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The Safety of COX-2 Inhibitors

The Safety of COX-2 Inhibitors. John J. Cush, MD Presbyterian Hospital of Dallas. RA. OA (72 %), RA (28 %). Patients. GI Outcomes Trials: Design. VIGOR (n=8076). CLASS (n=7982). Drug. Rofecoxib 50 mg QD (2x max chronic dose). Celecoxib 400 mg BID (2x max chronic dose). Comparator.

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The Safety of COX-2 Inhibitors

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  1. The Safety of COX-2 Inhibitors John J. Cush, MD Presbyterian Hospital of Dallas

  2. RA OA (72 %), RA (28 %) Patients GI Outcomes Trials: Design VIGOR (n=8076) CLASS (n=7982) Drug Rofecoxib 50 mg QD (2x max chronic dose) Celecoxib 400 mg BID (2x max chronic dose) Comparator Naproxen 500 mg BID Ibuprofen 800 mg TID Diclofenac 75 mg BID Yes (21 %) No Low dose ASA Duration Median 9 months Maximum 13 months 6 months reported Median 9 months Maximum 13 months Silverstein et al. JAMA. 2000; 284:1247-1255. Bombardier et al. N Engl J Med. 2000;343:1520-1528

  3. NSAID Impact/Cost • 13 million chronic users (70 million Rx/yr) • Dyspepsia 20% > Gastric ulcers 10% • Serious GI complications • 1.3 % RA pts • 0.73% OA pts • Hospitalization (UGI bleed) 103,000/year • 5-10% mortality (est 16,500 deaths/year) • NSAID deaths 15th most common cause in USA • Cost > $2 billion/year

  4. NSAID Concerns Mortality for 7 Selected Disorders (1997) • 13 million chronic users (U.S.) • Dyspepsia in 10-20% • Serious GI complications in 1.3% • Fatalities in 5-10% of these • Direct cost/year > $2 billion • ~ 15th most common cause of death (U.S.) Wolfe, et al: NEJM 1999

  5. CO2H Arachidonic acid Mechanism of Action of NSAIDs COX-1“Constitutive” COX-2“Inducible” Non-specific NSAIDs COX-2 NSAIDs GI Mucosa Platelet Prostaglandins Prostaglandins Thromboxane Mediate pain, inflammation, and fever Hemostasis GI mucosal Protection Bakhle et al. Med Inflamm. 1996;5:305-323. Vane et al. Inflamm Res. 1995;44:1-10.

  6. RA OA (72 %), RA (28 %) Patients GI Outcomes Trials: Design VIGOR (n=8076) CLASS (n=7982) Drug Rofecoxib 50 mg QD (2x max chronic dose) Celecoxib 400 mg BID (2x max chronic dose) Comparator Naproxen 500 mg BID Ibuprofen 800 mg TID Diclofenac 75 mg BID Yes (21 %) No Low dose ASA Duration Median 9 months Maximum 13 months 6 months reported Median 9 months Maximum 13 months Silverstein et al. JAMA. 2000; 284:1247-1255. Bombardier et al. N Engl J Med. 2000;343:1520-1528

  7. CLASS Trial: Upper GI Complications Alone and With Symptomatic Ulcers = celecoxib p = 0.02 = NSAIDs (ibuprofen + diclofenac) 49 / 1384 p = 0.09 All Patients 30 / 1441 20 / 1384 11 / 1441 p = 0.02 p = 0.04 Patients Not Taking Aspirin 32 / 1101 14 / 1101 16 / 1143 Annualized Incidence % 5 / 1143 p = 0.49 17 / 283 14/ 298 p = 0.92 Patients Taking Aspirin 6 / 283 6 / 298 Symptomatic Ulcers and Ulcer Complications Ulcer Complications Silverstein et al. JAMA 2000; 284:1247-1255

  8. Events Leading up to FDA Mtg • Results of VIGOR and CLASS • 9/30/04 Merck voluntary w/d of Vioxx (based on APPOVE trial) • Reanalyses of all COX2 data • 12/9/04 FDA warning of CV events in Bextra CABG trial • 12/17/04 NCI stop APC trial (concerns over celecoxib data) • 12/20/04 NIH stops ADAPT trial (concerns over naproxen)

  9. FDA: COX-2 SafetyFebruary 16-18, 2005 • Arthritis Advisory Committee • Drug Safety and Risk Management • Other speakers, SGEs • 8 rheums, 19 physicians, 8 statisticians, 1 ethicist, patient and industry representatives • ISSUES: • Does the agent pose a risk for CV events?; • Does the risk versus benefit profile of the drug support its marketing in the U.S.? • If continued marketing is supported, what actions are recommended to ensure its safe use?

