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N ENGL j Med 2005; 352:1071-80

Cardiovascular Risk Associated with Celecoxib in a Clinical Trial for Colorectal Adenoma Prevention. N ENGL j Med 2005; 352:1071-80. Background. COX-2 Tumorigenesis Mechanism of AX VIOXX (APROVe). Study Design.

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N ENGL j Med 2005; 352:1071-80

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  1. Cardiovascular Risk Associated with Celecoxib in a Clinical Trial for Colorectal Adenoma Prevention N ENGL j Med 2005; 352:1071-80

  2. Background • COX-2 Tumorigenesis • Mechanism of AX • VIOXX (APROVe)

  3. Study Design • Prospective, randomized, double-blind, multicenter trial assessing the efficacy of celecoxib for the prevention of adenomatous polyps in patients who had under gone endoscopic polypectomy.

  4. Methods • The APC study compared the efficacy and safety of 200mg BID, 400mg of Celecoxib BID, and a placebo in reducing the occurrence of adenomatous polyps in the colon and rectum one year and three years after endoscopic polypectomy. • 91 sites participated • 32-88yrs( had significant risk of colorectal adenoma). All Adenomas were removed prior to tx.

  5. Methods • 2035 patients (1:1:1 ratio) • Enrollment began Nov. 1999-March 2002 • Pill count and monitoring of MR q6-12wks.

  6. Review of Cardiovascular Safety • All deaths and potential non fatal cardiovascular events • MI • Stroke • HF • USA • Need for CV procedure

  7. Results • 77% of the 2035 patients completed the study • The rest had completed at least 2.8 yrs of fu. • The baseline charact. were similar among the 3 groups. • 200mg bid/HR2.3 • 400mg bid/ HR 3.4 • There were 6 deaths in the placebo, 6 in the 200mg and 9 in the 400mg, and 1,3 and 6were due to CV causes • There was no apparent increase in the risk of USA,TE arrhythmia or the need for CV procedure • The HR associated with celecoxib was not significantly affected by any of the baseline charact; including ASA.

  8. Baseline Characteristics of the Patients Solomon, S. D. et al. N Engl J Med 2005;352:1071-1080

  9. Incidence of and Hazard Ratios for the Composite End Points in the Celecoxib Groups Relative to the Placebo Group Solomon, S. D. et al. N Engl J Med 2005;352:1071-1080

  10. Incidence of Individual Cardiovascular and Fatal Events Solomon, S. D. et al. N Engl J Med 2005;352:1071-1080

  11. Kaplan-Meier Estimates of the Risk of the Composite End Point of Death from Cardiovascular Causes, Myocardial Infarction, Stroke, or Heart Failure among Patients Who Received Celecoxib (200 mg Twice Daily or 400 mg Twice Daily) or Placebo Solomon, S. D. et al. N Engl J Med 2005;352:1071-1080

  12. Incidence of Death from Cardiovascular Causes, Myocardial Infarction, Stroke, or Heart Failure According to Baseline Characteristics Solomon, S. D. et al. N Engl J Med 2005;352:1071-1080

  13. Conclusions • 200mg or 400mg bid led to a dose- related increase in the risk of serious CV events (MI, stroke and HF) • PreSAP- found no increase in the risk • Mechanism of action for COX-2 • COX-2 may elevate BP • VIGOR and APPROVe

  14. Complications of the COX-2 Inhibitors Parecoxib and Valdecoxib after Cardiac Surgery N ENGL j MED 2005; 352:1081-91

  15. Study Design and Procedures • The CABG surgery was conducted at 175 centers in 27 countries from January 2003 to January 2004. • Randomized double-blind, parallel-group , multiple dose, placebo controlled study involving 10 days of study-drug administration and 30 days of follow up. • All received ASA

  16. Dosing schemes • Group #1- IV parecoxib 40mg on AM of surgery(day#1) and then 20mg of parecoxib q12hrs x3d, oral valdecoxib q12hrsx 10d • Placebo IV q12hrsx3d, followed by 20mg of oral valdecoxib q12hrs x10d • Placebo

  17. Study Design and Procedures • No NSAIDS, sedating antihistamines, prophylactic antiemetic agents, intrathecal or epidural opioids, and local analgesics applied to the surgical incision.

  18. End Points • CV events (MI and severe myocardial ischemia, sudden death from cardiac causes) • Renal events • Surgical-wound complication • GI complications

  19. Patient Population • Those undergoing elective, primary CABG with cardiopulmonary bypass • 18-80y/o • NYHA I,II,III or EF>35% • BMI<40 and >55kg

  20. Exclusion Criteria • CVA, TIA,DVT or PE<3m before enrollment • MI<1wk • PUD<60d • Contrast IV<1d • Uncontrolled DM;>350mg/dl and HBAIC>9 • Coagulopathy • OFF PUMP CABG • Concomitant Vascular or Valvular surgery and OFF PUMP>3.5hrs • New MI, IABP, CI<1.5, >2 pressors, Symptomatic dysrhythmias, new neuro deficit, significant bleeding (CT>500ml), HBG<8, UO<50ml/hr, Scr>1.8 or >30%inc.

  21. Enrollment and Outcome Nussmeier, N. A. et al. N Engl J Med 2005;352:1081-1091

  22. Preoperative Characteristics of All Randomized Patients Nussmeier, N. A. et al. N Engl J Med 2005;352:1081-1091

  23. Primary End Point The incidence of at least one pre-defined adverse event was also significantly higher in the pooled COX-2 group than in the placebo (7.4% vs 4.0%; risk ratio 1.9) CV events were more frequent in the group given parecoxib and valdecoxib than in the placebo (2vs 0.5%) The incidence of CV events in the group given placebo and valdecoxib, did not differ significantly from that in either of the other two groups.

  24. Primary End Point • In fact , three of the six events in the group given placebo and valdecoxib occurred in patients who had not yet begun treatment with valdecoxib. • The time-to-event analysis revealed that CV events occurred throughout and after the 10 day period of drug administration in all groups. • Analysis of CV events in the pooled COX-2 group and the control group did not reveal significant differences.

  25. Primary End Point • The incidence of non CV predefined adverse events (wound healing complications, RF and PUD) did not reach statistical significance • Eight deaths were reported during the study: seven during the study period and one after the 30 day f/u period. Of these deaths 4 occurred in patients given parecoxib and valdecoxib (cardiac arrest, vfib, MI and PE). Three deaths occurred among patients given placebo and valdecoxib (cardiac arrest, HF and Pneumonia) all these deaths occurred in patients who had not yet begun valdecoxib. One patient in the placebo group died of intestinal perf.

  26. Kaplan-Meier Estimates of the Time to a Cardiovascular Event Nussmeier, N. A. et al. N Engl J Med 2005;352:1081-1091

  27. Characteristics of the Surgical Procedures Nussmeier, N. A. et al. N Engl J Med 2005;352:1081-1091

  28. Incidence of and Risk Ratios for Predefined Adverse Events and Death among Patients Who Received the Assigned Treatment Nussmeier, N. A. et al. N Engl J Med 2005;352:1081-1091

  29. Conclusions • Short term COX-2 inhibition is associated with a significant risk of thromboembolic events among patients receiving parecoxib and valdecoxib than placebo • Mechanism of TE events • Inbalance TX/PC; Cardiopulmonary bypass increases the levels of both PC and TX • ASA resistance • COX-2 should be avoided in CABG

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