Cardiovascular Risk Associated with Celecoxib in a Clinical Trial for Colorectal Adenoma Prevention

1
Cardiovascular Risk Associated with Celecoxib in
a Clinical Trial for Colorectal Adenoma Prevention

• N ENGL j Med 2005 3521071-80

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 (111 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
20053521071-1080
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
20053521071-1080
10
Incidence of Individual Cardiovascular and Fatal
Events
Solomon, S. D. et al. N Engl J Med
20053521071-1080
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
20053521071-1080
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
20053521071-1080
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 3521081-91

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(day1) 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 EFgt35
• BMIlt40 and gt55kg

20
Exclusion Criteria

• CVA, TIA,DVT or PElt3m before enrollment
• MIlt1wk
• PUDlt60d
• Contrast IVlt1d
• Uncontrolled DMgt350mg/dl and HBAICgt9
• Coagulopathy
• OFF PUMP CABG
• Concomitant Vascular or Valvular surgery and OFF
  PUMPgt3.5hrs
• New MI, IABP, CIlt1.5, gt2 pressors, Symptomatic
  dysrhythmias, new neuro deficit, significant
  bleeding (CTgt500ml), HBGlt8, UOlt50ml/hr, Scrgt1.8
  or gt30inc.

21
Enrollment and Outcome
Nussmeier, N. A. et al. N Engl J Med
20053521081-1091
22
Preoperative Characteristics of All Randomized
Patients
Nussmeier, N. A. et al. N Engl J Med
20053521081-1091
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
20053521081-1091
27
Characteristics of the Surgical Procedures
Nussmeier, N. A. et al. N Engl J Med
20053521081-1091
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
20053521081-1091
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