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Cardiovascular Risk and NSAIDs Arthritis Advisory Committee Meeting April 12, 2007. Sharon Hertz, M.D. Deputy Director Division of Analgesia, Anesthesia, and Rheumatology Products Center for Drug Evaluation and Research Food and Drug Administration. Overview of Presentation.

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Cardiovascular Risk and NSAIDs Arthritis Advisory Committee Meeting April 12, 2007


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    1. Cardiovascular Risk and NSAIDsArthritis Advisory Committee Meeting April 12, 2007 Sharon Hertz, M.D. Deputy Director Division of Analgesia, Anesthesia, and Rheumatology Products Center for Drug Evaluation and Research Food and Drug Administration

    2. Overview of Presentation • Cardiovascular findings from COX-2 development • FDA conclusions about CV Risk and NSAIDs

    3. February 2005 • Joint advisory committee meeting with arthritis and drug safety committees • Data presented on rofecoxib, celecoxib, lumiracoxib, etoricoxib

    4. Vioxx May 20, 1999 Approval of New Drug Application for Vioxx (rofecoxib) for the treatment of acute pain in adults, dysmenorrhea and osteoarthritis • ~ 5000 subjects • - 700+ at least 1 year (12.5 and 25 mg) • No cardiovascular signal – small number of events, no dose response

    5. Vioxx - VIGOR • Rofecoxib 50 mg daily vs. naproxen 500 mg BID • 8,000 RA patients, no ASA • Median exposure - 9 months • Endpoints • serious GI events • serious CV/thrombotic events

    6. Vioxx - VIGOR • Cardiovascular risk identified for rofecoxib vs. naproxen • All CV events - RR 2.37 • MI - RR 5.0 (20 vs. 4) • Incidence increased over time • Results taken to AC February, 2001

    7. Vioxx - Alzheimer’s Disease • To slow progression or prevent onset • 3 placebo-controlled, double-blind, multicenter studies • Rofecoxib 25 mg vs. placebo • 15-24 months • N=~2800 patients • No consistent cardiovascular signal

    8. Vioxx - APPROVe • Reduce incidence of adenomatous polyps in patients with history of colorectal adenomas • Randomized, placebo-controlled, double-blind, 3 years + 1 year • Rofecoxib 25 mg vs. placebo • 2586 patients

    9. Vioxx - APPROVe • September 27, 2004 – Merck informs FDA of CV signal for rofecoxib vs. placebo in APPROVe • All CV events – RR 1.8 • MI – RR 2.5 • Ischemic CVA – RR 1.8 • September 30, 2004 – Merck withdraws Vioxx from the market

    10. Vioxx – APPROVe Effect of ASA on APTC

    11. Celebrex December 31, 1998 Approval of New Drug Application for Celebrex (celecoxib) for the signs and symptoms of osteoarthritis (200 mg/day) and rheumatoid arthritis 200-400 mg/day) • N= 9600 patients • No CV signal with initial application

    12. Celebrex - CLASS CLASS • Double-blind, active-controlled, 1 year • ~ 8,000 patients with OA or RA, ASA if indicated • Celecoxib 400 mg twice daily • Endpoint – serious GI events • No cardiovascular signal vs. ibuprofen 800 mg TID or diclofenac 75 mg BID

    13. CLASSMyocardial Infarction

    14. Celebrex - APC APC (Prevention of Sporadic Colorectal Adenomas with Celecoxib) • Double-blind, placebo-controlled, 3 years, over 1900 patients, ASA use by ~30% • Celebrex 400 mg twice daily (N=671) • Celebrex 200 mg twice daily (N=685) • Placebo (N=679)

    15. Celebrex - APC • December 16, 2004 – APC study halted due to CV signal for celecoxib vs. placebo • Death from CV causes, MI, or stroke • celecoxib 200 mg bid vs. placebo RR 2.5 • celecoxib 400 mg bid vs. placebo RR 3.4

    16. Incidence of Hierarchical Cardiovascular Composite Endpoints in the APC Trial Solomon SD, et al: N Engl J Med 352, 2005

    17. Hazard Ratios for Hierarchical CV Composite Endpoints in the APC Trial *Relative to placebo Solomon SD, et al: N Engl J Med 352, 2005

    18. Celebrex - APC 671 *In this analysis, “serious CV events” include death from CV causes, MI, stroke, or heart failure Solomon SD, et al: N Engl J Med 352, 2005

    19. Celebrex - PreSAP Celecoxib in Adenoma Prevention • Double-blind, placebo-controlled, 3 years, over 1900 patients • Celebrex 400 mg once daily • Placebo • ASA use by ~16%

    20. Hazard Ratio for Hierarchical CV Composite Endpoints in the PreSAP Trial *Relative to placebo

    21. Hazard Ratio for Hierarchical CV Composite Endpoints in the PreSAP Trial *Relative to placebo

    22. Celebrex - ADAPT Alzheimer’s prevention study • December 17, 2004 – ADAPT trial halted • Celecoxib 200 mg bid, naproxen 220 mg bid, placebo • N=~2500 patients • Cardiovascular risk not found for celecoxib vs. placebo in this data set, while a risk for naproxen compared to placebo was suggested.

    23. TARGET • Therapeutic COX-189 Arthritis Research and Gastrointestinal Event Trial • 52 weeks • 18,000 patients with osteoarthritis • Two sub-studies: • 0117: lumiracoxib 400 mg, naproxen 500 mg bid • 2332: lumiracoxib 400 mg, ibuprofen 800 mg tid • 25% of patients on low dose aspirin (ASA)

    24. TARGET Confirmed & Probable APTC Events

    25. TARGET Confirmed /Probable APTC Endpoint KM plot (%) Study 0117 Study 2332

    26. Epidemiological Studies • Consistent risk associated with high dose rofecoxib • Variable findings of risk associated with other selective and nonselective NSAIDs

    27. FDA Conclusions • April 6, 2005 Decisional Memorandum: “Analysis and recommendations for Agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk” • http://www.fda.gov/cder/drug/infopage/COX2/NSAIDdecisionMemo.pdf

    28. FDA Conclusions “The three approved COX-2 selective NSAIDs (i.e., celecoxib, rofecoxib, and valdecoxib) are associated with an increased risk of serious adverse CV events compared to placebo. The available data do not permit a rank ordering of these drugs with regard to CV risk.”

    29. FDA Conclusions “Data from large long-term controlled clinical trials that have included a comparison of COX-2 selective and non-selective NSAIDs do not clearly demonstrate that the COX-2 selective agents confer a greater risk of serious adverse CV events than non-selective NSAIDs.”

    30. FDA Regulatory Actions April 7, 2005 • Boxed warning all Rx NSAIDs • Potential increased risk serious CV events • May be higher with prior history of CV disease/risk • Added GI warnings to box • Contraindication perioperative CABG

    31. FDA Regulatory Actions • Class Medication Guide for all Rx NSAIDs • Revised warnings for OTC NSAIDs

    32. Information Request • Review of all clinical trial data from controlled studies • Unable to draw conclusions • Small sample size, even with pooling • Very small number of CV events • Short duration of treatment

    33. Additional slides

    34. TARGETConfirmed & Probable MI by ASA Use

    35. TARGETNew Analysis -2007 • Farkouh et. al. Annals of Rheumatic Disease, 2007 Apr 5; [Epub ahead of print] • Post hoc analysis stratified by BL CV risk, treatment assignment and low-dose ASA use • Primary composite endpoint – CV mortality, nonfatal MI, stroke at 1 year • Secondary – congestive heart failure

    36. TARGETNew Analysis -2007