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- MEDAL Program: Multinational Etoricoxib and Diclofenac Arthritis Long-term

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

Presenter Disclosure Information 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 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

COX-1 Constitutive PGs COX-2 Inducible PGs  Inflammation — Fever — Pain — Headache  Carcinogenesis  GI cytoprotection  Platelet aggregation  Renal function (blood flow) Arachidonic Acid CO 2 H The COX-2 Hypothesis

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: Accessed October Decision Resources. Arthritic Pain

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

Cardiovascular Results From Chemo- prevention Trials of Rofecoxib and Celecoxib *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. P=0.008 Placebo Rofecoxib 25 mg/d Months % of patients Months Probability of composite endpoint Celecoxib 400 mg/d Celecoxib 200 mg/d P=0.01 Placebo Confirmed Serious Thrombotic EventsComposite CV Endpoint*

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

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

CV Events: Indirect Comparisons Imputed from Coxib Meta-analysis: Traditional NSAIDs vs Placebo Kearney, et al. BMJ. 2006;332;1302. NSAIDRR95% CI Diclofenac Ibuprofen Naproxen

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

FDA Class Warning  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).

Effect of NSAIDs on Platelet Aggregation Steady State % Inhibition from Baseline During Dosing Interval Day (Hours) Day 6 0 hours Day 6 2 hours Day 6 4 hours Day 6 8 hours Placebo Rofecoxib (25 mg) Diclofenac Ibuprofen 800 tid Naproxen 500 bid

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

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

Questions arising with COX-2 selective and traditional NSAID therapies These studies raise many questions: 1.Does greater COX-2 selectivity increase CV risk vs traditional NSAIDs? 2.Is high-dose naproxen, with its sustained antiplatelet effect, different? 3.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)

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 Design: MEDAL Program Trials n=17,412 RANDOMIZERANDOMIZE Etoricoxib 60 or 90 mg/d (OA) 90 mg/d (RA) Diclofenac 150 mg/d ( 50 mg tid or 75 mg bid) n=17,289  ≥ 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 Mean duration of therapy=18 months

No. of Patients (%) Etoricoxib (n=17,412) Diclofenac (n=17,289) Mean age, years (SD)63.2 (8.5) Female12,925 (74.2)12,823 (74.2) Osteoarthritis12,533 (72.0)12,380 (71.6) Rheumatoid arthritis4878 (28.0)4909 (28.4) Diabetes1810 (10.4)1855 (10.7) Hypertension8109 (46.6)8221 (47.6) Dyslipidemia5097 (29.3)5034 (29.1) Current smoker2034 (11.7)2037 (11.8) Established atherosclerotic CV disease2014 (11.6)2010 (11.6) ≥2 CV risk factors* or established atherosclerotic CV disease 6586 (37.8)6639 (38.4) Baseline Patient Characteristics *Included hypertension, diabetes mellitus, dyslipidemia, family history of CV disease, or smoking.

Etoricoxib (320 events) Diclofenac (323 events) Primary Endpoint: Cumulative Incidence of Thrombotic CV Events Months No. of patients at risk* Etoricoxib Diclofenac 16,819 16,483 13,35910, ,14212, Cumulative incidence (%) with 95% CI Etoricoxib vs diclofenac HR = % CI = ( ) *Per protocol population.

Etoricoxib (216 events) Diclofenac (216 events) Etoricoxib (272 events) Diclofenac (272 events) Cumulative Incidence of Arterial Thrombotic CV and APTC Events 16,819 16,483 13,362 12,801 10,735 10, No. of patients at risk Etoricoxib Diclofenac Months Etoricoxib vs diclofenac HR = % CI = ( ) Cumulative incidence (%) with 95% CI Cumulative incidence (%) with 95% CI Etoricoxib vs diclofenac HR = % CI = ( ) Months 16,819 16,483 13,366 12,814 10,745 10, No. of patients at risk Etoricoxib Diclofenac Arterial Thrombotic CV EventsAPTC Events (CVD/MI/Stroke)

Thrombotic CV Event Types Etoricoxib (n=16,819) Diclofenac (n=16,483) HR (95% CI) Rate* Fatal Thrombotic CV Events ( ) Cardiac Events Non-fatal MI Fatal MI Sudden cardiac death Unstable angina pectoris Resuscitated cardiac arrest Cardiac thrombus ( ) Cerebrovascular Events Non-fatal ischemic stroke Fatal ischemic stroke Cerebrovascular venous thrombosis Transient ischemic attack ( ) Peripheral Vascular Events Non-fatal pulmonary embolism Fatal pulmonary embolism Non-fatal peripheral artert. thrombosis Fatal peripheral arterial thrombosis Peripheral venous thrombosis ( ) *Events per 100 patient-years. Per protocol population

