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The Vioxx Withdrawal

The Vioxx Withdrawal . What Happened? John A. Baron Dartmouth Medical School for the APPROVe Investigators. Vioxx. A Recent Quote The licensing of Vioxx and its continued use …. have been public-health catastrophes. (Lancet, Nov 5). COX-2 Inhibitors. What are They? Should we Care? .

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The Vioxx Withdrawal

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  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. Membrane phospholipids Arachidonate PGG2 COX PGH2 PGE2 PGF2 PGD2 PGI2 TXA2 Cyclooxygenase & Prostaglandins

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

  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

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

  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)

  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.

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

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

  14. APPROVe Eligibility • Inclusion Criteria • ≥ 40 years old • histologically confirmed large bowel adenoma • Prior MI, PTCA, CABG OK if > 1year prior T0 • Exclusion Criteria • Uncontrolled hypertension (>165/95 mm Hg), angina at rest or minimal activity, CHF at rest

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

  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 *APTC = Antiplatelet Trialists’ Collaboration BMJ. 1994

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

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

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

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

  21. APPROVe Thrombotic Events • 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 • 1st 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

  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

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

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

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

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

  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 = 81 mm Hg Baseline mean = 136 mm Hg 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 Published commentary uninformed

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