N ENGL j Med 2005; 352:1071-80

Cardiovascular Risk Associated with Cardiovascular Risk Associated with Celecoxib in a Clinical Trial for Celecoxib in a Clinical Trial for

Colorectal Adenoma PreventionColorectal Adenoma Prevention

N ENGL j Med 2005; 352:1071-80N ENGL j Med 2005; 352:1071-80

BackgroundBackground

COX-2 TumorigenesisCOX-2 Tumorigenesis Mechanism of AXMechanism of AX VIOXX (APROVe)VIOXX (APROVe)

Study DesignStudy Design

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

MethodsMethods The APC study compared the efficacy and safety The APC study compared the efficacy and safety

of 200mg BID, 400mg of Celecoxib BID, and a of 200mg BID, 400mg of Celecoxib BID, and a placebo in reducing the occurrence of placebo in reducing the occurrence of adenomatous polyps in the colon and rectum one adenomatous polyps in the colon and rectum one year and three years after endoscopic year and three years after endoscopic polypectomy.polypectomy.

91 sites participated91 sites participated 32-88yrs( had significant risk of colorectal 32-88yrs( had significant risk of colorectal

adenoma). All Adenomas were removed prior to adenoma). All Adenomas were removed prior to tx.tx.

MethodsMethods

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

Review of Cardiovascular SafetyReview of Cardiovascular Safety

All deaths and potential non fatal All deaths and potential non fatal cardiovascular eventscardiovascular events

MIMI StrokeStroke HFHF USAUSA Need for CV procedureNeed for CV procedure

ResultsResults 77% of the 2035 patients completed the study77% of the 2035 patients completed the study The rest had completed at least 2.8 yrs of fu.The rest had completed at least 2.8 yrs of fu. The baseline charact. were similar among the 3 groups.The baseline charact. were similar among the 3 groups. 200mg bid/HR2.3200mg bid/HR2.3 400mg bid/ HR 3.4400mg bid/ HR 3.4 There were 6 deaths in the placebo, 6 in the 200mg and 9 in There were 6 deaths in the placebo, 6 in the 200mg and 9 in

the 400mg, and 1,3 and 6were due to CV causesthe 400mg, and 1,3 and 6were due to CV causes There was no apparent increase in the risk of USA,TE There was no apparent increase in the risk of USA,TE

arrhythmia or the need for CV procedurearrhythmia or the need for CV procedure The HR associated with celecoxib was not significantly The HR associated with celecoxib was not significantly

affected by any of the baseline charact; including ASA.affected by any of the baseline charact; including ASA.

Solomon, S. D. et al. N Engl J Med 2005;352:1071-1080

Baseline Characteristics of the Patients


Incidence of and Hazard Ratios for the Composite End Points in the Celecoxib Groups Relative to the Placebo Group


Incidence of Individual Cardiovascular and Fatal Events


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


Incidence of Death from Cardiovascular Causes, Myocardial Infarction, Stroke, or Heart Failure According to Baseline Characteristics

ConclusionsConclusions

200mg or 400mg bid led to a dose- related 200mg or 400mg bid led to a dose- related increase in the risk of serious CV events (MI, increase in the risk of serious CV events (MI, stroke and HF)stroke and HF)

PreSAP- found no increase in the riskPreSAP- found no increase in the risk Mechanism of action for COX-2Mechanism of action for COX-2 COX-2 may elevate BPCOX-2 may elevate BP VIGOR and APPROVeVIGOR and APPROVe

Complications of the COX-2 Complications of the COX-2 Inhibitors Parecoxib and Valdecoxib Inhibitors Parecoxib and Valdecoxib

after Cardiac Surgeryafter Cardiac Surgery

N ENGL j MED 2005; 352:1081-91N ENGL j MED 2005; 352:1081-91

Study Design and ProceduresStudy Design and Procedures

The CABG surgery was conducted at 175 The CABG surgery was conducted at 175 centers in 27 countries from January 2003 to centers in 27 countries from January 2003 to January 2004.January 2004.

Randomized double-blind, parallel-group , Randomized double-blind, parallel-group , multiple dose, placebo controlled study multiple dose, placebo controlled study involving 10 days of study-drug involving 10 days of study-drug administration and 30 days of follow up.administration and 30 days of follow up.

All received ASAAll received ASA

Dosing schemesDosing schemes

Group #1- IV parecoxib 40mg on AM of Group #1- IV parecoxib 40mg on AM of surgery(day#1) and then 20mg of parecoxib surgery(day#1) and then 20mg of parecoxib q12hrs x3d, oral valdecoxib q12hrsx 10dq12hrs x3d, oral valdecoxib q12hrsx 10d

Placebo IV q12hrsx3d, followed by 20mg of Placebo IV q12hrsx3d, followed by 20mg of oral valdecoxib q12hrs x10doral valdecoxib q12hrs x10d

PlaceboPlacebo

Study Design and ProceduresStudy Design and Procedures

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

End PointsEnd Points

CV events (MI and severe myocardial CV events (MI and severe myocardial ischemia, sudden death from cardiac ischemia, sudden death from cardiac causes)causes)

