1. The Vioxx Withdrawal What Happened? John A. Baron Dartmouth Medical School for the APPROVe Investigators

2. Vioxx A Recent Quote The licensing of Vioxx and its continued use …. have been public-health catastrophes. (Lancet, Nov 5)

3. COX-2 Inhibitors What are They? Should we Care?

4. Cyclooxygenase & Prostaglandins Membrane phospholipids Arachidonate PGH 2 PGE 2 PGF 2 PGD 2 PGI 2 TXA 2 PGG 2 COX

5. Prostanoids Cell Signaling Molecules Peroxidase Isomerase Phospholipase A2 PGG2 PGH2 Prostaglandins Thromboxanes Angiogenesis Apoptosis Vascular Reactivity Invasiveness Inflammation Platelet function NSAIDs COX Phospholipids, Arachidonic Acid

6. Cyclooxygenase 2 Isoforms Cox-1 Cox-2 consitutive inducible house-keeping inflammation, cancer Cox-2 w/o Cox-1 inhibition may offer:  Anti-inflammatory effects  Cancer prevention AND  Protection of stomach  No bleeding Cox-2 w/o Cox-1 inhibition may offer:  Anti-inflammatory effects  Cancer prevention AND  Protection of stomach  No bleeding

7. Vioxx Early History Vioxx (Rofecoxib) released in 1999 An “early” COX-2 inhibitor more selective than celecoxib Premise of COX-2 inhibitors: greater safety than traditional NSAIDs at least equal efficacy

8. Thrombotic CV Events: the VIGOR Study Overall RR: 2.38 (1.39, 4.00)

9. Overall RR 1.09 (0.69,1.73) Thrombotic CV Events: Phase II OA

10. Cardiovascular Background Summary In randomized trials prior to APPROVe cardiovascular risk for rofecoxib was : Higher than for naproxen Similar to non-naproxen NSAIDs Similar to Placebo (limited data beyond 2 years) Summary In randomized trials prior to APPROVe cardiovascular risk for rofecoxib was : Higher than for naproxen Similar to non-naproxen NSAIDs Similar to Placebo (limited data beyond 2 years)

11. APPROVe Study (Adenomatous Polyp Prevention with VIOXX) Standard Adenoma Prevention Study Subjects with recent adenoma 3-year adenoma endpoint 1-year research colonoscopy Rofecoxib 25 mg vs. placebo 107(!) sites, 39 in U.S. (Adenomatous Polyp Prevention with VIOXX) Standard Adenoma Prevention Study Subjects with recent adenoma 3-year adenoma endpoint 1-year research colonoscopy Rofecoxib 25 mg vs. placebo 107(!) sites, 39 in U.S.

12. APPROVe Study Study overseen by External Steering Committee External Safety Monitoring Board (ESMB) Adjudication of Serious CV Events Prespecified Protocol for CV effects Study overseen by External Steering Committee External Safety Monitoring Board (ESMB) Adjudication of Serious CV Events Prespecified Protocol for CV effects

13. APPROVe Study Design Study Visit Randomization Placebo (N~1214) Rofecoxib 25 mg (N~1214) *non-study, within 3 months prior to screening 36 12 Month -4.5 0 0 -1.5 Colo* Colo 24

14. APPROVe Eligibility Inclusion Criteria ≥ 40 years old histologically confirmed large bowel adenoma Prior MI, PTCA, CABG OK if > 1year prior T 0 Exclusion Criteria Uncontrolled hypertension (>165/95 mm Hg), angina at rest or minimal activity, CHF at rest Inclusion Criteria ≥ 40 years old histologically confirmed large bowel adenoma Prior MI, PTCA, CABG OK if > 1year prior T 0 Exclusion Criteria Uncontrolled hypertension (>165/95 mm Hg), angina at rest or minimal activity, CHF at rest

15. Male (%) Mean age Aspirin use (%) Hypertension (%)  CV risk* (%) Current Smoker (%) Male (%) Mean age Aspirin use (%) Hypertension (%)  CV risk* (%) Current Smoker (%) 62 59 years 19 36 29 22 62 59 years 19 36 29 22 62 59 years 18 34 26 22 62 59 years 18 34 26 22 * CV hx, or ≥2 of: hx of DM,  cholesterol, HTN, smoker Rofecoxib N=1287 Rofecoxib N=1287 Placebo N=1299 Placebo N=1299 APPROVe Baseline Characteristics

16. APPROVe CV Events, as of 8/16/2004 118 Investigator-reported events 70 Confirmed Thrombotic Events MI, Unstable Angina, Sudden Death Stroke, TIA DVT, PE, Arterial Thrombosis 49 Confirmed APTC events* Death: CV or unknown cause MI Stroke 118 Investigator-reported events 70 Confirmed Thrombotic Events MI, Unstable Angina, Sudden Death Stroke, TIA DVT, PE, Arterial Thrombosis 49 Confirmed APTC events* Death: CV or unknown cause MI Stroke *APTC = Antiplatelet Trialists’ Collaboration BMJ. 1994 *APTC = Antiplatelet Trialists’ Collaboration BMJ. 1994