  10. FDA COX-2 Hearing • Limitations of available data • Most trials of short duration, using low dose • Most trials done with efficacy endpoints • Few designed with CVS safety endpoint • Most trials were active comparator and NOT placebo controlled trials • Observational studies (presented) are for generating signals and hypotheses • Safety signals drawn from other indications are valid, but not conclusive unless repeated or of sufficiently great magnitude

  11. Vioxx 50 mg Naproxen Serious CV/T1 EventsDifferent Endpoints (VIGOR) 64 45 35 32 19 18 Investigator CV/ T Adjudicated 2 APTC 3 1 Cardiovascular Thrombotic. 2Confirmed by CV adjudication committee. 3 Antiplatelet Trialist Collaboration composite endpoint: CV & unknown cause of death, non-fatal myocardial infarction and non-fatal stroke.

  12. Vioxx - APPROVe APTC EventsTime to Event Plot • Rofecoxib25 Placebo

  13. Vioxx – APPROVe: Effect of ASA on APTC * * Based on October 2004, submission (no final dataset).

  14. CV Signal in Vioxx Databases AAC Labeling changes 1998 2000 2001-2002 NDA VIGOR 102 RAe SURs/AD ----Epi and re-analyses----- Versus Plac+NSAIDs Napr Napr Napr Placebo N= no signal. Y= Clear signal. t =Trend. AAC: February 8, 2001 FDA Arthritis Advisory Committee meeting. RAe: Rheumatoid Arthritis efficacy supplement. SURs/AD: Safety Update Reports including Alzheimer’s disease studies. Epi= epidemiologic studies. NF= non-fatal.

  15. CLASS - APTC-like Events

  16. FDA COX-2 Hearing • Vote: Retain on the market • Celecoxib 32-0 • Valdecoxib 17-13 (2 abstentions) • Rofecoxib 17-15 • Unanimously in favor of: • “Black box” warning for CV risk & COX-2 drugs • Education measures for pts and physicians • Restrictions on direct-to-consumer advertising • “Warning” added to Current NSAIDs • Compassionate use liquid rofecoxib for kids

  17. Summary • COX-2 inhibitors equipotent to NSAIDs • GI Toxicity lower with COX-2, but negated by low dose ASA 81 mg/d • Would this be off-set by use of PPI • CV risk modestly higher w/ COX-2 inhibitor • Same for NSAIDs? • Not affected by use of low dose ASA

  18. FDA: COX-2 Safety • Risk/benefit of COX-2 inhibitors favors continued use in U.S • Patients should be counseled about cardiovascular risks. • While all NSAIDs may impose similar cardiovascular risks, some agents (naproxen 500 mg bid, celecoxib 200 mg qd) appear to be safer than others (e.g., rofecoxib, valdecoxib, diclofenac, and ibuprofen). • Cardiovascular risks of the COX-2 inhibitors may be greater with higher doses, longer durations of therapy, and when used in high risk individuals. • The use of low dose aspirin does not consistently abrogate the potential CV risk of a COX-2 inhibitor. Patients who require the cardioprotective effects of aspirin may not be ideal candidates for COX-2 inhibitor or NSAID therapy. • The use of COX-2 inhibitors (and other NSAIDs thought to increase CV risk) should be avoided in high risk individuals