Renal eventsRenal events Surgical-wound complicationSurgical-wound complication GI complicationsGI complications

Patient PopulationPatient Population

Those undergoing elective, primary CABG Those undergoing elective, primary CABG with cardiopulmonary bypasswith cardiopulmonary bypass

18-80y/o18-80y/o NYHA I,II,III or EF>35%NYHA I,II,III or EF>35% BMI<40 and >55kgBMI<40 and >55kg

Exclusion CriteriaExclusion Criteria CVA, TIA,DVT or PE<3m before enrollmentCVA, TIA,DVT or PE<3m before enrollment MI<1wkMI<1wk PUD<60dPUD<60d Contrast IV<1dContrast IV<1d Uncontrolled DM;>350mg/dl and HBAIC>9Uncontrolled DM;>350mg/dl and HBAIC>9 CoagulopathyCoagulopathy OFF PUMP CABGOFF PUMP CABG Concomitant Vascular or Valvular surgery and OFF Concomitant Vascular or Valvular surgery and OFF

PUMP>3.5hrsPUMP>3.5hrs New MI, IABP, CI<1.5, >2 pressors, Symptomatic New MI, IABP, CI<1.5, >2 pressors, Symptomatic

dysrhythmias, new neuro deficit, significant bleeding dysrhythmias, new neuro deficit, significant bleeding (CT>500ml), HBG<8, UO<50ml/hr, Scr>1.8 or >30%inc.(CT>500ml), HBG<8, UO<50ml/hr, Scr>1.8 or >30%inc.

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

Enrollment and Outcome


Preoperative Characteristics of All Randomized Patients

Primary End PointPrimary End Point

The incidence of at least one pre-defined adverse The incidence of at least one pre-defined adverse event was also significantly higher in the pooled event was also significantly higher in the pooled COX-2 group than in the placebo (7.4% vs 4.0%; COX-2 group than in the placebo (7.4% vs 4.0%; risk ratio 1.9)risk ratio 1.9)

CV events were more frequent in the group given CV events were more frequent in the group given parecoxib and valdecoxib than in the placebo (2vs parecoxib and valdecoxib than in the placebo (2vs 0.5%)0.5%)

The incidence of CV events in the group given The incidence of CV events in the group given placebo and valdecoxib, did not differ significantly placebo and valdecoxib, did not differ significantly from that in either of the other two groups.from that in either of the other two groups.

Primary End PointPrimary End Point In fact , three of the six events in the group given In fact , three of the six events in the group given

placebo and valdecoxib occurred in patients who placebo and valdecoxib occurred in patients who had not yet begun treatment with valdecoxib.had not yet begun treatment with valdecoxib.

The time-to-event analysis revealed that CV The time-to-event analysis revealed that CV events occurred throughout and after the 10 day events occurred throughout and after the 10 day period of drug administration in all groups.period of drug administration in all groups.

Analysis of CV events in the pooled COX-2 group Analysis of CV events in the pooled COX-2 group and the control group did not reveal significant and the control group did not reveal significant differences.differences.

Primary End PointPrimary End Point The incidence of non CV predefined adverse events The incidence of non CV predefined adverse events

(wound healing complications, RF and PUD) did not reach (wound healing complications, RF and PUD) did not reach statistical significancestatistical significance

Eight deaths were reported during the study: seven during Eight deaths were reported during the study: seven during the study period and one after the 30 day f/u period. Of the study period and one after the 30 day f/u period. Of these deaths 4 occurred in patients given parecoxib and these deaths 4 occurred in patients given parecoxib and valdecoxib (cardiac arrest, vfib, MI and PE). Three deaths valdecoxib (cardiac arrest, vfib, MI and PE). Three deaths occurred among patients given placebo and valdecoxib occurred among patients given placebo and valdecoxib (cardiac arrest, HF and Pneumonia) all these deaths (cardiac arrest, HF and Pneumonia) all these deaths occurred in patients who had not yet begun valdecoxib. One occurred in patients who had not yet begun valdecoxib. One patient in the placebo group died of intestinal perf. patient in the placebo group died of intestinal perf.


Kaplan-Meier Estimates of the Time to a Cardiovascular Event


Characteristics of the Surgical Procedures


Incidence of and Risk Ratios for Predefined Adverse Events and Death among Patients Who Received the Assigned Treatment

ConclusionsConclusions Short term COX-2 inhibition is associated Short term COX-2 inhibition is associated

with a significant risk of thromboembolic with a significant risk of thromboembolic events among patients receiving parecoxib events among patients receiving parecoxib and valdecoxib than placeboand valdecoxib than placebo

Mechanism of TE eventsMechanism of TE events Inbalance TX/PC; Cardiopulmonary bypass Inbalance TX/PC; Cardiopulmonary bypass

increases the levels of both PC and TXincreases the levels of both PC and TX ASA resistanceASA resistance COX-2 should be avoided in CABGCOX-2 should be avoided in CABG

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N ENGL j Med 2005; 352:1071-80