Age Gender Low-dose aspirin use at baseline Hazard Ratio (Etoricoxib vs Diclofenac) Established ASCVD or ≥2 CV Risk Factors Diabetes Etoricoxib LowerDiclofenac Lower Yes No Yes No Disease <65 ≥65 to <75 Male Female ≥75 Etoricoxib dose OA RA 60mg 90mg Yes * Per protocol population; † P=NS for all treatments by subgroup interactions. Primary Endpoint: Thrombotic CV Events Across Prespecified Subgroups* HR † Etoricoxib Event Rates Diclofenac Established ASCVD Yes No

Pre-specified Safety Endpoints by Dose: Pooled MEDAL Program Absolute difference in incidences (%) [95% CI] Etoricoxib LowerDiclofenac Lower CHF D/C: Hypertension D/C: Clinical GI AEs D/C: Hepatic AEs D/C: Edema D/C: Renal Dys CHF D/C: Hypertension D/C: Clinical GI AEs D/C: Hepatic AEs D/C: Edema D/C: Renal Dys Percent of patients Etori 60 mg/d Etori 90 mg/d Diclo 150 mg/d Etoricoxib 60 mg/d Etoricoxib 90 mg/d

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

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

Cumulative Incidence of Confirmed Upper GI Events (Perforations, Ulcers, and Bleeds)* POBs † Months No. of patients at risk Etoricoxib Diclofenac Cumulative incidence (%) with 95% CI Etoricoxib vs diclofenac HR = % CI = ( ) *ITT (14 days) population. 50.6% of patients were on gastroprotective agents. Etoricoxib (176 events) Diclofenac (246 events) † No significant difference in perforations, obstructions, or major bleeds.

Clinical Upper GI Events Stratified by Aspirin and PPI Use EtoricoxibDiclofenac HR (95% CI) n/NRate*n/NRate* Aspirin114/ / ( ) No aspirin62/ / ( ) PPI104/ / ( ) No PPI72/ / ( )

 Comparable CV thrombotic event rates  Significantly lower upper GI clinical events (no difference in complicated upper GI events) Conclusion 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:

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.

COX Selectivity of COX-2 Selective and Traditional NSAIDs Antman et al. Circulation. 2005;112: Relative inhibition (log[IC 80 ratio, COX-2/COX-1]) COX-1 selectivity COX-2 selectivity Fenoprofen Nimesulide Meloxicam Etodolac Valdecoxib Etoricoxib Rofecoxib Lumiracoxib Sodium salicylate Diflunisal Piroxicam Tomoxiprol Eclofenamate Diclofenac Celecoxib Zomepirac Niflumic Ketorolac Flurbiprofen Suprofen Ketoprofen Indomethacin Aspirin Naproxen Tolmetin Ibuprofen Ampyrone

Ibuprofen 800 mg/d 3 Diclofenac 50 mg tid 2 Naproxen 500 mg bid 1 Urinary Prostanoid Metabolites* Following Treatment With NSAIDs Placebo 1 Etoricoxib 90 mg/d 1 Celecoxib 200 mg bid 1 LS Mean Percent Change (SE) Urinary TxB2 Urinary PGI-M *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.

Inhibition of COX-1 and COX-2 by NSAIDs* WBA = whole blood assay. *Assays performed in different laboratories. Data on file, Merck.; Van Hecken et al. J Clin Pharmacol, 2000;40: Placebo Etoricoxib 90 mg/d Celecoxib 200 mg bid Diclofenac 75 mg bid Weighted Average Change From Baseline Serum TxB 2 (COX-1) WBA PGE 2 (COX-2) Placebo Van Hecken et al. Ibuprofen 800 mg tid Naproxen 500 mg bid Study 091 (Preliminary Data). Data on file, Merck.

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)

ASA/NSAIDs/COX-2 Effects and CV Risk PGI 2 TxA 2 Thrombotic Risk Low-Dose ASA Conventional NSAIDs Prob Naproxen (high-dose) Prob COX-2 Inhibitors + ASA ?? COX-2COX-1

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