17. APPROVe CV Events Placebo N=1299 Rofecoxib N=1287 Relative Risk (95%CI) 0.75 (25/3315) 0.48 (16/3322) 0.75 (25/3315) 0.48 (16/3322) 1.48 (45/3041 ) 1.08 (33/3053) 1.48 (45/3041 ) 1.08 (33/3053) Thrombotic (70 Events) APTC (49 Events) Thrombotic (70 Events) APTC (49 Events) 1.96 (1.20, 3.19) 2.25 (1.24, 4.08) 1.96 (1.20, 3.19) 2.25 (1.24, 4.08) Rate per 100 (N/ P-Yrs) RR for CHF/PE/Cardiac Failure: 4.29 (1.43, 12.82)

18. APPROVe Confirmed Thrombotic Events Cardiac Events Cerebrovascular Events Peripheral Vascular Events Placebo (N=1299)Rofecoxib (N=1287) 11 7 30 15 3

19. APPROVe Confirmed Thrombotic Endpoints Overall RR: 1.96 (1.20, 3.19)

20. Thrombotic CV Events Overall RR 1.01 (0.67,1.53) Alzheimer’s Disease Studies

21. APPROVe Thrombotic Events Subgroup analyses Age Aspirin use Hypertension Cigarette smoking Diabetes  CV risk* Hypercholesterolemia No treatment by Subgroup Interactions Subgroup analyses Age Aspirin use Hypertension Cigarette smoking Diabetes  CV risk* Hypercholesterolemia No treatment by Subgroup Interactions *CV hx, or ≥2 of: hx of DM,  cholesterol, HTN, smoker

22. APPROVe: Blood Pressure Preliminary analyses not suggestive of a relationship between blood pressure rise and risk

23. APPROVe CV Events Summary  risk of thrombotic CV events after 18 months of Tx 1 st 18 months consistent with prior placebo-controlled and nonnaproxen controlled data On the basis of these data, VIOXX was withdrawn Summary  risk of thrombotic CV events after 18 months of Tx 1 st 18 months consistent with prior placebo-controlled and nonnaproxen controlled data On the basis of these data, VIOXX was withdrawn

24. APPROVe: The Future Mechanism of CV toxicity uncertain Analyses ongoing Patients will be followed for one year per protocol Adenoma data will be analyzed Study within 3 months of completion anyway ~75% of subjects had completed treatment Mechanism of CV toxicity uncertain Analyses ongoing Patients will be followed for one year per protocol Adenoma data will be analyzed Study within 3 months of completion anyway ~75% of subjects had completed treatment

25. APPROVe Research Team John Baron †, Robert S Bresalier ††, Robert Sandler ‡, Robert Riddell §, Angel Lanas ║, Dion Morton ¶, Alise Reicin #, Bettina Oxenius #, Kevin Horgan #, Hui Quan # † Dartmouth Medical School †† University of Texas MD Anderson Cancer Center; ‡ University of North Carolina at Chapel Hill; § Mount Sinai Hospital, Toronto; ║ University Clinic Hospital, Zaragoza, Spain; ¶ University of Birmingham, UK; # Merck Research Laboratories John Baron †, Robert S Bresalier ††, Robert Sandler ‡, Robert Riddell §, Angel Lanas ║, Dion Morton ¶, Alise Reicin #, Bettina Oxenius #, Kevin Horgan #, Hui Quan # † Dartmouth Medical School †† University of Texas MD Anderson Cancer Center; ‡ University of North Carolina at Chapel Hill; § Mount Sinai Hospital, Toronto; ║ University Clinic Hospital, Zaragoza, Spain; ¶ University of Birmingham, UK; # Merck Research Laboratories

26. MI (not Total CVD) Year 1997 1998 1999 2000 2002 # Events 16 40 64 # Patients 5193 13,269 21,432 Combined RR = 2.24 (1.24-4.02 Cumulative Metaanalysis Juni et al, 2004 Juni et al, 2004 VIGOR Study

27. Naproxen & MI Risk Observational Data Combined RR (0.86 0.75-0.99) Jick (2000) Rahme (2002) Ray (2002) Schlienger (2002) Solomon (2002) Watson (2002) Mamdani (2003) Kimmel (2004) Graham (2004) Garcia Rdoriguez (2004) Juni et al, 2004 Juni et al, 2004

28. COX-2 Inhibitors & CVD What are the Possible Mechanisms?

29. Aspirin COX-1 Thromboxane Prostacyclin Thromboxane COX-2 Inhibition Decreased CV events Prostacyclin Increased CV events COX-2

30. Atherosclerosis An Inflammatory Process Cox-2 over expressed in atheroma Cox-2 inhibitors might be beneficial??

31. NSAIDs and Blood Pressure Frishman, Am J Cardiol, 2002

32. Baseline mean = 136 mm Hg Change from baseline (mm Hg) Baseline mean = 136 mm Hg Baseline mean = 81 mm Hg Frishman, 2002 Frishman, 2002

33. NSAIDs & GFR Harris, Am J Cardiol, 2002

34. NSAIDs and CHF “An Underrecognized Public Health Problem” NSAIDs can  CHF Stronger effect with Hx of CVD (Especially drugs w/ long half life) Heerdink et al, Arch Intern Med, 1998 Page & Henry, Arch Intern Med, 2000 Feenstra et al, Arch Intern Med, 2002

35. COX-2 & Cardiovascular Disease Background COX-2  vascular prostacyclin COX-2  inflammation Net effect on atherosclerotic disease? COX-2 involved in renal tubular function COX-2 inhibition may lead to: fluid retention HTN

36. Vioxx Summary Increases in CVD Probably delayed Probably rare Summary Increases in CVD Probably delayed Probably rare Published commentary uninformed