  19. FDA Action: 4/7/05 • BextraWe have concluded that the overall risk versus benefit profile for this product is unfavorable and we have requested Pfizer to voluntarily withdraw the product from the market.  They have agreed to suspend sales and marketing in the U.S., pending further discussions with the Agency.  To resume marketing of the drug, the sponsor would have to demonstrate that Bextra has a clear benefit over existing therapies or a lower risk compared to other COX-2 selective inhibitors. • CelebrexWe have concluded that Celebrex should remain available as a prescription drug, but with changes to the labeling, a MedGuide, and commitments from Pfizer for additional studies to better define the cardiovascular effects of the drug. • VioxxA proposal by Merck to reintroduce Vioxx to the market would require a supplemental new drug application.  Such an application would be reviewed with consideration of the risk to benefit balance of the proposed indications and populations for use, warnings in the label, and all relevant data.  We expect that the proposal would also be reviewed at a public Advisory Committee meeting. • Prescription Non-Selective NSAIDs- Based upon the available data, we have concluded that an increased risk of CV events may be a class effect for NSAIDs.  Therefore, at this time, changes to the prescribing information for all of these drugs are warranted, until the risk profile of the individual agents can be better assessed.  • Non-prescription Non-Selective NSAIDs- The labeling for low dose, non-prescription products that contain ibuprofen, naproxen and ketoprofen will be revised to include warnings about potential CV and GI risks, advisories recommending certain patients seek physician input before use and stronger reminders to follow the instructions of the label concerning dose and duration of treatment

  20. A New Standard for Drug Development • Any new NSAID, must be clinically better than current alternatives • Any new NSAID, must be safer • Usual phase IV trials must be done before approval, not after.

  21. NSAIDs Available by Prescription NSAIDs SALICYLATES COX-2 INHIBITORS Diclofenac (Voltaren) Aspirina (Zorprin, Easprin) Celecoxib (Celebrex) Diclofenac/Misoprostol (Arthrotec)b Diflunisal (Dolobid) Valdecoxib (Bextra) Fenoprofen (Nalfon) Salsalate (Disalcid, Salflex) Flurbiprofen (Ansaid) Choline salicylate (Trilisate) Ibuprofen (Motrin)a Magnesium salicylate (Magan) Indomethacin (Indocin) Ketoprofen (Orudis)aIn Development Meclofenamate Etoricoxib Mefenamic acid (Ponstel) Parecoxibc Nabumetone (Relafen) Lumiracoxib Naproxen (Naprosyn, Anaprox)a Oxaprozin (Daypro) Previously Available Piroxicam (Feldene) Rofecoxib (Vioxx) Sulindac (Clinoril) Tolmetin (Tolectin) a Also available as over-the-counter preparations in the U.S. b Combination tablet of NSAID/synthetic prostaglandin E1 c Parenterally administered 2004 Physician’s Desk Reference

  22. In Vitro Selectivity: COX-2/COX-1 Ratio lumiracoxib etoricoxib rofecoxib > 50-fold COX-2 selective valdecoxib etodolac nimesulide 5- 50-fold COX-2 selective diclofenac celecoxib meloxicam fenoprofen < 5-fold COX-2 selective ibuprofen tolmetin naproxen aspirin indomethacin ketoprofen flurbiprofen Warner et al. FASEB J. 2004:18:790-804 ketorolac -3 -2 -1 0 1 2 3 Increasingly COX-2 Selective Increasingly COX-1 Selective Range of COX Selectivity for COX-1 and COX-2 (log10 IC50 COX-2/COX-1)

  23. RR OF MYOCARDIAL INFARCTION Garcia Rodriguez 2004 RR=1.04 [1.00-1.08 NSAIDs RR=0.88 [0.8-0.95] NAPROXEN IBUPROFEN RR = 1.03 [.96-1.1] NAPROXEN : HALF AS GOOD AS ASPIRIN?

  24. Long-term NSAID Use May Increase Risks of Cardiovascular Death-Norwegian Study, 2005 • Population-based, nested case-control study of 454 Scandinavian patients diagnosed with oral cancer between 1975 and 2003, and 454 gender- and age-matched controls. (Sudbo J, et al. 2005 - Manuscript submitted) CV deaths 2.06 42 Any NSAID 1.16 2 Aspirin 2.86 12 Ibuprofen 1.70 7 Naproxen 2.26 Indomethacin 10 1.84 Piroxicam 7 1.90 Ketoprofen 4 0 1 2 3 4 5 6 Hazard Ratio for CV Death in Long-term NSAID Users Compared to Non-users (with 95% Confidence Intervals)

  25. On Safety… “The desire for safety stands against every great and noble enterprise” - Tacitus “ I think we too often make choices based on the safety of cynicism, and what we’re lead to is a life not fully lived” - Ken Burns

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