Events 0.17 0.96 (0.63-1.46) Cardiac Events Non-fatal MI Fatal MI Sudden cardiac death Unstable angina pectoris Resuscitated cardiac arrest Cardiac thrombus 0.71 0.41 0.02 0.11 0.16 0.01 0.78 0.42 0.07 0.09 0.21 0.90 (0.74-1.10) Cerebrovascular Events Non-fatal ischemic stroke Fatal ischemic stroke Cerebrovascular venous thrombosis Transient ischemic attack 0.34 0.12 0.32 0.22 1.08 (0.80-1.46) Peripheral Vascular Events Non-fatal pulmonary embolism Fatal pulmonary embolism Non-fatal peripheral artert. thrombosis Fatal peripheral arterial thrombosis Peripheral venous thrombosis 0.20 0.10 0.92 (0.63-1.35) *Events per 100 patient-years. Per protocol population

Primary Endpoint: Thrombotic CV Events Across Prespecified Subgroups* Etoricoxib Event Rates Diclofenac 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.

Pre-specified Safety Endpoints by Dose: Pooled MEDAL Program Absolute difference in incidences (%) [95% CI] 2 4 6 8 10 Percent of patients Etori 60 mg/d Etori 90 mg/d Diclo150 mg/d 0.3 0.4 2.2 2.4 4.7 6.6 0.8 1.2 1.0 0.2 1.6 7.1 9.0 1.8 3.2 0.7 0.6 0.9 Etoricoxib Lower Diclofenac Lower CHF Etoricoxib Dose 60 mg/d 90 mg/d D/C: Hypertension 60 mg/d 90 mg/d D/C: Edema 60 mg/d 90 mg/d D/C: Renal Dys. 60 mg/d 90 mg/d D/C: Clinical GI AEs 60 mg/d 90 mg/d D/C: Hepatic AEs 60 mg/d 90 mg/d -6 6 -4 -2 2 4

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

Remaining Questions to be addressed (in randomized trials - not observational studies) Naproxen Does the lower risk seen in the meta-analysis comparing naproxen to COX-2 inhibitors relate to its antiplatelet effect? Does high-dose naproxen have increased risk vs. placebo? Ibuprofen Does it negate clinical benefit of ASA? Risk vs. naproxen? Aspirin effect Would aspirin modify the risk of COX-2 inhibitors 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 (e.g., increased risk of GI ulcer)

For the lower risk upper GI clinical events with etoricoxib: “Our results show that patients with arthritis treated with the COX-2 selective NSAID etoricoxib and those given the traditional NSAID diclofenac have nearly identical rates of thrombotic cardiovascular events.” Dr. Loren Laine is presenting preliminary GI subgroup data at Am. Coll. Rheumatology in Wash DC today For the lower risk upper GI clinical events with etoricoxib:  Generally consistent benefit in ASA and PPI subgroups Cannon CP, Curtis S, FitzGerald GA, et al. Lancet. 2006:368 (published online) www.thelancet.com